Conditions: Healthy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: yes

Brief summary:
The main objectives of the study are as follows:

* To assess the mass balance recovery of (C-14) BI 730357-radioactivity (also expressed as 14C-BI 730357-EQ) in urine and faeces after a single oral dose of 50 mg BI 730357 base (BS) (C-14) in healthy male subjects
* To provide plasma, urine, and faecal samples for metabolite profiling and structural identification

Detailed description:

Arms:
arm 1: All participants were administered an oral single dose of 50 milligram (mg) BI 730357 containing \[C-14\] BI 730357 base (BS) (pure 14C-labelled "hot" drug substance) and BI 730357 BS (unlabelled "cold" drug substance). This mixture corresponds to the warm substance BI 730357 BS (C-14) containing a radioactive dose of approximately 3.7 MegaBecquerel (MBq), (100 microcurie (µCi)), and was administered in a solution of 10 milliliter (mL) volume with 240 mL of water after an overnight fast of at least 10 hours (h).

Interventions: intervention 1: BI 730357 mixed with [C-14]BI 730357 BS
Intervention descriptions: intervention 1: Oral Solution

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c22159106-02
EudraCT No.:
BI Trial No.:
2018-001837-41
1407-0031
BI Investigational
Product:
BI 730357
Title:
A phase I, open-label, single-dose trial to investigate metabolism and 
pharmacokinetics of BI 730357 BS (C-14) administered as oral 
solution in healthy male volunteers
Lay Title:
A study in healthy men to test how BI 730357 is processed by the body
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax: 
Principal Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 1))
Version and Date:
Version: 2.0
Date: 25 September 2018
Page 1 of 69
Proprietary confidential information
© 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 730357
Protocol date:
Trial number:
Revision date:
25 September 2018
27 July 2018
1407-0031
Title of trial:
A phase I, open-label, single-dose trial to investigate metabolism and 
pharmacokinetics of BI 730357 BS (C-14) administered as oral solution in healthy 
male volunteers
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate the basic pharmacokinetics of BI 730357 and [14C]-radioactivity, 
including mass balance, excretion pathways and metabolism following a single oral 
dose of 50 mg BI 730357 BS (C-14) given to healthy male volunteers
Methodology:
Open-label, single dose, non-randomized, single period design
No. of subjects: 
total entered:
6*
each treatment:
6*
* In case a subject vomits within 8 hours after administration of trial drug on Day 1, 
additional subjects may be entered and dosed in order to have 6 evaluable subjects. 
Thus, the actual number of subjects entered may increase up to 8.
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 65 years, body mass index (BMI) of 18.5 to 
29.9 kg/m2
Test product:
BI 730357 BS (C-14) oral solution
dose:
50 mg

In 10 mL oral solution (5 mg/mL)

containing a radioactive dose of approximately 3.7 MBq (100 µCi)
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h
Comparator product:
Not applicable
Duration of treatment: Single dose


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 730357
Protocol date:
Trial number:
Revision date:
25 September 2018
27 July 2018
1407-0031
Criteria for
pharmacokinetics:
Primary endpoints:
Mass balance recovery of total [14C]-radioactivity in urine and faeces: 
Amount of radioactivity excreted as a percentage of the administered dose (fe0-t2) for 
urine and faeces, feurine, 0-t2 and fefaeces, 0-t2
Secondary endpoints: 
Assessment of the pharmacokinetics of an oral solution formulation of BI 730357 BS
(C-14) by calculation of the following parameters for total [14C]-radioactivity and BI 
730357 in plasma: Cmax and AUC0-tz
Criteria for safety:
Adverse events (AEs) including clinically relevant findings from the physical 
examination, safety laboratory tests, 12-lead electrocardiogram (ECG), vital signs 
(blood pressure [BP], pulse rate [PR])
Statistical methods:
Descriptive statistics and graphical displays


