Clinical trial NCT04267276
Conditions: Healthy Volunteers
Sponsor: Boehringer Ingelheim
Start date: 2020-02-18; Completion date: 2020-04-02
Enrollment: 7 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
To investigate rates and routes of excretion, mass balance, pharmacokinetics of parent drug, any known metabolites, and total radioactivity, metabolite profiling, metabolite identification, if suitable assays are available, safety and tolerability in healthy male subjects.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Part 1: BI 1265162 - intravenous intervention 2: Part 2: BI 1265162 - oral
Intervention descriptions: intervention 1: Intravenous solution intervention 2: Oral solution

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c29266057-03
EudraCT No.
2019-003389-42
BI Trial No.
1399-0013
BI Investigational
Medicinal Product
BI 1265162
Title
Investigation of metabolism and pharmacokinetics of BI 1265162 
(C-14) after intravenous administration (Part 1) and investigation 
of metabolism and pharmacokinetics of BI 1265162 (C-14) after 
oral administration (Part 2) in healthy male subjects following a 
non-randomized, open-label, single-dose, single arm per trial part
mass balance design
Lay Title
A study in healthy men to test how BI 1265162 is taken up and 
processed by the body
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax:
Principal 
Investigator
Phone:
Fax:
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0
Date: 25 February 2020
Page 1 of 81
Proprietary confidential information
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


Boehringer Ingelheim
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BI Trial No.: 1399-0013
c29266057-03
Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
02 January 2020
Revision date
25 February 2020
BI trial number
1399-0013
Title of trial
Investigation of metabolism and pharmacokinetics of BI 1265162 (C-14) after 
intravenous administration (Part 1) and investigation of metabolism and 
pharmacokinetics of BI 1265162 (C-14) after oral administration (Part 2) in 
healthy male subjects following a non-randomized, open-label, single-dose,
single arm per trial part mass balance design
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
To characterize the mass balance, metabolic profile and routes of elimination of 
BI 1265162
Trial objectives
To investigate (a) rates and routes of excretion, (b) mass balance, (c) 
pharmacokinetics of parent drug, any known metabolites, and total radioactivity, 
(d) metabolite profiling, metabolite identification, if suitable assays are available, 
(e) safety and tolerability
Trial design
(Part 1 & 2) Non-randomized, open-label, single-dose, single arm, mass balance 
design


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BI Trial No.: 1399-0013
c29266057-03
Trial Protocol
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Trial endpoints
Primary endpoints
Mass balance recovery:
(Part 1 & 2) Mass balance recovery of total (C-14) BI 1265162-radioactivity in 
urine and faeces (and vomit, if applicable):
Amount of radioactivity excreted as a percentage of the administered single 
intravenous or oral dose of BI 1265162 (C-14) in urine (feurine, 0-t2),and faeces 
(fefaeces, 0-t2) (and vomit (fevomit, 0-t2), if feasible and appropriate)
Secondary endpoints
Pharmacokinetics:
(Part 1 & 2) Assessment of the pharmacokinetics of a single intravenous or oral
dose of BI 1265162 (C-14) by calculation of the following parameters for total 
radioactivity and BI 1265162/ metabolite M582 (1) in plasma:
AUC0-tz and Cmax
Safety:
Percentage of subjects with drug related adverse events (AEs) 
Number of subjects
total entered
(Part 1 & 2) 7 each, total 14
each treatment
(Part 1 & 2) 7 each, total 14
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 65 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
(Part 1) Test product
Intravenous solution
Dose
50 µg of BI 1265162 (C-14) consisting of 45 μg unlabelled BI 1265162 mixed 
with 5 μg labelled (C-14) BI 1265162 as10 mL intravenous solution (5 μg 
BI 1265162 (C-14)/ mL). The radioactive dose per infusion has been calculated to 
not exceed 0.018 MBq (0.486 μCi).
mode of admin.
Intravenous infusion of 1 hour after an overnight fast of at least 10 h.
(Part 2) Test product
Oral solution
Dose
5 mg of BI 1265162 (C-14) consisting of 4.915 mg unlabelled BI 1265162 mixed 
with 85.4 μg labelled (C-14) BI 1265162 as 20 mL of oral solution (0.25 mg/ mL) 
containing a radioactive dose of about 0.306 MBq (8.27 μCi).
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h.


Boehringer Ingelheim
25 Feb 2020
BI Trial No.: 1399-0013
c29266057-03
Trial Protocol
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Reference product
N/A
Dose
N/A
mode of admin.
N/A
Duration of treatments
(Part 1) Single intravenous dose of BI 1265162 (C-14) over 1 hour on Day 1.
(Part 2) Single oral dose of BI 1265162 (C-14) on Day 1.
Statistical methods
(Part 1 & 2) Descriptive statistics will be calculated for all endpoints (as feasible 
and appropriate).


Boehringer Ingelheim
25 Feb 2020
BI Trial No.: 1399-0013
c29266057-03
Trial Protocol
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FLOW CHART 1 – INTRAVENOUS BI 1265162 (C-14)
Visit
Day17
Planned time (relative to 
drug administration 
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment
Intravenous admin.
Safety laboratory
PK blood/ plasma
2
PK urine
6
PK faeces
7
Blood sampling for 
metabolic profiling15
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy9
1
-21 to -2
Screening (SCR)1
A
x
x
2
-1
-24:00
08:00
x14
-18:00
14:00
Admission to trial site
B5
▲
-14:00
18:00
Light dinner (voluntary)
x
│
-10:30
21:30
Snack (voluntary)16
│
1
-2:00
06:00
x3,8,19
x3
x3
x3
x3
│
0:00
08:00
Drug administration
▲
▲
▲
│
0:05
08:05
│
x
│
│
│
0:30
08:30
│
x
│
│
x
│
0:59
08:59
▼
x
│
│
x
│
1:05
09:05
x
│
│
│
1:10
09:10
x
│
│
│
1:40
09:40
x
│
│
│
2:00
10:00
240 mL fluid intake
x8
x
│
│
x
│
3:00
11:00
x
│
│
│
4:00
12:00
240 mL fluid intake, thereafter 
lunch4
x8
x
┼
│
│
│
x
x
x
│
│
5:00
13:00
x
│
│
│
7:00
15:00
x
│
│
│
8:00
16:00
Snack (voluntary)4
x8
┼
│
x
│
9:00
17:00
x
│
│
│
11:00
19:00
Dinner
x
│
│
│
12:00
20:00
x
┼
│
x
x
x
│
2
24:00
08:00
x
┼
┼
x
x
│
3
48:00
08:00
x8
x
┼
┼
x
│
4
72:00
08:00
x
┼
┼
x
│
5
96:00
08:00
x20
┼
┼
x
│
6
120:00
08:00
x20
┼
┼
x
│
7
144:00
08:00
x20
┼
┼
x
│
8
168:00
08:00
x21
┼
┼
x
│
9
192:00
08:00
Discharge from trial site
B
x21
▼
▼
x
x
x
│
14
312:00
08:00
Start home collection
▲
┼
▼
│
15
336:00
08:00
Admission to trial site11,12
▲
▼
│
16
360:00
08:00
Discharge from trial site11
│
21
480:00
08:00
Start home collection
▲
┼
▼
│
22
504:00
08:00
Admission to trial site11,12
▲
▼
│
23
528:00
08:00
Discharge from trial site11
│
28
648:00
08:00
Start home collection
▲
┼
▼
│
29
672:00
08:00
Admission to trial site11,12
▲
▼
│
30
696:00
08:00
Discharge from trial site11
│
35
816:00
08:00
Start home collection
▲
┼
▼
│
36
840:00
08:00
Admission to trial site11,12
▲
▼
│
37
864:00
08:00
Discharge from trial site11
B
x
x
│
3
9 to 38
End-of-trial (EoT) 
examination10,13
A18
x
x
▼


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25 Feb 2020
BI Trial No.: 1399-0013
c29266057-03
Trial Protocol
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A & B: Safety laboratory sets (see Table 5.2.3: 1)
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
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 1265162 and its metabolite(s) in plasma (see Section 5.3.2.3); (C-14) BI 1265162 -
radioactivity in whole blood and plasma (see Section 5.3.2.2). Blood sampling for an individual subject can be stopped,
if (C-14) BI 1265162 -radioactivity in plasma is below limit of detection (< LLOQ 10 dpm/ mL) at two consecutive 
sampling time points for this subject (earliest stopping after Day 9).
3.
The time is approximate; the respective procedure is to be performed and completed within 3 hours prior to drug 
administration.
4.
If several actions are indicated at the same time point, the intake of meals will be the last action.
5.
Safety laboratory including urine drug and alcohol screening.
6.
Urine collection intervals (for PK/(C-14) BI 1265162 -radioactivity assessment and metabolic profiling; planned time): 
on Day -1 or Day 1 pre-dose (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, and 168-192 hours after administration of BI 1265162 
(C-14). Thereafter 24-h collections are to be performed on Days 15-16, 22-23, 29-30, and 36-37. Urine sampling for 
PK/ (C-14) BI 1265162 -radioactivity will be stopped when release criteria for radioactivity recovery (see Section 3.1) 
have been met (earliest stopping on Day 9). “┼” means end of last collection interval, start of following collection 
interval. For details on sample usage, see Section 5.3.2.5.
7.
All stools (for (C-14) BI 1265162 -radioactivity and metabolic profiling) will be collected quantitatively in portions up 
to 192 hours (sampling intervals of 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168,168-192 hours) after 
administration of BI 1265162 (C-14). Thereafter 24-h collections are to be performed on Days 14-16, 21-23, 28-30, and 
35-37. A blank sample will be collected before drug administration on Day -2, Day -1 or Day 1 (see Section 5.3.2.6). 
Faeces sampling for (C-14) BI 1265162 -radioactivity assessment will be stopped when the release criteria for 
radioactivity recovery (see Section 3.1) have been met (earliest stopping on Day 9). “┼” means end of last collection 
interval, start of following collection interval. For details on sample usage, see Section 5.3.2.6.
8.
Measurement of haematocrit and potassium, only.
9.
AEs and concomitant therapies will be recorded throughout the trial. At 1:05, 2 , 4 , 8, 24, 48, 192h after the infusion, 
local tolerability will be assessed according to the criteria put down in Section 2.2.2.4.
10. End-of-trial (EoT) examination to be performed after last discharge from the trial centre, or, if all once-weekly 24-hour 
sampling periods are needed, after discharge on Day 37. EoT examination includes physical examination, vital signs, 
ECG, safety laboratory, recording of AEs and concomitant therapies.
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 hours to the planned time.
12. Subjects are to collect faeces at home within 24-hour intervals before admission to once-weekly in-house collection 
intervals. Home collection intervals: Days 14-16, 21-23, 28-30, and 35-37. 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. Subjects will collect a pre-dose faeces sample at home or at the site in specific containers provided by 
15. Metabolic profiling sampling times may be adapted based on information obtained during the trial (e.g. levels of 
radioactivity in each urine and/ or plasma sample) as long as the overall blood volume stays the same. Some time points 
require different sample volumes; for details, see lab manual.
16. To be consumed within 30 minutes to allow 10-hour fasting prior to drug administration.
17. Days 9 to 38 are optional until release criteria are fulfilled.
18. Laboratory A, if performed on Day 9.
19. One additional blood sample for pharmacogenomics analyses will be taken.
20. Only plasma and whole blood total radioactivity samples; for details, see lab manual.
21. Only plasma total radioactivity sample; for details, see lab manual.


Boehringer Ingelheim
25 Feb 2020
BI Trial No.: 1399-0013
c29266057-03
Trial Protocol
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FLOW CHART 2 – ORAL BI 1265162 (C-14)
A & B: Safety laboratory sets (see Table 5.2.3: 1)
Visit
Day17
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
PK urine
6
PK faeces
7
Blood sampling for 
metabolic profiling15
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy9
1
-21 to -2
Screening (SCR)1
A
x
x
2
-1
-24:00
08:00
x14
▲
-18:00
14:00
Admission to trial site
B5
│
-14:00
18:00
Light dinner (voluntary)
x
│
-10:30
21:30
Snack (voluntary)16
│
1
-2:00
06:00
x3,8,19
x3
x3
x3
x3
│
0:00
08:00
Drug administration
▲
▲
│
0:30
08:30
x
│
│
x
│
0:45
08:45
x
│
│
│
1:00
09:00
x
│
│
x
│
2:00
10:00
240 mL fluid intake
x8
x
│
│
x
│
3:00
11:00
x
│
│
│
4:00
12:00
240 mL fluid intake, thereafter 
lunch4
x8
x
┼
│
│
│
x
x
x
│
│
6:00
14:00
x
│
│
│
8:00
16:00
Snack (voluntary)4
x8
x
┼
│
x
│
11:00
19:00
Dinner
│
│
│
12:00
20:00
x
┼
│
x
x
x
│
2
24:00
08:00
x
┼
┼
x
x
│
3
48:00
08:00
x8
x
┼
┼
x
│
4
72:00
08:00
x
┼
┼
x
│
5
96:00
08:00
x
┼
┼
x
│
6
120:00
08:00
x
┼
┼
x
│
7
144:00
08:00
x20
┼
┼
x
│
8
168:00
08:00
x21
┼
┼
x
│
9
192:00
08:00
Discharge from trial site
B
x21
▼
▼
x
x
x
│
14
312:00
08:00
Start home collection
▲
┼
▼
│
15
336:00
08:00
Admission to trial site11,12
▲
▼
│
16
360:00
08:00
Discharge from trial site11
│
21
480:00
08:00
Start home collection
▲
┼
▼
│
22
504:00
08:00
Admission to trial site11,12
▲
▼
│
23
528:00
08:00
Discharge from trial site11
│
28
648:00
08:00
Start home collection
▲
┼
▼
│
29
672:00
08:00
Admission to trial site11,12
▲
▼
│
30
696:00
08:00
Discharge from trial site11
│
35
816:00
08:00
Start home collection
▲
┼
▼
│
36
840:00
08:00
Admission to trial site11,12
▲
▼
│
37
864:00
08:00
Discharge from trial site11
B
x
x
│
3
9 to 38
End-of-trial (EoT) 
examination10,13
A18
x
x
▼