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FLOW CHART
Visit
Day
Planned time (relative to 
drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood / plasma
2
PK urine
6
PK faeces
7
Blood sampling for 
metabolic profiling16
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 9
1
-21 to -
1
Screening (SCR)1
x
x
x
2
-2
-48:00
08:00
x14
▲
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
-1
-18:00
14:00
Admission to trial site
x5
x
-14:00
18:00
Light Supper (voluntary)
-10:30
21:30
Snack (voluntary)17
1
-2:00
06:00
x3
x3,15
x3
x3
x3
0:00
08:00
Drug administration
▲
▲
0:30
08:30
x
│
│
1:00
09:00
x
│
│
x
1:30
09:30
x
│
│
2:00
10:00
240 mL fluid intake
x8
x
│
│
x
4:00
12:00
240 mL fluid intake, thereafter lunch4
x8
x
┼
│
x
x
x
8:00
16:00
Snack (voluntary)4
x
┼
│
x
11:00
19:00
Dinner
│
│
12:00
20:00
x8
x
┼
│
x
x
x
2
24:00
08:00
x8
x
┼
┼
x
x
3
48:00
08:00
x
┼
┼
x
4
72:00
08:00
x
┼
┼
x
5
96:00
08:00
┼
┼
6
120:00
08:00
x
┼
┼
7
144:00
08:00
┼
┼
8
168:00
08:00
x
x
┼
┼
9
192:00
08:00
┼
┼
10
216:00
08:00
x
┼
┼
11
240:00
08:00
┼
┼
12
264:00
08:00
x
┼
┼
13
288:00
08:00
┼
┼
14
312:00
08:00
x
┼
┼
15
336:00
08:00
Discharge from trial site9
x
▼
▼
x
x
20
461:00
13:00
Start home collection
▲
┼
▼
21
485:00
13:00
Admission to trial site11,12
x
▲
▼
22
509:00
13:00
Discharge from trial site11
27
629:00
13:00
Start home collection
▲
┼
▼
28
653:00
13:00
Admission to trial site11,12
x
▲
▼
29
677:00
13:00
Discharge from trial site11
34
797:00
13:00
Start home collection
▲
┼
▼
35
821:00
13:00
Admission to trial site11,12
x
x
▲
▼
36
845:00
13:00
Discharge from trial site11
41
965:00
13:00
Start home collection
▲
42
989:00
13:00
Admission to trial site11,12
x
▲
┼
43
1013:00
13:00
Discharge from trial site11
▼
▼


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48
1133:00
13:00
Start home collection
▲
┼
▼
│
▼
49
1157:00
13:00
Admission to trial site11,12
x
▲
▼
50
1181:00
13:00
Discharge from trial site11
3
16 to 
50
End-of-trial (EoTrial) 
examination10,13
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
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 730357
 in plasma; [14C]-radioactivity in whole blood and 
plasma (see Section 5.5.2.2). Blood sampling for an individual subject can be stopped if [14C]-radioactivity in plasma is 
below limit of detection (<LLOQ 10 dpm/mL) at two consecutive sampling time points for this subject (earliest 
stopping after 168 h).
3. 
The time is approximate; the respective procedure is to be performed and completed within 3 h 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 lab including urine drug and alcohol screening 
6.
Urine collection intervals (for PK/[14C]-radioactivity assessment and metabolic profiling; planned time): on Day -1 or 
Day 1 predose (blank) sample, on Day 1 prior to start of urine collection voiding of the bladder, 0-4 , 4-8, 8-12, 12-24,
24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264, 264-288, 288-312 and 312-336 
hours after administration of BI 730357 BS (C-14). Thereafter, if warranted, 24 h collections are to be performed every 
7 days starting on Day 21. Urine sampling for PK/[14C]-radioactivity will be stopped when release criteria for 
radioactivity recovery (see Section 3.1) have been met (earliest stopping on Day 15). “┼” means end of last collection 
interval, start of following collection interval. For details on sample usage please refer to Section 5.5.2.5. 
7.
All stools (for [14C]-radioactivity and metabolic profiling) will be collected quantitatively in portions up to 336 hours 
(sampling intervals of 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264, 264-
288, 288-312 and 312-336 hours) after administration of BI 730357 BS (C-14). Thereafter, if warranted, 24 h 
collections are to be performed every 7 days starting on day 20. A blank sample will be collected before drug 
administration on Day -2, Day -1 or Day 1 (see Section 5.5.2.6). Faeces sampling for [14C]-radioactivity assessment will
be stopped when the release criteria for radioactivity recovery (see Section 3.1) have been met (earliest stopping on day 
15). “┼” means end of last collection interval, start of following collection interval. For details on sample usage please 
refer to Section 5.5.2.6.
8. 
9.
AEs and concomitant therapies will be recorded throughout the trial; during in-house days subjects will be specifically 
asked for twice daily.
10. End-of-trial (EoTrial) examination to be performed within 1 to 7 days after last discharge from the study centre, or, if all 
once-weekly 24 h sampling periods are needed, prior to discharge on Day 50. End-of-trial 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 h to the planned time.
12. Subjects are to collect faeces at home within 24 h intervals before admission to once-weekly in-house collection 
intervals. Home collection intervals: Day 20-21, 27-28, 34-35, 41-42, and 48-49. If faeces are collected in the 
subsequent in-house collection interval, faeces collected at home will be discarded. If no faeces is collected in the 
subsequent in-house collection interval (no defecation), faeces collected at home will be used instead for analysis.
13. For definition of the individual subject’s end of trial see Section 6.2.3
14. Subjects will collect a pre-dose faeces sample at home or at the site in specific containers provided by 
15. Including pharmacogenomics sample
16. 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. 
17. To be consumed within 30 min to allow 10 h fasting prior to drug administration.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................13
1.2.1
Nonclinical data.....................................................................................13
1.2.1.1
Efficacy and selectivity............................................................13
1.2.1.2
Safety pharmacology ...............................................................14
1.2.1.3
Toxicology...............................................................................14
1.2.1.4
Non-clinical pharmacokinetics and metabolism......................16
1.2.2
Clinical Data..........................................................................................17
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 20
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................20
2.2
TRIAL OBJECTIVES.......................................................................................20
2.3
BENEFIT - RISK ASSESSMENT ...................................................................20
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 24
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................24
3.1.1
Administrative structure of the trial...................................................25
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................25
3.3
SELECTION OF TRIAL POPULATION ......................................................26
3.3.1
Main diagnosis for study entry............................................................26
3.3.2
Inclusion criteria...................................................................................26
3.3.3
Exclusion criteria ..................................................................................27
3.3.4
Removal of subjects from therapy or assessments.............................28
3.3.4.1
Removal of individual subjects................................................28
3.3.4.2
Discontinuation of the trial by the sponsor..............................29
3.3.5
Replacement of subjects .......................................................................29
4.
TREATMENTS........................................................................................ 31
4.1
TREATMENTS TO BE ADMINISTERED....................................................31
4.1.1
Identity of BI investigational product.................................................31
4.1.2
Method of assigning subjects to treatment groups ............................31
4.1.3
Selection of doses in the trial................................................................31


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4.1.4
Drug assignment and administration of doses for each subject .......32
4.1.5
Blinding and procedures for unblinding ............................................32
4.1.6
Packaging, labelling, and re-supply ....................................................32
4.1.7
Storage conditions.................................................................................33
4.1.8
Drug accountability ..............................................................................33
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................34
4.2.1
Other treatments and emergency procedures....................................34
4.2.2
Restrictions............................................................................................34
4.2.2.1
Restrictions regarding concomitant treatment .........................34
4.2.2.2
Restrictions on diet and life style.............................................34
4.3
TREATMENT COMPLIANCE.......................................................................35
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 36
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................36
5.1.1
Endpoints of efficacy.............................................................................36
5.1.2
Assessment of efficacy...........................................................................36
5.2
SAFETY..............................................................................................................36
5.2.1
Endpoints of safety................................................................................36
5.2.2
Assessment of adverse events...............................................................36
5.2.2.1
Definitions of adverse events...................................................36
5.2.2.2
Adverse event collection and reporting ...................................39
5.2.3
Assessment of safety laboratory parameters......................................41
5.2.4
Electrocardiogram................................................................................44
5.2.4.1
12-lead resting ECG.................................................................44
5.2.5
Assessment of other safety parameters...............................................45
5.2.5.1
Vital signs ................................................................................45
5.2.5.2
Medical examinations..............................................................45
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................46
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................46
5.5.1
Pharmacokinetic endpoints..................................................................46
5.5.1.1
Primary endpoints....................................................................46
5.5.1.2
Secondary endpoints................................................................46
5.5.2
Methods of sample collection...............................................................49
5.5.2.1
Sampling of whole blood and plasma......................................49
5.5.2.2
Sampling of whole blood and plasma for [14C]-radioactivity 
analysis in whole blood and plasma and quantification of BI 
730357 
...............................................50
5.5.2.3
Sampling of plasma for metabolic profiling............................50


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5.5.2.4
    
5.5.2.5
Urine sampling.........................................................................51
5.5.2.6
Faeces sampling.......................................................................52
5.5.2.7
Collection of vomit ..................................................................52
5.5.2.8
Further investigations...............................................................52
5.5.3
Analytical determinations ....................................................................53
5.5.3.1
Analytical determinations of BI 730357
 
and BI 730357 urine concentrations ........................................53
5.5.3.3
Radiokinetic and Excretion Balance........................................53
6.
INVESTIGATIONAL PLAN.................................................................. 54
6.1
VISIT SCHEDULE............................................................................................54
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................54
6.2.1
Screening period....................................................................................54
6.2.2
Treatment period ..................................................................................54
6.2.3
End-of-trial period................................................................................55
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 56
7.1
STATISTICAL DESIGN – MODEL ...............................................................56
7.1.1
Objectives...............................................................................................56
7.1.2
Endpoints...............................................................................................56
7.1.3
Model......................................................................................................56
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................56
7.3
PLANNED ANALYSES....................................................................................56
7.3.1
Primary analyses...................................................................................57
7.3.2
Secondary analyses ...............................................................................57
7.3.3
Safety analyses.......................................................................................57
7.3.4
Interim analyses ....................................................................................58
7.3.5
Pharmacokinetic analyses ....................................................................58
7.4
HANDLING OF MISSING DATA ..................................................................59
7.4.1
Safety......................................................................................................59
7.4.2
Blood/plasma/urine/faeces drug or [14C]-radioactivity 
concentration - time profiles ................................................................59
7.4.3
Pharmacokinetic parameters...............................................................59
7.5
RANDOMISATION ..........................................................................................59
7.6
DETERMINATION OF SAMPLE SIZE ........................................................60
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 61
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................61