Boehringer Ingelheim
25 Feb 2020
BI Trial No.: 1399-0013
c29266057-03
Trial Protocol
Page 8 of 81
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001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
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 1265162 and its metabolite in plasma (see Section 5.3.2.3); (C-14) BI 1265162 -
radioactivity in whole blood and plasma (see Section 5.3.2.2). Blood sampling for an individual subject can be stopped,
if (C-14) BI 1265162 -radioactivity in plasma is below limit of detection (< LLOQ 10 dpm/mL) at two consecutive 
sampling time points for this subject (earliest stopping after Day 9).
3.
The time is approximate; the respective procedure is to be performed and completed within 3 hours prior to drug 
administration.
4.
If several actions are indicated at the same time point, the intake of meals will be the last action.
5.
Safety laboratory including urine drug and alcohol screening.
6.
Urine collection intervals (for PK/(C-14) BI 1265162 -radioactivity assessment and metabolic profiling; planned time): 
on Day -1 or Day 1 pre-dose (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, and 168-192hours after administration of BI 1265162 
(C-14). Thereafter 24-h collections are to be performed on Days 15-16, 22-23, 29-30, and 36-37. Urine sampling for 
PK/ (C-14) BI 1265162 -radioactivity will be stopped when release criteria for radioactivity recovery (see Section 3.1) 
have been met (earliest stopping on Day 9). “┼” means end of last collection interval, start of following collection 
interval. For details on sample usage, see Section 5.3.2.5.
7.
All stools (for (C-14) BI 1265162 -radioactivity and metabolic profiling) will be collected quantitatively in portions up 
to 192 hours (sampling intervals of 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168,168-192 hours) after 
administration of BI 1265162 (C-14). Thereafter 24-h collections are to be performed on Days 14-16, 21-23, 28-30, and 
35-37. A blank sample will be collected before drug administration on Day -2, Day -1 or Day 1 (see Section 5.3.2.6). 
Faeces sampling for (C-14) BI 1265162 -radioactivity assessment will be stopped when the release criteria for 
radioactivity recovery (see Section 3.1) have been met (earliest stopping on Day 9). “┼” means end of last collection 
interval, start of following collection interval. For details on sample usage, see Section 5.3.2.6.
8.
Measurement of haematocrit and potassium, only.
9.
AEs and concomitant therapies will be recorded throughout the trial.
10. End-of-trial (EoT) examination to be performed after last discharge from the trial centre, or, if all once-weekly 24-hour 
sampling periods are needed, after discharge on Day 37. EoT examination includes physical examination, vital signs, 
ECG, safety laboratory, recording of AEs and concomitant therapies.
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 hours to the planned time.
12. Subjects are to collect faeces at home within 24-hour intervals before admission to once-weekly in-house collection 
intervals. Home collection intervals: Days 14-16, 21-23, 28-30, and 35-37. 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. Subjects will collect a pre-dose faeces sample at home or at the site in specific containers provided by 
15. Metabolic profiling sampling times may be adapted based on information obtained during the trial (e.g. levels of 
radioactivity in each urine and/or plasma sample) as long as the overall blood volume stays the same. Some time points 
require different sample volumes; for details, see lab manual.
16. To be consumed within 30 minutes to allow 10-hour fasting prior to drug administration.
17. Days 9 to 38 are optional until release criteria are fulfilled.
18. Laboratory A, if performed on Day 9.
19. One additional blood sample for pharmacogenomics analyses will be taken.
20. Only plasma and whole blood total radioactivity samples; for details, see lab manual.
21. Only plasma total radioactivity sample; for details, see lab manual.


Boehringer Ingelheim
25 Feb 2020
BI Trial No.: 1399-0013
c29266057-03
Trial Protocol
Page 9 of 81
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001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART 1 – INTRAVENOUS BI 1265162 (C-14)..............................5
FLOW CHART 2 – ORAL BI 1265162 (C-14)................................................7
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS.......................................................................................... 13
1.
INTRODUCTION.................................................................................... 17
1.1
MEDICAL BACKGROUND............................................................................17
1.2
DRUG PROFILE...............................................................................................18
1.2.2
Safety pharmacology ............................................................................18
1.2.3
Toxicology..............................................................................................18
1.2.6
Residual Effect Period..........................................................................23
1.2.7
Drug product.........................................................................................23
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................24
1.4
BENEFIT - RISK ASSESSMENT ...................................................................26
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 29
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......29
2.1.1
Main objectives......................................................................................29
2.1.2
Primary endpoints ................................................................................29
2.1.3
Secondary endpoint ..............................................................................29
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS .........................30
2.2.1
Further objectives.................................................................................30
2.2.2
Further endpoints .................................................................................30
2.2.2.1
Further pharmacokinetic endpoints..........................................30
2.2.2.2
Further mass balance endpoints...............................................31
2.2.2.3
Determination of the blood cell/ plasma and blood/ plasma 
ratios of (C-14)-radioactivity...................................................32
2.2.2.4
Local tolerability......................................................................32
2.2.2.5
Further safety and systemic tolerability endpoints ..................32
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 33
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................33
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................34
3.3
SELECTION OF TRIAL POPULATION ......................................................35


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3.3.1
Main diagnosis for trial entry..............................................................35
3.3.2
Inclusion criteria...................................................................................35
3.3.3
Exclusion criteria ..................................................................................36
3.3.4
Withdrawal of subjects from treatment or assessments ...................37
3.3.4.1
Removal of individual subjects................................................38
3.3.4.2
Withdrawal of consent to trial participation ............................38
3.3.4.3
Discontinuation of the trial by the sponsor..............................38
3.3.5
Replacement of subjects .......................................................................39
4.
TREATMENTS........................................................................................ 40
4.1
INVESTIGATIONAL TREATMENTS ..........................................................40
4.1.1
Identity of the Investigational Medicinal Products ...........................40
4.1.2
Selection of doses in the trial................................................................41
4.1.3
Method of assigning subjects to treatment groups ............................41
4.1.4
Drug assignment and administration of doses for each subject .......42
4.1.5
Blinding and procedures for unblinding ............................................43
4.1.6
Packaging, labelling, and re-supply ....................................................43
4.1.7
Storage conditions.................................................................................43
4.1.8
Drug accountability ..............................................................................43
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................44
4.2.1
Other treatments and emergency procedures....................................44
4.2.2
Restrictions............................................................................................44
4.2.2.1
Restrictions regarding concomitant treatment .........................44
4.2.2.2
Restrictions on diet and life style.............................................44
4.3
TREATMENT COMPLIANCE.......................................................................45
5.
ASSESSMENTS....................................................................................... 46
5.1
ASSESSMENT OF EFFICACY.......................................................................46
5.2
ASSESSMENT OF SAFETY............................................................................46
5.2.1
Physical examination ............................................................................46
5.2.2
Vital signs...............................................................................................46
5.2.3
Safety laboratory parameters..............................................................46
5.2.4
Electrocardiogram................................................................................48
5.2.5
Other safety parameters.......................................................................49
5.2.5.1
Local tolerability......................................................................49
5.2.6
Assessment of adverse events...............................................................49
5.2.6.1
Definitions of adverse events...................................................49


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Adverse event ............................................................49
5.2.6.1.1
Serious adverse event ................................................50
5.2.6.1.2
AEs considered ‘Always Serious’.............................50
5.2.6.1.3
Adverse events of special interest .............................50
5.2.6.1.4
Intensity (severity) of AEs.........................................51
5.2.6.1.5
Causal relationship of AEs ........................................51
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................52
AE collection.............................................................52
5.2.6.2.1
AE reporting to the sponsor and timelines ................53
5.2.6.2.2
Information required..................................................53
5.2.6.2.3
Pregnancy ..................................................................53
5.2.6.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................54
5.3.1
Assessment of pharmacokinetics .........................................................54
5.3.2
Methods of sample collection...............................................................54
5.3.2.1
Sampling of whole blood and plasma......................................54
5.3.2.2
Sampling of whole blood and plasma for (C-14)-
radioactivity analysis in whole blood and plasma ..................54
5.3.2.3
Sampling of plasma for metabolic profiling and structural 
elucidation................................................................................55
5.3.2.4
Sampling of blood for haematocrit for blood cell/    
plasma ratio..............................................................................55
5.3.2.5
Sampling of urine.....................................................................55
5.3.2.6
Faeces sampling.......................................................................56
5.3.2.7
Collection of vomit ..................................................................56
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................59
6.
INVESTIGATIONAL PLAN.................................................................. 60
6.1
VISIT SCHEDULE............................................................................................60
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................60
6.2.1
Screening period....................................................................................60
6.2.2
Treatment period ..................................................................................60
6.2.3
Follow-up period and trial completion ...............................................62


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 63
7.1
STATISTICAL DESIGN – MODEL ...............................................................63
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................63
7.3
PLANNED ANALYSES....................................................................................63
7.3.1
Primary endpoint analyses...................................................................64
7.3.2
Secondary endpoint analyses ...............................................................64
7.3.4
Safety analyses.......................................................................................65
7.4
INTERIM ANALYSES .....................................................................................65
7.5
HANDLING OF MISSING DATA ..................................................................66
7.5.1
Safety......................................................................................................66
7.5.2
Pharmacokinetics..................................................................................66
7.6
RANDOMISATION ..........................................................................................66
7.7
DETERMINATION OF SAMPLE SIZE ........................................................66
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 67
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................67
8.2
DATA QUALITY ASSURANCE .....................................................................68
8.3
RECORDS..........................................................................................................68
8.3.1
Source documents .................................................................................68
8.3.2
Direct access to source data and documents.......................................69
8.3.3
Storage period of records.....................................................................69
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................69
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......69
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................70
8.6
TRIAL MILESTONES .....................................................................................70
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................71
9.
REFERENCES......................................................................................... 72
9.1
PUBLISHED REFERENCES...........................................................................72
9.2
UNPUBLISHED REFERENCES.....................................................................74
10. APPENDICES .......................................................................................... 76
10.1
RADIO BURDEN CALCULATION ...............................................................76
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 80
11.1
GLOBAL AMENDMENT 1 .............................................................................80
11.2
GLOBAL AMENDMENT 2 .............................................................................81


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
 
 
 
 
 
ALT
Alanine transaminase
AMS
Accelerator mass spectrometry
ASL
Airway surface liquid
AST
Aspartate transaminase
 
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
 
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
C-14
Carbon 14 labelled BI 1265162 ([14C]BI 1265162)
CA
Competent authority
CF
Cystic fibrosis
CFTR
Cystic fibrosis transmembrane conductance regulator
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
 
 
 
Cmax
Maximum measured concentration of the analyte in plasma
COPD
Chronic obstructive pulmonary disease
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)


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CRO
Contract research organization
CTM
Clinical Trial Monitor
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver injury
DRF
Dose Range Finding
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
ENaC
Epithelial sodium channel
EoT
End of trial
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
fefaeces,0-t2
Fraction of administered drug excreted in faeces from time point 0 to the 
last quantifiable time point
feurine, 0-t2
Fraction of administered drug excreted in urine from time point 0 to the 
last quantifiable time point
fevomit, 0-t2
Fraction of administered drug excreted in urine from time point 0 to the 
last quantifiable time point
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean
GMP
Good Manufacturing Practice
HED
Human Equivalent Dose
HR
Heart rate
IB
Investigator’s brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IH
Inhaled
iPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file


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i.t.
Intra-tracheal
IV
Intravenous
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LLOQ
Lower limit of quantification
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
 
 
NOAEL
No observed adverse effect level
PD
Pharmacodynamics
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PO
Oral
PP
Polypropylene
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
T
Test product or treatment
TMF
Trial master file
 
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
 


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WHO
World Health Organization
XTC
Ecstasy 


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
BI 1265162, an epithelial sodium channel (ENaC) inhibitor, is to be developed in cystic 
fibrosis (CF) and chronic obstructive pulmonary disease (COPD). CF and COPD are chronic 
respiratory disorders characterized by airflow obstruction. ENaC is expressed on airway 
epithelial cells and functions as an ion channel for sodium. It mediates sodium reabsorption 
and regulates the water content and volume of the luminal fluid, thereby maintaining airway 
surface liquid (ASL) and in turn regulating mucociliary clearance.
Cystic fibrosis is a lethal, inherited, multi-organ disease due to exocrine gland dysfunction 
that predominantly affects the lower respiratory tract and pancreas leading to chronic 
respiratory failure and pancreatic insufficiency. It is the most common lethal inherited disease 
in Caucasians [R01-1277] occurring in approximately 1 in 3000 births [R15-5503]. 
Pulmonary treatments include supportive care e.g. airway clearance techniques, antibacterial 
(including inhaled tobramycin and aztreonam), muco-active (e.g. dornase alpha and 
hypertonic saline) therapies and are the cornerstone of pharmacotherapy [P13-14084]. More 
recently, therapies are also targeting the CFTR [R17-1997]. Lung transplantation is used as 
well. Despite recent advances, over 90% of patients surviving the neonatal period will 
develop pulmonary involvement and at least 90% will die due to pulmonary complications 
[P96-3855]. The median age of death is below 40 years old [R15-5546].
In CF, the cystic fibrosis transmembrane conductance regulator (CFTR) gene is dysfunctional 
resulting in impaired epithelial chloride (Cl-) transport [R15-5486] leading, in turn, to 
reduced water secretion into the airway surface layer (ASL). The functional defect of the 
CFTR is also associated with an increase of ENaC activation, increased sodium [R15-5507] 
and water absorption from the airway epithelial lining fluid. These effects lead to mucus 
dehydration and reduction in the height of the pericilliary layer, which is normally tightly 
controlled to maintain optimal mucocillary clearance. The mucus becomes thickened, 
tenacious and adherent leading to collapsed cilia and poor mucus clearance [R15-4955]. The 
static mucus can, in itself, trigger an inflammatory response, but also provides an ideal 
environment for bacterial colonisation with bacterial infection that is often acquired in 
childhood and that persists throughout the patient’s life [R15-4984, R15-4955]. Lung 
destruction is caused by a cycle of infection, inflammation, and injury, with obstruction of the 
airways. The dehydrated, thickened secretions, resultant endobronchial infection, and 
exaggerated inflammatory response lead to mucus plugging, bronchiectasis and progressive 
obstructive airways disease.
COPD prevalence is still rising due to increased smoking, particularly among women and 
adolescents. According to the 2015 estimates of the World Health Organization (WHO), 
65 million people suffer from moderate to severe COPD. By 2030, COPD will be the third 
leading cause of death worldwide [R15-3034].
COPD is associated with significant morbidity and mortality. Smoking cessation is the only 
therapy known to alter the natural history of COPD. The management of stable COPD is 
directed towards reducing symptoms and future risk (prevention and treatment of 


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exacerbations and disease progression). Pharmacotherapy is based primarily on 
bronchodilator drugs including long acting beta agonists (LABA) and long acting-muscarinic 
antagonists (LAMA) and inhaled or oral corticosteroids. Other treatments include the anti-
inflammatory roflumilast, influenza and pneumococcal vaccinations, and treatment of 
exacerbations. The mucolytic therapy N-acetylcysteine may have a small effect on 
exacerbations [P11-05794]. An ENaC inhibitor would be expected to have additional effect 
compared to mucolytic therapies given the direct effects on mucus hydration.
ENaC is expressed widely on the apical side of epithelial cells in the lung and there is 
increasing evidence for the role of ENaC in the pathogenesis of both, CF and COPD. 
Despite the differences in the underlying pathology between the two diseases, changes in 
the biophysical characteristics of the mucus are apparent with impaired transport of mucus 
(reduced mucus clearance) leading to mucus plugging, airflow obstruction and a milieu 
conductive to bacterial colonisation which in turn leads to worsening symptoms, lung 
function, and an increase in exacerbations. In both, CF and COPD, inhibition of ENaC is 
anticipated to reduce sodium uptake and water absorption in the airways which should 
translate to improvement of mucociliary clearance, pulmonary function, symptoms and 
quality of life whilst reducing bacterial colonization of the lower airways, and exacerbations 
and hospitalizations. Administration of an inhaled formulation of the potassium sparing 
diuretic amiloride, an ENaC inhibitor, resulted in increased mucus clearance in cystic fibrosis 
patients [R15-5487, R15-5485, R15-5349] but no clinical efficacy, possibly due to poor 
pharmacokinetic properties of administering this normally oral drug by the inhalation route 
[R15-5349, R15-5599, R15-5505]. The more favourable potency and kinetics demonstrated 
by BI 1265162 is expected to translate into clinical efficacy.
1.2
DRUG PROFILE
BI 1265162 is a potent epithelial sodium channel (ENaC) inhibitor in phase 2 for the 
treatment of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).
 
 
 
1.2.2
Safety pharmacology
For a detailed description, refer to the current ‘Investigator’s Brochure’, c16304878.
1.2.3
Toxicology
For local tolerance, single and repeated inhaled dose toxicity, as well as genotoxicity studies,
refer to the current ‘Investigator’s Brochure’, c16304878.


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Oral toxicity studies
In the pivotal 7-day oral study in rats, nephropathy (bilateral, widespread tubular basophilia, 
interstitial mononuclear cell infiltration, tubular basement membrane thickening and 
glomerulosclerosis) was seen in 1 out of 10 female rats at the dose of 200 mg/kg/day. A 
BI 1265162-related effect could not be ruled out with certainty. The finding correlated with 
elevated kidney weight, higher blood urea and creatinine values, and protein in the urine in 
the affected animal only. Based on the equivocal finding in the kidney, the NOAEL was 
cautiously set at 100 mg/kg/day, corresponding to the Cmax of 19.8 and 38.9 nM and AUC0-24h
of 65.9 and 118 nM*h for males and females, respectively [n00264885].
Oral administration of BI 1265162 to dogs caused death of one male dog after 8 days given
30 mg/kg in the DRF study [n00260481]. Substantial electrolyte changes and high systemic 
exposure with Cmax values of 7480 and 3000 nM were seen on Days 1 and 8, respectively, in 
this animal. In the pivotal 7-day repeat dose study, plasma aldosterone at all doses and 
changes in urine electrolytes were observed at 10 mg/kg. The NOAEL was set at 
10 mg/kg/day, corresponding to the Cmax of 874 and 565 nM and AUC0-24h of 2300 and 
1320 nM*h for males or females, respectively [n00261317]. The NOEL level was set at 
3 mg/kg, corresponding to the Cmax of 283 and 146 nM and AUC0-24h of 670 and 415 nM*h 
for males or females, respectively.
Intravenous toxicity studies
In the pivotal 7-day IV study in rats, the NOAEL was set at the highest dose of 
1600 μg/kg/day, corresponding to the Cmax of 1360 nM and an AUC0-24h of 616 nM*h (males 
& females combined) [n00264887].
An intravenous administration of BI 1265162 over 30 minutes to dogs was well tolerated up 
to 500 μg/kg/day in the DRF and pivotal 7 day study [n00260429, n00260959]. 
Pharmacodynamic related increases in plasma aldosterone were observed at 150 and 
500 μg/kg/day. The IV NOAEL was set at 500 μg/kg/day, corresponding to the Cmax of 2300 
and 3520 nM and AUC0-24h of 1600 and 2030 nM*h for males or females, respectively.


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1.2.6
Residual Effect Period
The Residual Effect Period (REP) of BI 1265162 is 7 days. This is the period after the last 
dose with measurable drug levels and/ or pharmacodynamics effects is still likely to be 
present.
1.2.7
Drug product
BI 1265162 oral solution and concentrate for infusion
For this trial, an oral solution and a concentrate for infusion have been developed in addition 
to the inhalation formulation
 
.The concentrate for infusion contains 5 μg BI 1265162/ mL
(0.36 MBq/ mg).
The oral solution contains 0.25 mg BI 1265162/ mL (0.06 MBq/ mg).


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For shelf-life and storage conditions, refer to the instructions on the label.
For a more detailed description of the BI 1265162 profile, refer to the current ‘Investigator’s 
Brochure’, c16304878.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Rationale for trial
The development of BI 1265162 was optimized for inhalation. However, as the application of 
inhaled radio-labelled substance is technically challenging, the intravenous application of 
BI 1265162 (C-14) will mimic the systemic exposure as if the compound was inhaled. The 
oral dose investigates the absorption and metabolism of the swallowed portion of the inhaled 
dose.
Therefore, this trial will be performed in 2 parts to characterize by means of mass balance

(Part 1) basic pharmacokinetics, metabolism (metabolic profile) and routes of 
elimination of BI 1265162 (C-14) after intravenous administration, and

(Part 2) the extent of gastrointestinal absorption, metabolism (metabolic profile), and 
routes of elimination of BI 1265162 (C-14) after oral administration.
The oral application of BI 1265162 (C-14) is intended to determine the extent of absorption 
of BI 1265162 and/ or its metabolites from the gastrointestinal tract. Due to the optimization 
of BI 1265162 for inhalation, this oral fraction is small (see also Table 1.3: 1). If metabolites 
will be formed in the gastro-intestinal tract and absorbed into the systemic circulation, their 
presence will be detected.
The data are required for future regulatory interactions, to further understand the 
pharmacokinetics of BI 1265162, including the quantitative determination of elimination 
pathways and drug metabolites.
Rationale for dose selection
The dose selection is based on previous experience with orally, inhaled and intravenously 
applied BI 265162 in healthy male subjects.
(i)
Rationale for the intravenous dose
According to preliminary results of study 1399-0014, the single intravenous dose of 50 µg of 
BI 1265162 was well tolerated and safe. Comparing systemic exposures after the inhaled 
(trial 1399-0001, Table 1.2.4: 1) and intravenous (1399-0014, Table 1.2.4: 2) application of 
BI 1265162, mean Cmax and AUC values after the intravenous application of 50 µg should
correspond to those after the inhalation of 300 µg to 600 µg, and 600µg to 1200 µg, 
respectively. All doses were well tolerated and safe. The infusion time of 1 hour was chosen 
to limit the peak exposure and to better mimic the exposure after inhalation.


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(ii)
Rationale for the oral dose
According to preliminary results of study 1399-0014, the single oral dose of 1.25 mg of 
BI 1265162 seemed to be well tolerated and safe. The SAE was not assessed to be related to 
the oral application of BI 265162. Since the systemic exposure was lower than expected, the 
application of a 5 mg dose of BI 1265162 was chosen to achieve a meaningful systemic 
exposure in this study. For the pharmacokinetic rationale, see below.
However, an oral BI 1265162 dose of 5 mg has not been applied in humans before. A de-
novo estimation of a safe starting dose was performed by applying the relevant algorisms of 
the FDA guidance ‘Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers’ [R06-1037] and the ICH guideline M3(R2) on 
‘Non-clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing 
Authorisation for Pharmaceuticals’ [R15-0594]. The results are displayed in Table 1.3: 1
along with the relevant pharmacokinetics obtained from human studies.
Table 1.3: 1
Estimation of safe starting doses based on toxicological results in rats 
and dogs exposed to BI 1265162
Rat
Dog
Human
FDA Approach
NOAEL [mg/kg]
100
10
NOEL[mg/kg]
3
Conversion Factor
6.2
1.8
HED for 60 kg Human (NOAEL) [mg]
967
333
HED for 60 kg Human (NOEL) [mg]
99.6
Safety Factor of 10 on HED (NOAEL) [mg]
96.7
33.3
Safety Factor of 10 on HED (NOEL) [mg]
9.96
ICH M3(R2) Approach
HED for 60 kg Human (NOAEL) [mg]
967
333
Cmax at NOAEL [pmol/L] at Day 1
M: 927,000; F: 458,000
AUC at NOAEL [pmol·h/L] at Day 1
M: 2,620,000; F: 1,300,000
HED for 60 kg Human (NOEL)
99.6 mg
Cmax at NOEL [pmol/L] at Day 1
M: 228,000; F: 234,000
AUC at NOEL [pmol·h/L] at Day 1
M: 655,000; F: 544,000
Safety Factor of 50 on Cmax (NOEL) [pmol/L]
M: 4,560; F: 4,680
Safety Factor of 50 on AUC (NOEL) [pmol·h/L]
M: 13,100; F: 10,800
Human pharmacokinetic parameters (gMean (gCV)) after single doses of BI 1265162
1399-0001
Cmax after 1200 μg inhaled [pmol/L]
6500 (73.1)
AUC after 1200 μg inhaled [pmol·h/L]
3920 (76.4)
1399-0014 (ongoing)*
1.25 mg PO (N=4)
Cmax [pmol/L]
57.7 (69.0)
AUC0-∞[pmol·h/L]
316 (83.5)
50 µg IV (N=4)
Cmax [pmol/L]
1880 (8.79)
AUC0-∞[pmol·h/L]
2200 (12.2)
Absolute bioavailability[%]
0.6
*
Preliminary, not validated data; subject to change!


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According to the FDA algorithm, the dog is the most sensitive species after the oral 
application of BI 1265162.the dog NOEL is based on urine electrolyte changes . Using a
standard safety factor of 10 resulted in a maximum safe ORAL starting dose of 9.96 mg 
which is above the oral dose of 5 mg planned in this study.
The systemic exposures in female dogs at the HED of NOEL is 234,000 pmol/L for Cmax at 
Day 1 and 544,000 pmol*h/L for AUC. The application of a safety factor of 50, as 
recommended by the ICH M3(R2) guideline, results in systemic exposures of 4,680 pmol/L 
for Cmax and 10,800 pmol*h/L for AUC. These are well above the expected exposure to be 
seen with 5 mg oral dosing as referenced to the values obtained already with 1.25 mg oral 
administration in man.
Even though the intended oral application of 5 mg is 4-times higher than that applied in trial 
1399-0014, the expected corresponding systemic exposures should be below those seen after  
1200 µg inhaled and 50 µg IV as achieved safely in studies 1399-0001 and 1399-0014,
respectively.
Rationale for trial population
The inclusion of male healthy subjects as a trial population in phase I studies is ideal as they 
provide relatively stable physiological, biochemical and hormonal conditions for studying 
drug effects. Healthy subjects can be tested under standardised conditions in an environment 
which allows repeated testing.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this trial is without any (therapeutic) benefit for healthy subjects. Their 
participation in the trial, however, is of major importance to the development of BI 1265162. 
Subjects are exposed to the risks of the trial procedures and the risks related to the exposure 
to the trial medication. 
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may cause 
a syncope or result in mild bruising, and in rare cases, in transient inflammation of the wall of 
the vein, or nerve injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain 
for an indefinite period. The same risks apply to venepuncture for blood sampling.
The solvent for the intravenous infusion containing a mixture of labelled and unlabelled
BI 1265162 is isotonic sodium chloride solution (0.9%) adjusted to pH 4.0. Therefore, in case 
of inadvertent paravenous drug administration apart from local swelling, no tissue damage is 
expected.
The total volume of blood withdrawn per subject during the entire trial will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.