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8.2
DATA QUALITY ASSURANCE .....................................................................61
8.3
RECORDS..........................................................................................................62
8.3.1
Source documents .................................................................................62
8.3.2
Direct access to source data and documents.......................................62
8.3.3
Storage period of records.....................................................................62
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................62
8.5
STATEMENT OF CONFIDENTIALITY.......................................................62
8.6
COMPLETION OF TRIAL..............................................................................63
9.
REFERENCES......................................................................................... 64
9.1
PUBLISHED REFERENCES...........................................................................64
9.2
UNPUBLISHED REFERENCES.....................................................................64
10. APPENDICES .......................................................................................... 66
10.1
RADIO BURDEN CALCULATION ...............................................................66
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 68


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
AS
ankylosing spondylitis
 
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
 
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BS
base
CA
Competent authority
CL
Total clearance of the analyte in plasma after intravascular administration
 
 
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central nervous system
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver injury
ECG
Electrocardiogram
EDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
fe0-t2
Fraction of administered drug (% of dose) excreted over the time interval 
from 0 to t2 (where t2 is the last quantifiable data point across all subjects)
 
 
hERG
Human-ether-à-go-go related gene


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hLXRα
human liver X receptor α
IB
Investigator’s brochure
IBD
inflammatory bowel disease
IC50
50% inhibitory concentration
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography tandem mass spectrometry
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NOA
Not analysed
NOAEL
No observed adverse effect level
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
PSA
psoriatic arthritis
PSO
Psoriasis
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
RORα
Retinoic acid related orphan receptor α (protein)
RORβ
Retinoic acid related orphan receptor β (protein)
RORγ
Retinoic acid related orphan receptor γ (full length protein)
RORγt
Retinoic acid related orphan receptor γt (splice variant of RORγ protein)
SAE
Serious adverse event
SCR
Screening
SOP(s)
Operating Procedure(s)
SRD
Single-rising dose
ss
(at) steady state
SUSAR
Suspected Unexpected Serious Adverse Reaction


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TDMAP
Trial Data Management and Analysis Plan
TMF
Trial master file
 
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vd
Volume of distribution
 


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1.
INTRODUCTION
BI 730357 is an antagonist at the retinoic acid-related orphan receptor γt (RORγt). It is being 
developed as an oral therapy for the treatment of patients with psoriasis (PsO) as well as 
psoriatic arthritis (PsA), ankylosing spondylitis (AS), asthma, and Crohn’s disease (CD). 
RORγ antagonism is a novel mechanism of action. 
This trial is a mass balance study that aims at an in-depth understanding of metabolism and
pharmacokinetics of BI 730357 including quantitative determination of elimination pathways 
and drug metabolites.
1.1
MEDICAL BACKGROUND
Retinoic acid-related orphan receptor γt (RORγt) is a nuclear hormone receptor/transcription
factor expressed in Th17 cells and in distinct subsets of lymphoid cells, including natural 
killer cells, innate lymphoid cells, and γT-cells. Upon cell activation, in response to 
multiple activation signals including cytokines and T cell receptor engagement, RORγt 
regulates the transcription of interleukin (IL)-17A, IL-17F, and IL-22 genes, and of IL-23 
receptor gene. Emerging clinical science indicates a pivotal role for the Th17 axis in the 
pathogenesis of PsO, and other immunologically-mediated diseases. By blocking RORγt-
mediated transcription of critical pro-inflammatory cytokines, and IL-23R, and consequently 
their downstream signaling, RORγt antagonism could prove efficacious in the treatment of 
Th17-mediated diseases [c09228382-06].
1.2
DRUG PROFILE
1.2.1
Nonclinical data


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1.2.1.2
Safety pharmacology
1.2.1.3
Toxicology


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1.2.1.4
Non-clinical pharmacokinetics and metabolism


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1.2.2
Clinical Data


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Clinical pharmacokinetics and metabolism
Clinical safety