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Drug-related risks and safety measures
BI 1265162
As the nature of the target and the mechanism of action of BI 1265162 are well understood, 
comparable compounds have been tested internally and by other companies before, and the 
animal models are believed to be predictive for the effects in humans, BI 1265162 is not seen 
as a high risk compound. The specific mechanism of action is also well recognized for when 
administered systemically (orally) as a diuretic with a well-established safety profile.
The pharmacological effects of BI 1265162 seem to be dose dependent and no evidence for 
prolonged or irreversible effects has been observed. Both formulations, oral as well as 
intravenous, were used in the absolute bioavailability study 1399-0014. However, a 4-times 
higher oral dose of 5 mg is intended to be applied to ensure a meaningful exposure to the 
study drug.
A clinically relevant hyperkalaemia after the administration of a single dose of BI 1265162 is 
unlikely. However, safety laboratory will be performed with special focus on serum 
electrolytes (see Flow Chart).
BI 1265162 (C-14)
(Part 1) No therapeutic intravenous use is planned for BI 1265162. Therefore, in accordance 
with the guideline on non-clinical safety studies ICH-M3(R2) [R15-0594], the intravenous 
dose of 50 μg BI 1265162 (C-14) is considered adequately qualified by the existing oral 
toxicity studies. The investigation of intravenous local tolerance of drug substance is not 
recommended in this situation because the administered dose is very low (< 100 μg) and no 
novel solvent is used. BI 1265162 is labelled with the isotope (C-14) which is necessary for 
the purposes of this trial to identify the metabolism (metabolic profile) and routes of 
elimination BI 1265162.
(Part 2) BI 1265162 (C-14) is labelled with the isotope (C-14) 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 IV administration of 0.018 MBq is about 
0.001 mSv. The effective dose that each subject receives from ORAL administration of 
0.306 MBq is about 0.001 mSv.
Risk minimization
To mitigate the BI 1265162-related risks, the following safety measures will be applied in 
this trial with healthy subjects:

Careful dose selection (see Section 1.3) for the different formulations

Prior to starting the IV administration of trial medication there will be a function 
control of the venous access to prevent para-venous administration


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
The IV administration will be performed as a slow infusion over 1 hour to ensure 
slowly rising plasma concentrations

Hyperkalaemia after the application of a single dose of BI 1265162 seems to be 
unlikely. However, due to the mode of action of this compound, frequent 
examinations of serum potassium will be performed (see Flow Chart)

Subjects with impaired kidney function will be excluded from the trial

Subjects will stay at the trial site from the day prior each dosing until at least 8 days
after the administration of the trial drug
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety (see Section 5.2.6.1.4, adverse events of special interest).
To mitigate the radio-burden related risks, the following safety measures will be applied in 
this trial with healthy subjects:

Each subject participates either in Part 1 or in Part 2 but not in both parts.

(Part 1) The radioactive dose per infusion will be about 0.018 MBq giving a burden of 
0.001 mSv and thereby falls into the ICRP 1 category (trivial level of risk) based on 
the calculated ICRP Category I limit for administration of (C-14) BI 1265162 of 
1.8 MBq [c25192159, R15-3219].

(Part 2) The orally applied radioactive dose is 0.306 MBq which is expected to give a 
radiation burden of 0.0014 mSv. This is lower than the limit proposed by ICRP 
Category 1, (<0.1 mSv – risk defined as trivial). For details on the radiation burden 
calculation, see Appendix 10.1. For clinical investigations to study the disposition, 
metabolism and excretion of new pharmaceutical compounds in man an effective dose 
of below 0.1 mSv is considered to be trivial [R15-3219].


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objectives of this trial is to investigate (a) rates and routes of excretion, (b) mass 
balance, (c) pharmacokinetics of parent drug, any known metabolites, and total radioactivity, 
(d) metabolite profiling, metabolite identification, if suitable assays are available, (e) safety 
and tolerability in healthy male subjects.
2.1.2
Primary endpoints
The following parameters will be determined:
(Part 1 & 2) Mass balance recovery of total (C-14) BI 1265162-radioactivity in urine and
faeces (and vomit, if applicable). Amount of radioactivity excreted as a percentage of the 
administered single intravenous or oral dose of BI 1265162 (C-14) in

Urine - feurine, 0-t2 (fraction of (C-14)-radioactivity excreted in urine as percentage of 
the administered dose over the time interval from 0 to the last quantifiable time point)

Faeces - fefaeces, 0-t2 (fraction of (C-14)-radioactivity excreted in feaces as percentage 
of the administered dose over the time interval from 0 to the last quantifiable time 
point)

Vomit - fevomit, 0-t2 (fraction of (C-14)-radioactivity excreted in vomit as percentage of 
the administered oral dose over the time interval from 0 to the last quantifiable time
point) - if feasible and appropriate
The timeframe for determination of these endpoints depends on the time of discharge of each 
subject, based on radioactivity excretion, and is predicted to vary between 9 and 38 days after
drug administration.
2.1.3
Secondary endpoint
The following parameters will be determined:
(Part 1 & 2) Assessment of the pharmacokinetics of a single intravenous or oral dose of 
BI 1265162 (C-14) by means of the following parameters for total (C-14) BI 1265162-
radioactivity, BI 1265162 and metabolite M582 (1) in plasma:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
(Part 1 & 2) Evaluation of safety and tolerability of a single intravenous or oral dose of 
BI 1265162 (C-14) by means of 


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
Percentage of subjects with drug related adverse events (AEs) including clinically 
relevant findings from the physical examination
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS
2.2.1
Further objectives
(Part 1 & 2) The evaluation of further pharmacokinetic, mass balance and tolerability
parameters after a single intravenous or oral dose of BI 1265162 (C-14).
2.2.2
Further endpoints
2.2.2.1
Further pharmacokinetic endpoints
The following pharmacokinetic endpoints after a single intravenous and oral dose of 
BI 1265162 (C-14) will be calculated for total (C-14) BI 265162-radioactivity, BI 1265162 
and its metabolite(s) in whole blood, plasma, urine and faeces (as feasible and appropriate), 
and may include

AUCt1-t2 (Area under the concentration-time curve of the analyte in plasma over the 
time interval from time point t1 to t2)

AUC0-∞(Area under the concentration-time curve of the analyte over the time interval 
from 0 extrapolated to infinity)

%AUCtz-∞(the percentage of AUC0-∞obtained by extrapolation)

tmax (time from dosing to maximum measured concentration of the analyte)

λz (terminal rate constant)

t1/2 (terminal half-life of the analyte)

MRTpo (mean residence time of the analyte in the body after oral administration)

MRTiv (mean residence time of the analyte in the body after IV administration)

CL/F (apparent clearance of the analyte in the plasma after extravascular 
administration)

CL (apparent clearance of the analyte in the plasma after intravascular administration)

Vz/F (apparent volume of distribution during the terminal phase after extravascular 
administration)

Aeurine, t1-t2 (amount of analyte that is eliminated in urine from the time interval t1 to 
t2)


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
Aeurine, 0-t2 (amount of analyte that is eliminated in urine over the time interval from 0 
to the last quantifiable time point)

feurine, t1-t2 (fraction of administered drug excreted in urine from time point t1 to t2)

Aefaeces, t1-t2 (amount of analyte that is eliminated in faeces from the time interval t1 to 
t2)

Aefaeces, 0-t2 (amount of analyte that is eliminated in faeces over the time interval from 
0 to the last quantifiable time point)

fefaeces, t1-t2 (fraction of administered drug excreted in faeces from time point t1 to t2)

CLR, t1-t2 (renal clearance of the analyte in plasma from the time point t1 to t2)
Further pharmacokinetic parameters may be calculated as appropriate.
Determination of the metabolic pattern of BI 1265162 in plasma, urine and faeces after 
administration of BI 1265162 given intravenously (Part 1) and orally (Part 2) including 
structure elucidation of the metabolites (performed by AMS and classical methods; to be 
reported separately outside this report).
2.2.2.2
Further mass balance endpoints
Mass balance assessments
The following endpoints will be determined for urine:

Ae (C-14)-radioactivity

%Ae (fe) (C-14)-radioactivity

Cum Ae: cumulative recovery of (C-14)-radioactivity

Cum %Ae (fe): cumulative recovery of (C-14)-radioactivity expressed as a percentage
of the dose
For faeces:

Ae (C-14)-radioactivity

%Ae (fe) (C-14)-radioactivity

Cum Ae: cumulative recovery of (C-14)-radioactivity

Cum %Ae (fe): cumulative recovery of (C-14)-radioactivity expressed as a percentage 
of the dose


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Mass balance recovery of (C-14)-radioactivity from all excreta:

Ae (C-14)-radioactivity

%Ae (fe) (C-14)-radioactivity

Cum Ae: cumulative recovery of (C-14)-radioactivity

Cum %Ae (fe): cumulative recovery of (C-14)-radioactivity expressed as a percentage 
of the dose
Further pharmacokinetic parameters may be calculated as appropriate.
2.2.2.3
Determination of the blood cell/ plasma and blood/ plasma ratios of (C-14)-
radioactivity
The ratio of (C-14)-radioactivity in blood cells/ plasma (Cb/ Cp) will be calculated according 
to the formula at those time points as indicated in the Flow Chart.
Additionally, the ratio of concentration of (C-14)-radioactivity in blood and plasma
(Cblood/ Cplasma) will be calculated at all time points when (C-14)-radioactivity concentrations 
are quantifiable in blood and in plasma.
2.2.2.4
Local tolerability
(Part 1) Local tolerability will be assessed by the investigator on the basis of swelling, 
induration, heat, redness, pain, and other findings.
(Part 2) Not applicable.
2.2.2.5
Further safety and systemic tolerability endpoints

Safety laboratory tests

12-lead electrocardiogram (ECG), and

Vital signs (blood pressure [BP], pulse rate [PR])

Physical examination


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The overall trial design is depicted in Figure 3.1: 1 and Figure 3.1: 2.
Figure 3.1: 1
Design of intravenous trial part
Figure 3.1: 2
Design of oral trial part
The trial will consist of two trial parts, after the BI 1265162 (C-14) administration of single 
(Part 1) intravenous and (Part 2) oral doses. Both parts will be performed as a non-
randomized, open-label, single-dose, single arm, trial in healthy male subjects in order to
investigate by means of mass balance recovery (Part 1) metabolism (metabolic profile) and 
routes of elimination of (C-14) BI 1265162 after intravenous administration of 50 µg
BI 1265162 (C-14) and (Part 2) the extent of oral absorption, metabolism (metabolic profile), 


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and routes of elimination of (C-14) BI 1265162 after oral administration of 5 mg BI 1265162 
(C-14). For details, see Section 4.1.
Since in both parts different subjects will take part, there will be no washout period.
On Day 1, subjects will receive the (C-14)-labelled drug substance and will then stay in the 
trial centre up to the morning of Day 9 for collection of blood, urine, and faeces samples. 
Subjects will be readmitted to the trial centre for 24 hour collection intervals of urine and 
faeces on Days 15, 22, 29, and 36, if release criteria as specified below have not been met on 
Day 9 or during any subsequent 24-h collection visits. Within 24 hours before each of these 
once-weekly in-house collection intervals, subjects are to collect faeces at home. This 
24 hour interval home collection faeces will be used for analysis in case no defecation occurs 
in the subsequent 24 hours in-house collection interval. Otherwise it will be discarded.
For determination of whether release criteria have been reached for individual subjects,
(C-14)-radioactivity will be measured in excreta (urine and faeces) as well as in plasma. 
The actual recovery results will be reported as a percentage of the administered dose.
If one of the following release criteria is true, 24 hour collection intervals after Days 9, 16, 
23, 30, or 37, (whichever is applicable) will not be performed:

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 hour intervals, and

Concentration of total radioactivity in plasma <5% of Cmax of total radioactivity in 
plasma.
An overview of all relevant trial activities is provided in the Flow Charts. For visit schedule 
and details of trial procedures at selected visits, see Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
This is a standard design of a (C-14) human mass balance trial to determine absorption, 
metabolism, and excretion of BI 1265162.
The inclusion of a control group is not required for such an investigation.
The elimination of BI 1265162 is multi-exponential. The terminal mean half-life with 15.5h 
seems to be moderate. If drug can be absorbed all through the gastro-intestinal tract, this may 
result in low systemic concentrations for a longer period of time. Therefore, it cannot be 
excluded that prolonged sampling is necessary in humans. Hence, after8 in-house days after 
dosing during which excreta will be collection, subjects will return for in-house 24-h 
collection intervals on a weekly basis for up to 4 weeks after dosing as long as release criteria 
are not met (see also Section 3.1).


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The open-label treatment is not expected to bias results because all subjects receive the same 
treatment within each trial part and the main trial endpoints are derived from measurements
of plasma, urine and faeces concentrations of analytes which are provided by a bioanalytical 
laboratory.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 7 healthy male subjects will enter each trial part, i.e. in total 14 subjects. 
They will be recruited from the subject-pool of the trial site.
Only male subjects will be included in the trial to reduce variability of results.
The current trial is designed to investigate the basic pharmacokinetics of BI 1265162
including absorption, metabolism, and elimination and quantitative determination of 
excretion by mass balance. Samples will be generated for additional metabolic profiling and 
structural identification. 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. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy male subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests
2. Age of 18 to 65 years (inclusive)
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)
4. Signed and dated written informed consent prior to admission to the trial, 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 3 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


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
Condoms plus surgically sterilised partner (including hysterectomy), or

Condoms plus intrauterine device, or

Condoms plus partner of non-child bearing potential (including homosexual men)
Subjects are required to use condoms to prevent unintended exposure of the partner to the 
trial 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) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 139 mmHg, 
diastolic blood pressure outside the range of 45 to 89 mmHg, or pulse rate outside the 
range of 40 to 100 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Clinically significant gastrointestinal, hepatic, renal, respiratory, cardiovascular, 
metabolic, immunological or hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with 
the pharmacokinetics of the trial medication (except appendectomy or simple hernia 
repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication
or its excipients)
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/ QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoking habit other than incidental. Incidental smoker is defined as a person who will
not smoke more than 5 cigarettes per week
14. Inability to refrain from smoking in the clinical research unit


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15. Alcohol abuse (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))
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within 96 hours prior to the 
administration of trial medication and during the trial until the discharge at Day 9
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with trial requirements, or 
has a condition that would not allow safe participation in the trial
In addition, the following trial-specific exclusion criteria apply:
23. A history of chronic kidney disease
24. Participation in another ADME study with a radiation burden of 0.1-1.0 mSv in the 
period of 1 year prior to screening or 1.1-2.0 mSv in the past 2 years or 2.1-3.0 mSv in 
the past 3 years etc.
25. 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)
26. Irregular defecation pattern (less than a mean of one bowel movement every other day)
For trial restrictions, see Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; see Sections 3.3.4.1 and 3.3.4.2
below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. At the time of 
discontinuation, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.6), the discontinued subject should, if possible, be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 


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and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.
3.3.4.1
Removal of individual subjects
An individual subject will be removed from the trial if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/ or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/ or needs to be 
followed up according to the DILI checklist provided in the ISF
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation. For details, see Section 3.3.4.1.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information
invalidating the earlier positive benefit-risk-assessment. More specifically, the trial will 
be put on hold, and only proceed after mutual consultation between the Sponsor and the 
Principal Investigator, if more than 50% of the subjects have drug-related and clinically 
relevant adverse events of moderate or severe intensity, or if 1 or more drug-related 
serious adverse event is reported.
3. Violation of GCP, or the CTP, or the contract with BI impairing the appropriate conduct 
of the trial


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4. The sponsor decides to discontinue the further development of the investigational 
product.
The investigator/ trial site will be reimbursed for reasonable expenses incurred in case of trial 
termination (except, if item 3 applies).
3.3.5
Replacement of subjects
In case subjects in either trial part do not complete the trial, the Trial Clinical Leader together 
with the Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many 
subjects will be replaced. A replacement subject will be assigned a unique trial subject 
number, and will be assigned to the same treatment as the subject he replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
Radiolabelled BI 1265162 is administered as a solution of BI 1265162 (C-14). The oral and 
intravenous solution contains (C-14) BI 1265162 and unlabelled BI 1265162 which is
manufactured by BI Pharma GmbH & Co. KG. The final drug product oral solution and 
intravenous solution is made by
.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
(Part 1) Intravenous BI 1265162 (C-14)
Name:
BI 1265162 (C-14) intravenous solution 5 µg/mL (10 mL;
0.018 MBq)
Substance:
BI 1265162 and (C-14) BI 1265162
Pharmaceutical formulation: Intravenous solution
Source:
Unit strength:
50 µg
Posology:
1-0-0
Route of administration:
Intravenous
Duration of use:
Single dose
(Part 2) Oral BI 1265162 (C-14)
Name:
BI 1265162 (C-14) oral solution 0.25 mg/mL (20 mL;
0.306 MBq)
Substance:
BI 1265162 mixed with (C-14) BI 1265162
Pharmaceutical formulation: Oral solution
Source:
Unit strength:
5 mg
Posology:
1-0-0
Route of administration:
Oral
Duration of use:
Single dose


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The characteristics of the reference product are given below:
Not applicable.
4.1.2
Selection of doses in the trial
(Part 1) Intravenous BI 1265162 (C-14)
The intravenous dose of 50 µg BI 1265162 (C-14) is expected to yield exposures that will be 
similar to the systemic exposure which is achieved with a dose of 200 µg administered by 
inhalation, the highest dose being tested in phase II trials (1399-0003). This dose is below the 
already tested highest doses (single doses up to 1200 µg, multiple doses up to 75 µg BID
(150 µg/d)) of BI 1265162 in healthy subjects. In healthy subjects, a single dose of 1200 µg 
was safe and well-tolerated (Section 1.3). 
This dose, administered as intravenous solution, will include 0.018 MBq of BI 1265162
(C-14). The radiolabelled dose of 0.018 MBq is required for the objectives of the trial, i.e. to 
provide good detection limits for measurement of radioactivity in urine, faeces and plasma. 
The total effective dose (radiation burden) amounts to 0.001 mSv. This is below the limit of 
ICRP Category 1 and considered acceptable [R15-3219].
Radiation burden calculations are presented in Appendix 10.1. For risk-benefit assessment, 
see Section 1.4. 
(Part 2) Oral BI 1265162 (C-14)
The oral dose of 5 mg BI 1265162 (C-14) was chosen on the ground of preliminary results 
from the ongoing absolute bioavailability trial 1399-0014 (refer to Section 1.4). Since 
developed for inhalative administration, BI 1265162 has not been applied in an oral fashion. 
An oral dose of 5 mg is considered to be adequate for the objectives of the current trial.
This dose, administered as oral solution, will include 0.306 MBq of BI 1265162 (C-14). The
radiolabelled dose of 0.306 MBq is required for the objectives of the trial providing good
detection limits for measurement of radioactivity in urine, faeces and plasma. The total
effective dose (radiation burden) amounts to 0.0014 mSv. This is below the limit of ICRP
Category 1 and considered acceptable.
Radiation burden calculations are presented in Appendix 10.1. For risk-benefit assessment, 
see Section 1.4.
4.1.3
Method of assigning subjects to treatment groups
This is a non-randomized, open-label, single-dose, phase I trial. All subjects will receive the 
same treatment per trial part: BI 1265162 (C-14), either intravenously in Part 1 or orally in 
Part 2. Subjects will be assigned to one of these parts based on their temporal availability. 
Once a subject number has been assigned, it cannot be reassigned to any other subject.
The study drug administration of one trial part will be finished prior to start of study drug 
administration of the other trial part.


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4.1.4
Drug assignment and administration of doses for each subject
This is a non-randomised, open-label, single-dose, phase I trial. Within each trial part, all 
subjects receive the same treatment. Treatments to be evaluated are outlined in Table 4.1.4: 1.
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit 
strength
Volume
Total dose
Total 
radioactivity
T1 (Part 1)
BI 1265162
IV solution
5 μg/mL
10 mL
50 μg over 1h
0.018 MBq
T2 (Part 2)
BI 1265162
Oral solution
0.25 mg/mL
20 mL
5 mg
0.306 MBq
Each subject is expected to participate in 1 treatment (Days -2 to 38). Intravenous (Part 1) 
and oral (Part 2) BI 1265162 (C-14) administrations will be applied to different subject 
cohorts.
Administration of trial medication will be performed after subjects have fasted overnight; 
fasting is to start no later than 10 hours before the scheduled dosing. The so-called four-eye 
principle (two-person rule) should be applied. For this, one authorised employee of the trial 
site should witness the administration of trial medication, and – if applicable – its preparation 
(e.g. reconstitution), if correct dosage cannot be ensured otherwise.
Subjects will be kept under close medical surveillance until Day 9 after drug administration. 
Subject should be in a semi-supine position for 4 hours after dosing of the oral drug 
application.
(Part 1) Intravenous BI 1265162 (C-14)
An intravenous infusion of BI 1265162 will be administered as a constant intravenous 
infusion over 1 hour to a subject in the semi supine position under supervision of the 
investigating physician or an authorised designee. Start and end time of the infusion will be 
recorded. For the administration an indwelling catheter is placed into an arm vein of the 
subject and will be kept patent with a saline infusion. A second indwelling catheter used for
collection of blood samples will be placed on the contralateral arm.
(Part 2) Oral BI 1265162 (C-14)
An oral dose will be administered by the investigator (or authorised designee) together with 
about 240 mL of water to subjects who are in a sitting position. A part of this water can be 
used to rinse the vial in which the medication is provided. For drug administration, the so-
called four-eye principle (two-person rule) should be applied. For this, one authorised 
employee of the trial site should witness the administration of trial medication, and – if 
applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.


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4.1.5
Blinding and procedures for unblinding
This phase I trial investigating only one treatment per trial part will be handled in an open 
fashion throughout (i.e., during the conduct, including data cleaning and preparation of the 
analysis). This is considered acceptable because the potential for bias seems to be low and 
does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the
It consists of containers holding the trial medication which is labelled with trial identification. 
The required information according to the Local Drug Law as well as Annex 13/ EU GMP 
Guideline will be provided on the containers.
Radiolabeled drug product manufacturing is done by 
 The final container used for 
administration of the radiolabeled drug product will be a syringe for intravenous infusions or 
a vial for oral application.
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB/ ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site


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
Approval/ notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch/ serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that all unused or partially used drug supplies have been 
returned by the clinical trial subject and that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on trial days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, subjects will be instructed not to consume any foods or drinks 
other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 hours after start of infusion 
(Part 1)/ drug intake (Part 2).


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From 1 hour before start of infusion (Part 1)/ drug intake (Part 2) until lunch, fluid intake is 
restricted to the water administered with the drug (Part 2), and an additional 240 mL of water 
at 2 hours and 4 hours after start of infusion/ (Part 1) drug intake (Part 2). From lunch until 
24 hours after start of infusion (Part 1)/ drug intake (Part 2), total fluid intake is restricted to
3000 mL.
Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products containing St. John's wort (Hypericum perforatum) are not permitted starting
7 days before the first administration of trial medication until discharge at Day 9 after the last 
administration of trial medication.
Alcoholic beverages not permitted from 48 hours before each trial drug administration and 
until 24 hours after administration of trial medication.
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 24 hours before until discharge at Day 9.
Excessive physical activity (such as competitive sport) should be avoided from 96 hours
before the first administration of trial medication until discharge at Day 9.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/ or urinary excretion of trial medication will provide additional confirmation of 
compliance.
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, see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported), 
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 including determination of weight.
5.2.2
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 (e.g 
,
) at the times indicated in the Flow Chart, after 
subjects have rested for at least 5 minutes in a supine position. All recordings should be made 
using the same type of blood pressure recording instrument on the same arm, if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 4 h. 
For retests, at the discretion of the investigator or designee, overnight fasting is not required.
If safety laboratory measurement is performed with other blood collection, e.g. 
pharmacokinetic sampling, safety laboratory measurement will always be performed first, 
preferably without any tourniquet.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10.
Manual differential white blood cell count or urine sediment examinations will only be 
performed, if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.
Additional haematocrit measurements will be performed at the time points as indicated in the 
Flow Chart.
For electrolyte/ potassium concentration measurements, blood will be sampled without any 
tourniquet at time points as indicated in the Flow Chart (safety laboratory). 


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/ abbreviation]
A
B
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/ Erythrocytes
White Blood Cells/ Leucocytes
Platelet Count/ Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/ Leukocytes; Eosinophils/ Leukocytes; Basophils/ 
Leukocytes; Monocytes/ Leukocytes; Lymphocytes/ Leukocytes
X
X
Automatic WBC 
differential, absolute
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; Monocytes, 
absol.; Lymphocytes, absol.
X
X
Manual differential 
WBC (if automatic 
differential WBC is 
abnormal and clinically 
relevant in the opinion of 
the investigator according 
to local procedures)
Neut. Poly (segs)/ Leukocytes; Neutrophils Bands/ Leukocytes;
Eosinophils/ Leukocytes; Basophils/ Leukocytes; Monocytes/ 
Leukocytes; Lymphocytes/ Leukocytes
X
X
Coagulation
Activated Partial Thromboplastin Time
Prothrombin Time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase]/ GOT, SGOT
ALT [Alanine transaminase]/ GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
X
--
Substrates
Glucose (Plasma)
Creatinine
GFR/ CKD-EPI2
Bilirubin, Total
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Electrolytes1
Sodium
Potassium
Chloride
Calcium
X
X
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic examination 
if erythrocytes, 
leukocytes, nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for instance, the presence of 
sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
X
X
A & B
Safety laboratory sets (for time points, see Flow Chart)


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1
Sample tubes will be centrifuged for about 8 minutes at about 4000 g and stored at room temperature until shipment to 
the clinical lab.
2
Estimated glomerular filtration rate according to CKD-EPI formula (R12-1392)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/ database and will not be reported in the 
CTR. It is planned to perform these tests during screening only. Drug screening will be 
performed at screening and prior to each treatment period on Day -1.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/ MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine
Methadone
Methamphetamines/ MDMA/ XTC
Opiates
Phencyclidine
Tricyclic Antidepressants
Infectious serology (blood)
Hepatitis B Surface Antigen (qualitative)
Hepatitis B Core Antibody (qualitative)
Hepatitis C Antibodies (qualitative)
HIV-1 and HIV-2 Antibody (qualitative)
To encourage compliance with alcoholic and drug restrictions, a urine alcohol and drug test 
(e.g. 
) will be performed prior to each treatment period, and 
may be repeated at any time during the trial at the discretion of an investigator or designee. 
The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
, 
. Urinanalyis 
stix and drug screening tests will be performed using e.g. 
 
respectively.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (
) at the times provided in the Flow 
Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.


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All ECGs will be recorded for a 10 second duration after subjects have rested for at least 
5 minutes in a supine position. ECG assessment will always precede all other trial procedures 
scheduled for the same time to avoid compromising 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. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening), if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment.
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons.
5.2.5
Other safety parameters
5.2.5.1
Local tolerability
After intravenous BI 1265162 (C-14) administration (Part 1), local tolerability will be 
assessed by the investigator on the basis of swelling, induration, heat, redness, pain, and other 
findings.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
Adverse event
5.2.6.1.1
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.


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Serious adverse event
5.2.6.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe

Requires inpatient hospitalisation

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital anomaly/birth defect

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
5.2.6.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, see 
Section 5.2.6.2.2.


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The following are considered as AESIs:

A confirmed elevation of serum potassium > upper limit of normal (ULN) in non-
haemolysed blood.