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
This trial is intended to examine basic pharmacokinetics of BI 730357, its metabolite 
and [14C]-radioactivity, including mass balance, excretion pathways and 
metabolism following a single oral dose of BI 730357 BS (C-14) in healthy male volunteers.
The data are necessary for in-depth understanding of the pharmacokinetics of BI 730357 
including quantitative determination of elimination pathways and drug metabolites and are 
required for submission to regulatory authorities.
2.2
TRIAL OBJECTIVES
The main objectives of the study are as follows:

To assess the mass balance recovery of [14C]-radioactivity in urine and faeces after a
single oral dose of 50 mg BI 730357 BS (C-14) in healthy male subjects
The secondary objective of the study is as follows:
To determine PK parameters of [14C]-radioactivity, BI 730357
 after 
single dose oral administration of BI 730357 BS (C-14) in healthy male subjects 

To determine the routes and rates of elimination of BI 730357
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of BI 730357.
The subjects are exposed to the risks of the study procedures and the risks related to the 
exposure to the trial medication and the intake of BI 730357 BS (C-14).


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Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venipuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
Drug-related risks and safety measures
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety, see also Section 5.2.2.1, adverse events of special interest.
Risks related to BI 730357 administration
As the nature of the target and the mechanism of action of BI 730357 are well understood
from pre-clinical studies, comparable compounds have been tested by other companies before
(although not a lot of published data are available), and the animal models are believed to be 
predictive for the effects in humans, BI 730357 is not seen as a high-risk compound.
Single dose administration up to 400 mg BI 730357 under fasted conditions is supported by 
preclinical, as well as clinical safety data from first-in-human trial 1407.1 (see Section 1.2.2).
As with other immune-targeted therapies, impaired host defense is a theoretical target-related
toxicity, potentially resulting in increased risk of infection and/or malignancy. Th17 cells
play an important role in defense against extracellular bacteria and fungi at mucosal surfaces
[R16-3166, R16-3149]. IL-17 antagonists are associated with increased infections 
[R13-2643]. Homozygous, but not heterozygous RORγ knockout mice have a high incidence 
of T-cell lymphoma, thought to originate in the thymus [R16-2630]. While the translatability 
of the knockout phenotype to pharmacological RORγ antagonism and to humans is unknown,


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this raises the hypothetical concern for clinical T-cell lymphoma risk. The exact cause of T-
cell lymphomas in RORγ knockout mice is not fully understood, but changes in homeostasis
in the thymus, such as thymocyte apoptosis and proliferation, are thought to play a role. AEs
and SAEs consistent with malignancy, and specifically those representing lymphoma, are to
be carefully monitored and evaluated throughout the BI 730357 clinical development
program, and monitoring of peripheral blood lymphocyte subsets integrated into clinical trials.
Based on the data obtained with BI 730357 so far, and based on the fact that in the current 
study a single dose of 50 mg will be used, the increased risk of infection and/or malignancy is 
considered to be extremely small.
As with all drugs, the potential for hypersensitivity and allergic reactions has to be taken into
consideration when BI 730357 is administered.
Risks related to administration of [C-14]-labelled BI 730357
BI 730357 BS (C-14) is labelled with the isotope [14C], which is necessary for the purposes 
of this mass balance trial. Therefore, subjects will be exposed to ionizing radiation. The 
effective dose each subject receives from the administration of 3.7 MBq is approximately 
0.14 mSv (see Appendix 10.1).
The radioactive dose proposed for administration in the planned human ADME study of 
3.7 MBq is lower than the limit specified by:

WHO Category 1 (<0.5 mSv – within variations of natural background radioactivity),
and lower than the limit proposed by:

ICRP Category 2a (<1 mSv – risk defined as minor).
For biomedical investigations in order to study the disposition, metabolism and excretion of 
new chemical entities in a small group of healthy volunteers, an effective dose of 0.1-1.0 mSv 
is considered acceptable [R18-1905, R15-3219].
Although it is common sense that any increase in the amount of radiation absorbed carries the 
risk of developing delayed serious and possibly fatal conditions, the risk associated with the 
administered dose of radiation in this trial is small and considered acceptable. 
Summary of benefit-risk assessment
In the first-in-human trial 1407.1, administration of single doses up to 400 mg BI 730357
under fasted conditions was safe and well tolerated [c16462083-01]. In the current trial, it is
planned that subjects will receive a single oral dose of 50 mg partially radioactive labelled BI 