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
eCD. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
Intensity (severity) of AEs
5.2.6.1.5
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
5.2.6.1.6
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)


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
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
AE collection
5.2.6.2.1
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/ concomitant diagnoses), and relevant changes from 
baseline are noted subsequently.
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial
o
All AEs (serious and non-serious) and all AESIs
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy subjects, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 


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these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process 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 send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
Pregnancy
5.2.6.2.4
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/ or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood and urine samples will be collected at the time 
points/ time intervals indicated in the Flow Chart. The actual sampling times will be recorded 
and used for determination of pharmacokinetic parameters.
Pharmacokinetic sampling times may be adapted during the trial based on information 
obtained during trial conduct (e.g. exploratory pharmacokinetic analysis) including addition 
of samples as long as the total blood volume taken per subject does not exceed 500 mL. Such 
changes would be implemented via non-substantial CTP Amendment.
5.3.2
Methods of sample collection
5.3.2.1
Sampling of whole blood and plasma
Whole blood and plasma will be collected at time points shown in the Flow Chart:

To determine (C-14)-radioactivity concentrations in whole blood and plasma

To determine concentrations of BI 1265162 and its metabolite
(1) in plasma

To identify further metabolites of BI 1265162 in plasma

To determine the blood cell/ plasma and blood/ plasma ratios of (C-14)-radioactivity
Blood for pharmacokinetics of BI 1265162 and for quantification of its metabolite 
 
will be taken from an antecubital or forearm vein into a 
 
 blood drawing tube at the times indicated in 
the Flow Chart.
For a detailed description of blood sampling, sample volume, sample handling, sample 
preparation, sample storage, tube labelling and sample shipment, refer to the laboratory 
manual.
5.3.2.2
Sampling of whole blood and plasma for (C-14)-radioactivity analysis in whole
blood and plasma
Whole blood and plasma will be taken from an antecubital or forearm vein into a 
 
 blood drawing tube at the times 
indicated in the Flow Chart.
Premature stopping of blood sampling
In case (C-14)-radioactivity in plasma samples is not detectable
) at 
two consecutive time points for a subject, blood sampling can be stopped for this subject.
However, all samples until and including the Day 9 sample have to be taken.


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For a detailed description of blood sampling, sample volume, sample handling, sample 
preparation, sample storage, tube labelling and sample shipment, refer to the laboratory 
manual.
5.3.2.3
Sampling of plasma for metabolic profiling and structural elucidation
Additional
) plasma samples for the 
identification of drug metabolites will be investigated.
The blood samples will be drawn in parallel to pharmacokinetics (see Flow Chart). 
For a detailed description of blood sampling, sample volume, sample handling, sample 
preparation, sample storage, tube labelling and sample shipment, refer to the laboratory 
manual.
5.3.2.4
Sampling of blood for haematocrit for blood cell/ plasma ratio
At each time point listed in the Flow Chart, a blood sample will be taken. This blood will be 
used for measurement of haematocrit which is needed for determination of blood cell/ plasma 
ratio (see Section 2.2.2.3).
Haematocrit will be measured at
For a detailed description of blood sampling, sample volume, sample handling, sample 
preparation, sample storage, tube labelling and sample shipment, refer to the laboratory 
manual.
5.3.2.5
Sampling of urine
Urine will be collected during the trial as indicated in the Flow Chart.
A blank urine sample will be collected within 14 hours prior to drug administration. All urine 
voided will be collected in containers, according to intervals, given in the Flow Chart. 
 
or 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. Volunteers will empty their bladders at the end of each sampling 
interval. The exact start and end times of the urine collection intervals will be recorded in the 
CRF.
All samples after the intake of BI 1265162 (C-14) are planned to be used for determination of 
(C-14)-radioactivity, BI 1265162 concentrations and its metabolites.
Samples to be used for metabolic profiling will be selected according to the levels of
radioactivity in each urine sample interval.


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For a detailed description of urine sampling, sample volume, sample handling, sample 
preparation, sample storage, tube labelling and sample shipment, refer to the laboratory 
manual.
5.3.2.6
Faeces sampling
Faeces will be collected during the trial as indicated in the Flow Chart.
A blank faeces sample will be collected prior to drug administration.
All stool samples will be collected quantitatively in portions up to Day 37 after drug
administration. The weight of faeces and the exact times of faeces collection will be recorded 
in the eCRF.
All faeces samples are planned to be used for determination of (C-14)-radioactivity and 
metabolic profiling.
Samples to be used for metabolic profiling will be selected according to the levels of
radioactivity in each faeces sample interval.
For a detailed description of faeces sampling, sample volume, sample handling, sample 
preparation, sample storage, tube labelling and sample shipment, refer to the laboratory 
manual.
5.3.2.7
Collection of vomit
If vomiting occurs in a subject within 4 hours after drug administration, the vomit will be 
collected for determination of weight and (C-14)-radioactivity.
For a detailed description of vomit sampling, sample volume, sample handling, sample 
preparation, sample storage, tube labelling and sample shipment, refer to the laboratory 
manual.


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5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an intravenously/ orally administered drug, and are 
widely used in clinical trials. The pharmacokinetic parameters and measurements outlined in 
Section 5.3 are generally used assessments of drug exposure in human mass-balance trials.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Trial measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 30 minutes for the first 4 hours after drug administration and ± 45 minutes
thereafter.
In the event assessments are planned for the same scheme time in the Flow Chart, the order of 
the assessments should be arranged in such a way that pharmacokinetic (and 
pharmacodynamic) blood sampling will be done after the ECG and vital signs recordings 
have been conducted, with pharmacokinetic blood sampling exactly on time.
For planned blood sampling times and urine and faeces collection intervals, refer to the Flow 
Chart. While these nominal times should be adhered to as closely as possible, the actual 
sampling times will be recorded and used for the determination of pharmacokinetic 
parameters.
If a subject misses an appointment, it will be rescheduled, if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the trial.
For information regarding physical examination, vital signs, laboratory tests (including drug 
and virus screening), and ECG, refer to Sections 5.2.1 to 5.2.5.
6.2.2
Treatment period
Each subject is expected to participate in 1 treatment period (Days -1 to 37). Intravenous 
(Part 1) and oral (Part 2) BI 1265162 (C-14) administrations will be applied to different 
subject cohorts.
(Part 1) Intravenous BI 1265162 (C-14)
From Day -1 (prior to the application of trial medication), subjects will collect a pre-dose 
faeces sample at home or at the site in specific containers provided by 


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On Day -1 or Day 1, subjects will collect a pre-dose (blank) urine sample prior to start of 
urine collection.
On Day -1, subjects will be admitted to the trial site. On Day 1, subjects will receive the 
(C-14)-labelled drug substance, i.e. 50 µg BI 1265162 (C-14) as a short infusion over 1 hour
and will then stay in the trial centre up to the morning of Day 9 for collection of samples of 
blood, urine, and faeces.
Subjects will be readmitted to the trial centre for 24 hours collection intervals of urine and 
faeces on Days 15, 22, 29 and 36, if release criteria as described in Section 3.1 have not been 
met on Day 9. Within 24 hours before each of these once-weekly in-house collection 
intervals, subjects are to collect faeces at home. This 24 hour interval home collections will 
be used for analysis in case no defecation occurs in the subsequent 24 hours in-house 
collection interval. Otherwise it will be discarded. Once release criteria are reached, home 
collections will be stopped.
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 the last collection interval 
on Day 37, no further collections are planned.
For details on time points and procedures for collection of whole blood, plasma, urine and 
faeces samples for pharmacokinetic analysis, see Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.3
of this protocol and in the Flow Chart. For details on times of all other trial procedures, see
Flow Chart. AEs and concomitant therapy will be assessed continuously from screening until 
the end of trial examination.
(Part 2) Oral BI 1265162 (C-14)
From Day -1 to Day 1 (prior to the application of trial medication), subjects will collect a pre-
dose faeces sample at home or at the site in specific containers provided by 
On Day -1 or Day 1, subjects will collect a pre-dose (blank) urine sample prior to start of 
urine collection.
On Day -1, subjects will be admitted to the trial site. On Day 1, subjects will receive the 
(C-14)-labelled drug substance, i.e. 5 mg BI 1265162 (C-14) as an oral solution together with 
240 mL of water and will then stay in the trial centre up to the morning of Day 9 for 
collection of samples of blood, urine, and faeces.
Subjects will be readmitted to the trial centre for 24 hour collection intervals of urine and 
faeces on Days 15, 22, 29, and 36, if release criteria as described in Section 3.1 have not been 
met on Day 9. Within 24 hours before each of these once-weekly in-house collection 
intervals, subjects are to collect faeces at home. This 24 hour interval home collections will 
be used for analysis in case no defecation occurs in the subsequent 24 hours in-house 


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collection interval. Otherwise it will be discarded. Once release criteria are reached, home 
collections will be stopped.
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 the last collection interval 
on Day 37, no further collections are planned.
For details on time points and procedures for collection of whole blood, plasma, urine and 
faeces samples for pharmacokinetic analysis, see Flow Chart and Section 5.3.2.
Safety measurements performed during the treatment period are specified in Section 5.3 of 
this protocol and in the Flow Chart. For details on times of all other trial procedures, see
Flow Chart. AEs and concomitant therapy will be assessed continuously from screening until 
the end of trial examination.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue before the end of the planned treatment period should undergo the
EoT Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoT Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can 
be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate by means of mass balance recovery the 
metabolism (metabolic profile) and routes of elimination of (C-14) BI 1265162 after 
intravenous administration and the extent of gastro-intestinal absorption, metabolism 
(metabolic profile), and routes of elimination of (C-14) BI 1265162 after oral administration 
of 5 mg BI 1265162 (C-14) to healthy male subjects. 
!"#$%&'() $*+"#,-."/ '(" ,0" ".'12',-$% $3 pharmacokinetic parameters specified in Section 
2.1.3 and /'3",) '%& ,$1"('*-1-,)4
Further objectives are to evaluate further pharmacokinetic, mass balance and tolerability 
parameters.
5$ /,',-/,-#'1 #$67'(-/$% 8-11 *" #$%&2#,"& 3$( ,0-/ /,2&)4 9',' 8-11 *" ("7$(,"& 8-,0 
&"/#(-7,-." /,',-/,-#/4
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
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were entered and treated 
with one dose of trial drug. The treated set will be used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects from the 
treated set (TS) who provide at least one pharmacokinetic endpoint that was defined 
as primary or secondary and was not excluded due to a protocol deviation relevant to 
the evaluation of pharmacokinetics or due to pharmacokinetic non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Descriptive analyses of 
pharmacokinetic parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be specified in the Integrated Quality and Risk Management Plan, iPDs 
will be identified no later than in the Report Planning Meeting, and the iPD categories will be 
updated as needed.


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Pharmacokinetics
Pharmacokinetic parameters listed in Section 2.1 for drug (C-14) BI 1265162 will be 
calculated according to the relevant SOP of the Sponsor (001-MCS-36-472). 
Plasma, urine and faeces concentration data and parameters of a subject will be included in 
the statistical pharmacokinetic analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of pharmacokinetics (to be decided no later than in 
Report Planning Meeting) or due to pharmacokinetic non-evaluability (as revealed during 
data analysis, based on the criteria specified below). Exclusion of a subject’s data will be 
documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma and urine concentrations and/ or parameters of a subject will be considered as non-
evaluable, if for example

Missing samples/ concentration data at important phases of pharmacokinetic
disposition curve
Plasma/urine concentration data and parameters of a subject which is flagged for exclusion
will be reported with its individual values but will not be included in the statistical analyses. 
Descriptive statistics of pharmacokinetic parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
7.3.1
Primary endpoint analyses
All parameters will be calculated and analysed descriptively.
7.3.2
Secondary endpoint analyses
Secondary endpoints (refer to Section 2.1.3) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will be assessed statistically using the same 
methods as described for the primary endpoints.
For the assessment of the secondary endpoint regarding safety, see Section 7.3.4.


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7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the planned treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as 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 the screening period, those between trial medication intake and discharge from 
study site (see Section 1.2.6) will be assigned to the treatment period. Events occurring after 
discharge from study site but prior to end of trial termination date will be assigned to ’follow-
up’. These assignments including the corresponding time intervals will be defined in detail in 
the TSAP. Note that AEs occurring after the last per protocol contact but entered before final 
database lock will be reported to Pharmacovigilance only and will not be captured in the trial 
database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1.4), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs will be assessed with regard to possible on-treatment changes from baseline.
Relevant ECG findings will be reported as AEs.
7.4
INTERIM ANALYSES
No interim analysis is planned.


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7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing pharmacokinetic data will be performed according to the relevant 
Corporate Procedure (001-MCS-36-472).
Pharmacokinetic parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Randomisation is not applicable in this open-label, single arm per trial part clinical study. All 
subjects will receive the same treatment per trial part: BI 1265162 (C-14), either 
intravenously in Part 1 or orally in Part 2. Consecutive subject numbers will be assigned via 
the EDC system.
7.7
DETERMINATION OF SAMPLE SIZE
For this exploratory study, no prospective calculations of statistical power have been made.
The sample size of at least 6 evaluable subjects per trial part has been selected to provide 
sufficient information on safety, tolerability and pharmacokinetics of (C-14) BI 1265162 after 
intravenous administration (Part 1) or oral administration (Part 2) in healthy male subjects. In 
order to have at least 6 evaluable subjects per trial part, the sample size will be 7 in both
parts, in total 14 subjects.


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


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8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.
A quality assurance audit/ inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB/ IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, see
Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the eCRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history


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
AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/ exclusion criteria does not 
make the subject eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator/ institution will allow site trial-related monitoring, audits, IRB/ IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/ data, including progress notes, copies of laboratory and medical test results, 
which must be available at all times for review by the Clinical Research Associate, auditor 
and regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7.


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Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB/ IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

If applicable, a fit for purpose approach will be used for assay/ equipment validation 
depending on the intended use of the biomarker data
Samples and/ or data may be transferred to third parties and other countries as specified in the 
ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/ competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.