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730357. The dose of 50 mg is at the lower end of the anticipated therapeutic dose range and 
was selected based on safety aspects as well as solubility limitations. Each trial participant 
will receive only one radioactive dose. 
Trial participants are healthy volunteers from a broad age range to allow the trial to achieve 
the study goals. The trial design is optimized to collect as much relevant information as 
possible on the pharmacokinetics of BI 730357 without exposing participating volunteers to 
undue risk. The potential for side effects has been assessed to be minimal and thus acceptable. 
However, there is always the potential for subjects receiving medication to experience 
adverse events (AEs), and rarely also serious adverse events (SAEs). Risks for subjects will
be minimized and addressed by eligibility criteria, safety laboratory examinations, ECG and 
vital sign measurements, in-house observation periods and AE questioning.
If the investigator should have any clinical concern, the safety of subjects will be of upmost 
importance. The Investigator has the discretion to remove subjects from the trial should there 
be any safety concerns, or if the subjects’ wellbeing is at jeopardy.
The risk associated with the expected maximal radiation burden falls in ICRP category 2a 
with minor level risk and in WHO Category 1, i.e. within variations of natural background 
radioactivity. This is considered to be acceptable. 
The results of this trial are necessary for the further development of BI 730357. Successful 
development of BI 730357 is expected to provide a new valuable treatment option for 
patients suffering from psoriasis and Th17-mediated diseases.
The risks of the participating volunteers are minimized and justified when compared to the 
potential benefits of this trial. 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a non-randomized, open-label, single-arm, single-dose trial in 
healthy male subjects in order to investigate the basic pharmacokinetics of BI 730357,
 
 and [14C]-radioactivity, including mass balance, excretion pathways and
metabolism following a single oral dose of 50 mg BI 730357 BS (C-14).
A total of 6 healthy male subjects is planned to participate in the trial. 
The planned radioactive dose per subject is 3.7 MBq (100.0 µCi, 0.14 mSv). This is 
equivalent to 0.038 mSv/MBq (please refer to Appendix 10.1).
On Day 1, subjects will receive the drug product, that is, 50 mg BI 730357 BS (C-14) and 
will then stay in the study centre up to the morning of Day 15 for collection of samples of 
blood, urine and faeces. Subjects will be readmitted to the study centre for 24 h collection 
intervals of urine and faeces on Days 21, 28, 35, 42, and 49, if release criteria have not been 
met before. Within 24 h before each of these once-weekly in-house collection intervals, 
subjects are to collect faeces at home. This 24-h interval home collection faeces will be used 
for analysis in case no defecation occurs in the subsequent 24 h in-house collection interval.
Otherwise it will be discarded.
For determination of whether release criteria have been reached for individual subjects,
[14C]-radioactivity will be measured in excreta (urine and faeces). The actual recovery results
will be reported as a percentage of the administered dose.
If one of the following release criteria is true (i.e., release criteria have been met),
24 h collection intervals after Day 15 will not be performed / will be stopped:

Greater than or equal to 90% of the administered dose has been recovered in urine and 
faeces combined over the investigational period
or

If <1% of the dose administered has been collected in urine and faeces within 2 
separate, consecutive 24-h intervals, 
and
Concentration of total radioactivity in plasma and in blood is <5% of Cmax of total 
radioactivity in plasma
If a subject is unable to attend one of these ambulatory visits, they may be allowed to 
reschedule the visit if needed. Irrespective of whether release criteria have been met or not 
after collection interval day 49-50, no further collections are planned.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.


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3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The radiolabelled trial medication (drug product, BI 730357 BS (C-14) will be provided by 
.
The trial will be conducted at
, under the supervision of the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
).
The analyses of BI 730357
concentrations in plasma as well as BI 730357
concentrations in urine will be performed at the Department of Drug Metabolism and 
Pharmacokinetics, BI Pharma GmbH & Co. KG, Biberach, Germany.
The metabolite profiling and the identification in urine, plasma and faeces will be performed 
at BI and/or at a suitable Contract Research Organisation (CRO) under the responsibility of 
Boehringer Ingelheim (BI) Pharmaceutical Inc., Ridgefield, USA.
Concentrations of [14C]-radioactivity in blood, plasma, urine, faeces (and vomit if applicable)
will be determined at
 
On-site monitoring will be performed by BI or a contract research organisation appointed by
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs and/or 
by a suitable CRO under the responsibility of the Department of Biostatistics and Data 
Sciences, BI Pharma GmbH & Co. KG, Biberach, Germany.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
This is a standard design for a [14C]-human study for investigation of absorption, metabolism,
and excretion including determination of mass balance. 


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Inclusion of a control groups is not required for this investigation.
 
Therefore, following 14 days in-
house excreta collection after dosing, subjects will return on a weekly basis for in-house 24-h 
collection intervals for up to 7 weeks after dosing as long as release criteria are not met 
(Section 3.1).
Blinding is not necessary, because all subjects receive the same treatment.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 6 healthy male subjects will enter the study. They will be recruited from the 
pool of volunteers from the trial site’s database, or if necessary, via advertisement. In case a 
subject vomits within 8 h after trial drug administration assuming an incomplete absorption 
of the radiolabelled compound, an additional subject may be entered and dosed to assure that 
6 evaluable subjects will complete the study as per protocol. Thereby, the actual number of 
subjects entered may increase up to a maximum of 8.
The current trial is designed to investigate the basic pharmacokinetics of BI 730357
including absorption, metabolism, and elimination and quantitative 
determination of excretion mass balance. 
 