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8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at 
 
s, under the supervision of the Principal Investigator. Relevant documentation 
on the participating (Principal) Investigators (e.g. their curricula vitae) will be filed in the 
ISF.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of clinical trial monitors (CTM), Clinical 
Research Associates, and investigators of participating trial sites.
The non-labelled trial medication will be provided by the
 
The radiolabelled trial medication (intravenous and oral solution) will be provided by
 
Safety laboratory tests will be performed by the local laboratory of the trial site 
The analyses of unlabelled BI 1265162 concentrations in plasma will be performed at the 
Department of
or at a suitable contract research organisation.
The analyses of labelled BI 1265162 
 will
be conducted at 
Metabolic identification will be performed at the Department of
On-site monitoring will be performed by BI or a contract research organisation appointed by
BI.
Data management and statistical evaluation will be done by BI or a contract research
organisation appointed by BI according to BI SOPs. Tasks and functions assigned in order to 
organise, manage, and evaluate the trial are defined according to BI SOPs. A list of 
responsible persons and relevant local information can be found in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P96-3855
Ramsey BW. Management of pulmonary disease in patients with cystic 
fibrosis. N Engl J Med 1996;335(3):179-188.
P11-05794
Poole P, Black PN. Mucolytic agents for chronic bronchitis or chronic 
obstructive pulmonary disease (review). Cochrane Database Syst Rev 
2010(2).
P13-14084
Mogayzel PJ, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, 
Hoag JB, Lubsch L, Hazle L, Sabadosa K, Marshall B, Pulmonary Clinical 
Practice Guidelines Committee. Cystic fibrosis pulmonary guidelines: 
chronic medications for maintenance of lung health. Am J Respir Crit Care 
Med 2013;187(7):680-689.
R01-1277
Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care 
Med 1996;154:1229-1256.
R06-1037
Guidance for industry: estimating the maximum safe starting dose in initial 
clinical trials for therapeutics in adult healthy volunteers. U.S. Department 
of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER); 2005.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R12-1392
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI,
Kusek JW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI). A new equation to
estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604-612.
R15-0594
European Medicines Agency (EMA). ICH guideline M3(R2) on non-
clinical safety studies for the conduct of human clinical trials and marketing
authorisation for pharmaceuticals: step 5 (December 2009,
EMA/CPMP/ICH/286/1995). http://www.ema.europa.eu/docs/en_GB/
document_library/Scientific_guideline/2009/0 9/WC500002720.pdf (access 
date: 5 February 2015); London: European Medicines Agency (EMA); 
2009.
R15-0689
O'Riordan TG, Donn KH, Hodsman P, Ansede JH, Newcomb T, Lewis SA,
Flitter WD, White VS, Johnson MR, Montgomery AB, Warnock DG, 
Boucher RC. Acute hyperkalemia associated with inhalation of a potent 
ENaC antagonist: phase 1 trial of GS-9411. J Aerosol Med Pulm Drug 
Deliv 2014;27(3):200-208.
R15-1331
Elashoff JD. nQuery Advisor version 7.0 user's guide.
http://www.statsols.com/wp-
content/uploads/2013/10/nQ70_version2_manual.pdf 
(access date: 20 March 2015) ; Los Angeles: Statistical Solutions; 2007.


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R15-3034
Chronic respiratory diseases: burden of COPD.
http://www.who.int/respiratory/copd/burden/en/ (access date: 11 June
2015); World Health Organization; 2015.
R15-3219
International Commission on Radiological Protection (ICRP). 2007
Recommendations of the International Commission on Radiological
Protection (users edition): abstract. http://www.icrp.org/publication
.asp?id=ICRP%20Publication%20103%20(Users%20Editi on) (access date:
24 June 2015) ; (ICRP Publication; 103 (Users Edition)) International 
Commission on Radiological Protection (ICRP); 2007.
R15-4955
Clunes MT, Boucher RC, Virtual Lung Group. Cystic fibrosis: the
mechanisms of pathogenesis of an inherited lung disorder. Drug Discov
Today Dis Mech 2007;4(2):63-72.
R15-4984
Elborn JS, Shale DJ. Lung injury in cystic fibrosis. Thorax 1990;45:970-
973.
R15-5349
Knowles MR, Church NL, Waltner WE, Yankaskas JR, Gilligan P, King 
M, Edwards LJ, Helms RW, Boucher RC. A pilot study of aerosolized
amiloride for the treatment of lung disease in cystic fibrosis. N Engl J Med 
1990;322(17):1189-1194.
R15-5485
Matthys H, Koehler D. Bronchial clearance in cystic fibrosis. Eur J Respir 
Dis Suppl 1986;146:311-318.
R15-5486
Clarke LL, Grubb BR, Gabriel SE, Smithies O, Koller BH, Boucher RC.
Defective epithelial chloride transport in a gene-targeted mouse model of 
cystic fibrosis. Science 1992;257(5073):1125-1128.
R15-5487
Koehler D, App E, Schmitz-Schumann M, Wuertemberger G, Matthys H. 
Inhalation of amiloride improves the mucociliary and the cough clearance 
in patients with cystic fibroses. Eur J Respir Dis Suppl 1986;146:319-326.
R15-5503
Walters S, Mehta A. Epidemiology of cystic fibrosis. In: Hodson M,
Geddes D, Bush A, editors. Cystic fibrosis. 3rd ed. London: Hodder 
Arnold; 2007. p. 21-45.
R15-5505
Pons G, Marchand MC, D'Athis P, Sauvage E, Foucard C, Chaumet-
Riffaud P, Sautegeau A, Navarro J, Lenoir G, Amiloride-AFLM 
Collaborative Study Group. French multicenter randomized double-blind
placebo-controlled trial on nebulized amiloride in cystic fibrosis patients. 
Pediatr Pulmonol 2000;30(1):25-31.
R15-5507
Mall MA, Button B, Johannesson B, Zhou Z, Livraghi A, Caldwell RA, 
Schubert SC, Schultz C, O'Neal WK, Pradervand S, Hummler E, Rossier 
BC, Grubb BR, Boucher RC. Airway surface liquid volume regulation
determines different airway phenotypes in Liddle compared with
betaENaC-overexpressing mice. J Biol Chem 2010;285(35):26945-26955.


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R15-5546
Genes and human disease: monogenic diseases.
http://www.who.int/genomics/public/geneticdiseases/en/index2.html#CF
(access date: 28 October 2015) ; Geneva: World Health Organization
(WHO); 2015.
R15-5599
Graham A, Hasani A, Alton EWFW, Martin GP, Marriott C, Hodson ME, 
Clarke SW, Geddes DM. No added benefit from nebulized amiloride in
patients with cystic fibrosis. Eur Respir J 1993;6:1243-1248.
R17-1997
Rowe SM, Verkman AS. Cystic fibrosis transmembrane regulator
correctors and potentiators. Cold Spring Harb Perspect Med 
2013;3:a009761.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c16304878
 Investigator`s Brochure BI-1265162 Cystic fibrosis and COPD.
Current version.
c22991563
: Safety, tolerability and 
pharmacokinetics of single rising inhaled doses of BI 1265162 in healthy 
male volunteers in a partially randomised, single blind, placebo-controlled 
trial 1399-0001 12 Oct 2018.
c25192159
 Clinical trial protocol radiation burden calculation report
1346.16 14 May 2018.
n00256432
: Effect of BI01265162 on inhibition of water 
absorption from the airway epithelium in rats 2017-i-r-disease-positioning-
report3 23 May 2019.
n00259639
: Investigations on the in vitro 
metabolism of [ C]BI 1265162 and assessment of the human enzymes that 
are involved A426/17LU B6043 12 Jan 2018.
n00260429
BI 1265162: Escalating dose intravenous (30-min infusion) toxicity study 
in Beagle dogs (non-GLP) 18B015 13 Aug 2018.
n00260481
BI 1265162: Escalating dose oral (gavage) toxicity study in Beagle dogs
18B016 16 Nov 2018.
n00260959
BI 1265162: 7-day intravenous (30-min infusion) toxicity 
study in Beagle dogs 18B027.
n00261317
 
BI 1265162: 7-day oral (gavage) 
toxicity study in Beagle dogs 18B020.


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n00264885
. BI 1265162: A 7 Day Toxicity 
Study by Oral Gavage in Rats 507798 18 Apr 2019.
n00264887
BI 1265162: A 7 Day Toxicity Study by 
Intravenous (30 minute) Infusion in Rats 507824 16 Apr 2019.
n00265043
: A Dose Range Finding Study of 
BI 1265162 by Oral Gavage and Intravenous Infusion in Rats 507384 
08 Mar 2019.
n00266134
Metabolite profiling in plasma after single inhalative 
administration of BI 1265162 to healthy volunteers B6460 13 Feb 2019.


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10.
APPENDICES
10.1
RADIO BURDEN CALCULATION


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
10 Feb 2020
EudraCT number
EU number
2019-003389-42
BI Trial number
1399-0013
BI Investigational Medicinal 
Product(s)
BI 1265162
Title of protocol
Investigation of metabolism and pharmacokinetics of 
BI 1265162 (C-14) after intravenous administration 
(Part 1) and investigation of metabolism and 
pharmacokinetics of BI 1265162 (C-14) after oral 
administration (Part 2) in healthy male subjects 
following a non-randomized, open-label, single-
dose, single arm per trial part mass balance design
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
Synopsis
Flow Chart 1 and foot note 9
Flow Chart 2 and foot note 10
Section 1.2.5
Section 2.2.2.3
Section 3.3.3
Section 5.2.3, Table 5.2.3: 1
Section 5.3.2.1
Section 5.3.2.2
Description of change
Correction of typographical and factual errors as 
well as inconsistencies
Rationale for change
Correction of typographical and factual errors as 
well as inconsistencies


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BI Trial No.: 1399-0013
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Trial Protocol
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001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
11.2
GLOBAL AMENDMENT 2
Date of amendment
25 February 2020
EudraCT number
EU number
2019-003389-42
BI Trial number
1399-0013
BI Investigational Medicinal 
Product(s)
BI 1265162
Title of protocol
Investigation of metabolism and pharmacokinetics of 
BI 1265162 (C-14) after intravenous administration 
(Part 1) and investigation of metabolism and 
pharmacokinetics of BI 1265162 (C-14) after oral 
administration (Part 2) in healthy male subjects 
following a non-randomized, open-label, single-
dose, single arm per trial part mass balance design
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
Flow Chart 2
Section 5.3.2
Section 5.3.3
Section 5.6.1
Description of change
Logistical updates regarding PK, total radioactivity 
and metabolic samples. 
Typological correction in Flow Chart 2: Safety Lab 
Panel B, ECG and vital signs moved from day 30 to 
day 37 (identically to Flow Chart 1).
Rationale for change
Logistical reasons as well as typological and stylistic
corrections.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29266057
3.0
clinical-trial-protocol-version-03
Investigation of metabolism and pharmacokinetics of BI 1265162 (C-14) after
intravenous administration (Part 1) and investigation of metabolism and
pharmacokinetics of BI 1265162 (C-14) after oral administration (Part 2) in healthy
male subjects following a non-randomized, open-label, single-dose, single arm per
trial part mass balance design
Author-Trial Clinical
Pharmacokineticist
26 Feb 2020 09:39 CET
Author-Trial Statistician
26 Feb 2020 10:16 CET
Author-Clinical Trial Leader
26 Feb 2020 14:58 CET
Approval-Therapeutic Area Head
27 Feb 2020 11:43 CET
Verification-Paper Signature
Completion
27 Feb 2020 14:31 CET
Approval-Team Member Medicine
27 Feb 2020 22:27 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29266057
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c31568264-01
BI Trial No.:
1399-0013
Title:
Investigation of metabolism and pharmacokinetics of BI 1265162 
(C-14) after intravenous administration (Part 1) and investigation of 
metabolism and pharmacokinetics of BI 1265162 (C-14) after oral 
administration (Part 2) in healthy male subjects following a non-
randomized, open-label, single-dose, single arm per trial part mass 
balance design.
(including Protocol Amendments No.1-2 [c29266057-03])
Investigational
Product:
BI 1265162
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
18 MAR 2021 SIGNED
Version:
1
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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
5.3.3
Safety endpoints...................................................................................................10
5.4
OTHER VARIABLES ........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS...........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED ...........................................................................13
6.5
POOLING OF CENTRES..................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................14
7.
PLANNED ANALYSIS ......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........17
7.2
CONCOMITANT DISEASES AND MEDICATION......................................17
7.3
TREATMENT COMPLIANCE ........................................................................18
7.4
PRIMARY ENDPOINTS ...................................................................................18
7.4.1
Primary analysis of the primary endpoints ......................................................18
7.5
SECONDARY ENDPOINTS .............................................................................18
7.5.1
Key secondary endpoints ....................................................................................18
7.5.2
(Other) Secondary endpoints .............................................................................18
7.7
EXTENT OF EXPOSURE .................................................................................19
7.8
SAFETY ANALYSIS..........................................................................................19
7.8.1
Adverse Events ....................................................................................................19
7.8.2
Laboratory data...................................................................................................20
7.8.3
Vital signs.............................................................................................................21
7.8.4
ECG ......................................................................................................................21
7.8.5
Others ...................................................................................................................21


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10.
HISTORY TABLE..............................................................................................24


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................11
Table 6.3: 1
Subject sets analysed ........................................................................................14
Table 10: 1
History table .....................................................................................................24


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
ALT
Alanine transaminase
AST
Aspartate transaminase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BMI
Body mass index
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DILI
Drug induced liver injury
fefaeces,0-t2
fraction of (C-14)-radioactivity excreted in faeces as percentage of the 
administered dose over the time interval from 0 to the last quantifiable time 
point
feurine,0-t2
fraction of (C-14)-radioactivity excreted in urine as percentage of the 
administered dose over the time interval from 0 to the last quantifiable time 
point
fevomit,0-t2
fraction of (C-14)-radioactivity excreted in vomit as percentage of the 
administered dose over the time interval from 0 to the last quantifiable time 
point
gCV
Geometric coefficient of variation
gMean
Geometric mean
LLT
Lower level term
IQRMP
Integrated Quality and Risk Management Plan
iv
intravenous
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
Number non-missing observations
P10
10th percentile