 Healthy subjects are an ideal population for the objectives of this 
trial, since they provide relatively stable physiological, biochemical and hormonal conditions, 
i.e. the absence of disease-related variations and relevant concomitant medications.
A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry 
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 65 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
5. Subjects who are sexually active must use, with their partner, highly effective 
contraception from the time of administration of trial medication until 4 months after 
administration of trial medication. Adequate methods are:


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-
Condoms plus use of hormonal contraception by the female partner that started at 
least 2 months prior to administration of trial medication (e.g. implants, injectables, 
combined oral or vaginal contraceptives, intrauterine device) or
-
Condoms plus surgical sterilization (vasectomy at least 1 year prior to enrolment) or
-
Condoms plus surgically sterilised partner (including hysterectomy) or
-
Condoms plus intrauterine device or
-
Condoms plus partner of non-childbearing potential (including homosexual men)
Subjects are required to use condoms to prevent unintended exposure of the partner to 
the study drug via seminal fluid. Male and female condoms must not be used together.
Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred
and usual lifestyle. If a subject is usually not sexually active but becomes active, with
their partner, they must comply with the contraceptive requirements detailed above.
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. 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 judged as clinically relevant by the investigator
5. Clinically significant gastrointestinal (including known or suspected inflammatory bowel 
disease), hepatic, renal, respiratory, cardiovascular, metabolic, immunological or
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and 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 prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug


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13. Smoker (more than 5 cigarettes or 1 cigar or 1 pipe per day)
14. Inability to refrain from smoking on specified trial days
15. 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 60 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within 4 days prior to administration of 
trial medication or during the trial. 
19. Inability to comply with dietary regimen of trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTcF intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criteria apply:
23. 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.
24. 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)
25. Irregular defecation pattern (less than a mean of one bowel movement per 2 days)
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events (AEs), or diseases)
4. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.


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In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end-of-trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 1.2), the discontinued subject should be questioned for AEs and 
concomitant therapies at or after the end of the REP if possible to ascertain collection of AEs 
and concomitant therapies throughout the REP, if subject had not withdrawn consent. These 
discontinuations will be discussed in the CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
if more than 50 % of the subjects have drug-related and clinically relevant adverse events 
of moderate or severe intensity, or if at least one drug-related serious adverse event is 
reported. In this case, collection of pharmacokinetic samples and other scheduled 
activities should continue, if possible without undue risk to already dosed volunteer(s), 
but no further administrations of investigational drug will be done.
2. The expected enrolment goals overall are not met
3. Violation of GCP, or the CTP, or the contract with BI by a trial site or investigator, 
disturbing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects
In case a subject vomits within 8 h after trial drug administration assuming an incomplete 
absorption of the radiolabelled compound an additional subject may be entered and dosed to 
ensure that 6 evaluable subjects will complete the study as per protocol.


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In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide if and how many subjects will 
be replaced. Replacement of subjects and dosing of additional subjects as described above 
should always be done in mutual agreement with the principal investigator. A replacement 
subject will be assigned a unique study subject number.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The oral solution contains a mixture of [C-14]BI 730357 BS, i.e. pure 14C-labelled “hot” drug 
substance, and BI 730357 BS, i.e. unlabelled “cold” drug substance and the mixture is 
manufactured by BI Pharma GmbH & Co. KG. The oral solution from this mixture is made
by 
 
4.1.1
Identity of BI investigational product
The characteristics of the test product are given below:
Name:
BI 730357 BS (C-14) oral solution 5 mg/mL (10 mL; 3.7 MBq)
Substance:
BI 730357 mixed with [C-14]BI 730357 BS
Pharmaceutical formulation: Oral solution
Source:
Unit strength:
50 mg BI 730357

Containing BI 730357 BS (C-14) corresponding to a 
radioactive dose of 3.7 MBq (100 µCi)

In a solution of 10 mL volume
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
Single dose
4.1.2
Method of assigning subjects to treatment groups
This is an open-label, Phase I, single-dose study. All subjects receive the same treatment. 
Once a subject number has been assigned, it cannot be reassigned to any other subject.
4.1.3
Selection of doses in the trial
The dose of BI 730357 tested in this trial is one single dose of 50 mg.
 