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Term
Definition / description
P90
90th percentile
po
Oral
PKS
Pharmacokinetic parameter analysis set
Q1
1st quartile
Q3
3rd quartile
qd
Once daily
RAGe
Report Appendix Generator system
REP
Residual effect period
SD
Standard deviation
SOC
System organ class
TS
Treated set
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
Study data (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or higher, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including SAS® (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number of 
SAS®-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Recruitment stopped after Part 1 due to COVID-19 pandemic. Before the planned re-start of 
recruitment into Part 2, the study was prematurely stopped as Boehringer Ingelheim decided 
not to further develop the compound BI 1265162.
Consequently, only a subset of the analyses planned in the CTP will be performed, and only 
data from Part 1 (intravenous administration of the compound) will be analysed. For all study 
endpoints, listings will be provided. Tables will be provided for disposition, demography and 
adverse events (including one of the secondary endpoints) as well as for mass balance and PK 
endpoints (including the primary and all further secondary endpoints). For variables regarding 
medical history, concomitant medication and non-drug procedures, exposition, protocol 
deviations, laboratory data, vital signs and local tolerability, only listings will be provided and 
no descriptive analysis will be carried out.
In CTP section 7.3 the following was defined: Important protocol deviation (iPD) categories 
will be specified in the Integrated Quality and Risk Management Plan, iPDs will be identified 
no later than in the Report Planning Meeting, and the iPD categories will be updated as 
needed. 
Due to SOP changes, the iPD categories are no longer available in the IQRM plan but 
included in an iPD specification file (3). The iPD categories originally defined in IQRM plan 
were transferred to the iPD specification file. Minor changes regarding the iPD categories 
were performed only.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP:
The following parameters will be determined:
(Part 1 & 2) Mass balance recovery of total (C-14) BI 1265162-radioactivity in urine and 
faeces (and vomit, if applicable). Amount of radioactivity excreted as a percentage of the 
administered single intravenous or oral dose of BI 1265162 (C-14) in

Urine - feurine, 0-t2 (fraction of (C-14)-radioactivity excreted in urine as percentage of the 
administered dose over the time interval from 0 to the last quantifiable time point)

Faeces - fefaeces, 0-t2 (fraction of (C-14)-radioactivity excreted in faeces as percentage of 
the administered dose over the time interval from 0 to the last quantifiable time point)

Vomit - fevomit, 0-t2 (fraction of (C-14)-radioactivity excreted in vomit as percentage of 
the administered oral dose over the time interval from 0 to the last quantifiable time 
point) - if feasible and appropriate
The timeframe for determination of these endpoints depends on the time of discharge of each 
subject, based on radioactivity excretion, and is predicted to vary between 9 and 38 days after 
drug administration.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been specified in the 
protocol.
5.2.2
Secondary endpoints
Section 2.1.3 of the CTP:
The following parameters will be determined:
(Part 1 & 2) Assessment of the pharmacokinetics of a single intravenous or oral dose of 
BI 1265162 (C-14) by means of the following parameters for total (C-14) BI 1265162-
radioactivity, BI 1265162 and metabolite M582 (1) in plasma:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
(Part 1 & 2) Evaluation of safety and tolerability of a single intravenous or oral dose of 
BI 1265162 (C-14) by means of

Percentage of subjects with drug related adverse events (AEs) including clinically 
relevant findings from the physical examination


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5.3.3
Safety endpoints
Section 2.2.2.5 of the CTP:
Further safety and systemic tolerability endpoints:

Safety laboratory tests

12-lead electrocardiogram (ECG), and

Vital signs (blood pressure [BP], pulse rate [PR])

Physical examination
Additionally, local tolerability will be assessed in Part 1 with intravenous administration (see 
CTP section 2.2.2.4). 
5.4
OTHER VARIABLES
Section 5.2.1 of the CTP: At screening, the medical examination will include demographics, 
height and body weight, smoking and alcohol history (results not mandatory to be entered 
into CRF or to be reported), 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.
Age [years] will be determined as the difference between year of informed consent and year 
of birth.
BMI will be calculated as weight [kg] / (0.01 * height [cm])2.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatment and selection 
of doses, please see CTP, Section 4.
The study consists of 2 trial parts, Part 1 with intravenous administration and Part 2 with oral 
administration of the study medication. Each part follows a non-randomized, open-label, 
single-dose, single arm, mass balance design. It was planned that 7 healthy male subjects will 
enter each trial part, i.e. 14 subjects in total. Subjects will be treated with a single dose of the 
study medication as outlined in Table 6.1: 1 below.   
Table 6.1: 1
Treatments and labels used in the analysis
Part
Treatment
Short label
1
BI 1265162 (C-14) solution for infusion, 5 mcg/mL, 50mcg, iv, qd
BI-C-14 iv
2
BI 1265162 (C-14) oral solution, 0.25 mg/mL, 5mg, po, qd
BI-C-14 po
The study was prematurely stopped after Part 1 (intravenous administration of BI 1265162 
(C-14)). Therefore, all analyses will be performed for the first part only (n=7).
Section 1.2.6 of the CTP: The Residual Effect Period (REP) of BI 1265162 is 7 days. This is 
the period after the last dose with measurable drug levels and/ or pharmacodynamics effects 
is still likely to be present.
As the REP refers to the non-labelled BI agent but the investigational drug is radiolabelled, 
the definition of treatment-emergent AEs will be based on discharge from study site (see CTP 
Section 7.3.4). According to the study protocol, subjects will be discharged from study site at 
Day 9 at the earliest. In this discontinued trial, all subjects were discharged from study site at 
Day 9. Hence, the following study phases will be defined for the analysis of AEs:

Screening (ranging from 0:00 h on day of informed consent until date/time of first 
administration of study medication)

On treatment (ranging from the first time of administration of study medication until 
0:00h on the day after discharge from study site at Day 9)

Follow-up (F/U) (ranging from 0:00h on the day after discharge from study site at 
Day 9 until 0:00 h on the day after trial termination date)


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Section 7.3.4 of the CTP: Note that AEs occurring after the last per protocol contact but 
entered before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
The following AE displays will be provided in the report:
Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT) of the CTR
displays:
In these displays, the on-treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening and Follow-up period will not be included in this analysis.
Tables of AEs will present results by the above mentioned on-treatment phase.
In Section 15.4 and Appendix 16.2 (Listings) of the CTR displays, screening and follow-up 
periods will be included and no totals will be provided.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewers guide. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects.
Categories which are considered to be iPDs in this trial were defined in the integrated quality
and risk management plan (IQRMP) prior to trial initiation. The list of iPD categories was 
transferred into the iPD specification file (due to changes in the SOP) (3). Within this transfer 
some minor adaptations were done to comply with new naming conventions and 
categorisations.
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (RPM). At this meeting, all 
manual deviations identified at the sites by the CRAs and deviations too complex to program 
will be reviewed by the trial team to decide which are considered important. For definition of 
important protocol deviations (iPD), and for the process of identification of these, refer to the 
Boehringer Ingelheim (BI) SOP "Identify and Manage Important Protocol Deviations (iPD)" 
(2).
IPDs will be identified no later than in the Report Planning Meeting. If any iPDs are 
identified, they are to be summarised into categories and will be captured in the decision log 
and in the iPD specification file (3). The iPD categories will be updated as needed. The 
decision on exclusion of subjects from analysis sets will be made after discussion of 
exceptional cases and implications for analyses.
The iPDs will be listed.


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6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP: Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were entered and treated 
with one dose of trial drug. The treated set will be used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects from the 
treated set (TS) who provide at least one pharmacokinetic endpoint that was defined 
as primary or secondary and was not excluded due to a protocol deviation relevant to 
the evaluation of pharmacokinetics or due to pharmacokinetic non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Descriptive analyses of 
pharmacokinetic parameters will be based on the PKS.
[…]
Plasma, urine and faeces concentration data and parameters of a subject will be included in
the statistical pharmacokinetic analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of pharmacokinetics (to be decided no later than in 
Report Planning Meeting) or due to pharmacokinetic non-evaluability (as revealed during 
data analysis, based on the criteria specified below). Exclusion of a subject’s data will be 
documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma and urine concentrations and/ or parameters of a subject will be considered as non-
evaluable, if for example

Missing samples/ concentration data at important phases of pharmacokinetic 
disposition curve
Plasma/urine concentration data and parameters of a subject which is flagged for exclusion
will be reported with its individual values but will not be included in the statistical analyses.
The descriptive analysis of PK concentrations and endpoints will be based on the ADS ADPC 
as described in Section 7.


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Table 6.3: 1
Subject sets analysed
Subject set
Endpoint/data description
TS
PKS
Primary endpoints
X
Safety parameters (including secondary safety endpoint)
X
Secondary 
 endpoints
X
Demographic/baseline parameters
X
Important protocol deviations
X
Disposition
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see BI-KMED-BDS-
HTG-0035 (4)).
Missing data and outliers of PK data are handled according to BI standards (see BI-KMED-
TMCP-MAN-0012 (5) and BI-KMED-TMCP-MAN-0014 (6).
Missing baseline laboratory values will be imputed by the respective screening values.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before trial medication administration.
Section 6.1 of the CTP: Exact times of measurements outside the permitted time windows 
will be documented. The acceptable time windows for screening and the end of trial 
examination are provided in the CTP Flow Chart.


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Trial measurements and assessments scheduled to occur ‘before’ trial medication
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration. 
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 30 minutes for the first 4 hours after drug administration and ± 45 minutes 
thereafter.
According to the flow chart of the CTP, after day 9 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 hours to the planned time.
Adherence to time windows will be checked via the consistency check listings at the RPM.
Unscheduled measurements of laboratory data and vital signs data will be assumed to be 
repeat measurements of the most recent scheduled measurement (e.g. for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement.


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Descriptive data analysis of PK endpoints and concentrations (including mass balance 
endpoints) will be performed by the department 
 at
and will be presented in Section 15.6 of the CTR.
The format of the listings and tables will follow the BI standards (see BI-KMED-BDS-HTG-
0045 (7)) with the exception of those generated for PK-calculations following BI standards 
for PK/PD analysis (8).
The individual values of all subjects will be listed, sorted by treatment group, subject number, 
visit and actual treatment (if appropriate). 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
The data format for descriptive statistics of concentrations will be identical to the data format 
of the respective concentrations. The descriptive statistics of PK parameters will be 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.


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Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%). Percentages 
will be rounded to one decimal place and will be based on all subjects in the respective 
subject set whether they have non-missing values or not. The category 'missing' will be 
displayed only if there are actually missing values.
Exclusion of PK parameters
The ADS ADPP (PK parameters) contains column variables indicating inclusion/exclusion 
(APEXC) of a PK parameter and an analysis flag comment (APEXCO). All analyses based on 
the PKS will include parameters if they are not flagged for exclusion that is APEXC is equal 
to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC and ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation 
 
) only; the value is included for all other 
analyses.
Further details are given in BI-KMED-TMCP-MAN-0014 “Noncompartmental 
Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies” (6) and BI-KMED-
TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD Data Files” (9).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics for demographics are planned for this section of the report, based 
on the TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded using the latest version of the coding system of the 
Medical Dictionary for Drug Regulatory Activities (MedDRA). Medications will be coded 
using the latest version of the World Health Organization Drug Dictionary (WHO-DD). The 
coding version number will be displayed as a footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.


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The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the trial centre under supervision of the investigating physician or a designee. The 
measured plasma concentrations and/ or urinary excretion of trial medication will provide 
additional confirmation of compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM/DBLM (see Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
7.4.1
Primary analysis of the primary endpoints
Section 7.3.1 of the CTP: All parameters will be calculated and analysed descriptively.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoints
Section 7.3.2 of the CTP: Secondary endpoints (…) will be assessed statistically using the 
same methods as described for the primary endpoints.


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7.7
EXTENT OF EXPOSURE
The date and time of drug administration will be listed for each patient.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
The safety data for treated patients who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA. 
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in “Analysis and Presentation of Adverse Event Data from Clinical Trials – Display 
Template” [BI-KMED-BDS-HTG-0041] (10) and [BI-KMED-BDS-HTG-0066] (11). All 
analyses of AEs will be based on the number of subjects with AEs and not on the number of 
AEs.
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to ‘screening’, ‘on treatment’ or ‘follow-up’ phases as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 1. 
According to the clinical study protocol, adverse events of special interest (AESI) will be 
analysed:
Section 5.2.6.1.4 of the CTP: The following are considered as AESIs:

A confirmed elevation of serum potassium > upper limit of normal (ULN) in non-
haemolysed blood.

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory
parameters:
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine transaminase) 
≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold ULN measured 
in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the
eCD. In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure that these 
parameters are analysed, if necessary in an unscheduled blood test. Should the results 
meet the criteria of hepatic injury alert, the procedures described in the DILI checklist 
should be followed.


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According to ICH E3 (12), in addition to Deaths and serious adverse events, ‘other
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced 
or interrupted). An overall summary of adverse events will be presented.
An overall summary of AEs (including number of patients with any AE, drug related AEs, 
AESIs, serious AEs and drug related serious AEs) will be presented. 
The frequency of subjects with AEs will be summarised by treatment, primary system organ
class and PT. The MedDRA version number will be displayed as a footnote in the respective 
outputs. Separate tables will be provided for subjects with serious AEs, for subjects with 
drug-related AEs, for subjects with drug-related serious adverse events and for subjects with 
AESIs. In addition, the frequency of subjects with AEs will be summarised by treatment, 
worst intensity, primary system organ class (SOC) and preferred term (PT).
The SOC and PTs will be sorted by total frequency (within SOC).
In addition, frequencies of patients with non-serious AEs that had an incidence of > 5% in at 
least one study part will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
[BI-KMED-BDS-HTG-0042] (13). 
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possibly 
clinically significant will be flagged in the data listings.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significantly 
abnormal or not (at the RPM at the latest).


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7.8.3
Vital signs
For vital signs (blood pressure and pulse rate), listings including change from baseline will be 
presented by planned time point based on the last value of the subject at that planned time 
point (or assigned to that planned time point).
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
Clinically relevant abnormal findings will be reported as adverse events. No separate listing 
of ECG will be prepared.
7.8.5
Others
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of study drug) or as AE and will be
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.
Local tolerability
Listings of defined local adverse events will be presented for Part 1.


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