This dose of 50 mg
was already tested in the single rising dose study and was safe and well-tolerated (see 
Section 1.2). A dose of 50 mg is considered adequate for the objectives of the current trial. 
This dose administered as oral solution will include 3.7 MBq (100.0 µCi) of 
[14C]-radiolabelled BI 730357. The radioactive dose of 3.7 MBq is required for sufficient 
analytical sensitivity to enable metabolite quantification in a sufficiently low range. The total 
effective dose (radiation burden) amounts to 0.14 mSv. This is below the limit of 1.0 mSv, 
which is considered acceptable for biomedical investigations in small groups of human 


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volunteers [R18-1905]. Radiation burden calculations are presented in Appendix 10.1. For 
risk-benefit assessment, see Section 2.3.
4.1.4
Drug assignment and administration of doses for each subject
In the morning of Day 1, following an overnight fast of at least 10 h, all subjects will receive 
one single dose of the trial drug (BI 730357 BS (C-14) oral solution 5 mg/mL (10 mL; 
3.7 MBq)).
The medication will be administered as a single oral dose together with 240 mL of water to a 
subject in the sitting position under supervision of the investigator or an authorised designee.
After administration,
 will determine for each volunteer the residual 
amount of [14C]-radioactivity in the syringe used for administration. The amount of 
administered radiolabelled medication will be calculated based on pre- and post-dose weight 
of the syringe used for oral administration.
The so-called four-eye principle (two-person rule) should be applied for administration of 
trial medication.
During the first 4 h after drug administration, subjects are not allowed to lie down (i.e., no 
declination of the upper body of more than 45 degrees from upright posture) except for 
medical examination or if necessary for any medical reasons (e.g. adverse events). For 
restrictions with regard to diet and fluid intake see Section 4.2.2.2.
After drug administration subjects will be kept under close medical surveillance until planned 
discharge from the unit on Day 15. In case release criteria for radioactivity recovery have not 
been met on Day 15, subjects will come back to the unit for up to five once-weekly 24 h 
sampling periods until discharge criteria are met or after the last collection interval Day 49-50 
was completed (see Section 3.1).
4.1.5
Blinding and procedures for unblinding
This is an open-label study.
4.1.6
Packaging, labelling, and re-supply
Non-[14C]-labelled and radioactively-labelled drug supplies will be mixed and provided to 
 by the Department of Pharmaceutical Development of Boehringer Ingelheim Pharma 
GmbH & Co. KG, Biberach, Germany. 
Drug product manufacturing is done by 
. The clinical trial supply consists of containers 
holding the trial medication which are labelled with trial identification. The final container 
will be an oral syringe holding the Investigational Drug Products and will be labelled 
according to GMP Annex 13 / EU GMP guideline and local drug law. 
Examples of the labels will be available in the ISF.
No re-supply is planned.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
 pharmacy will deliver the investigational drugs to the investigator upon availability of a 
valid prescription from the investigator. 
The investigator will not order the drugs from the 
 pharmacy before the following 
requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the Sponsor and the 
Head of Trial Centre

Approval/notification of the regulatory authority, e.g. competent authority

Availability of a signed and dated clinical trial protocol or immediately imminent 
signing of the clinical trial protocol

Availability of licence for clinical research using radioactive isotopes
Only authorised personnel as documented in the form ‘Site Delegation Log’ may dispense 
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused trial medication must be returned to the Sponsor or disposed 
locally by the trial site upon written authorisation by the clinical monitor. Appropriate 
retention samples will be kept at 
until finalization of the clinical trial report. Receipt, 
usage and return or disposal must be documented on the respective forms. Account must be 
given for any discrepancies.
The Investigator must maintain records of the product’s delivery to the trial site, the
inventory at the site, the use by each subject, and the return to the Sponsor or alternatively
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 products and trial subjects. The 
Investigator will maintain records that document adequately that the subjects were provided 
the doses specified by the CTP, and that reconcile all investigational products received from 
the Sponsor. At the time of disposal or return to the Sponsor (and/or appointed CRO), the 
Investigator must verify that no remaining supplies are in the Investigator’s possession.


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4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no specific rescue drugs foreseen for the treatment of AEs. There are no special 
emergency procedures to be followed. No additional treatment is planned. However, in case 
of adverse events in need of treatment, the investigator can authorise symptomatic therapy. In 
those cases, subjects will be treated as necessary and, if required, kept under supervision at 
the trial site or transferred to a hospital until all medical evaluation results have returned to an 
acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed throughout the study except for paracetamol. 
Limited doses of paracetamol (up to 2 grams per day) are allowed prior to entry in the clinic 
and until the end of trial after prescription by a 
physician to treat aches and pains. 
However, in case of adverse events in need of treatment, a concomitant therapy will be 
permitted. All concomitant or rescue therapies will be recorded (including time of intake on 
study days) on the appropriate pages of the CRF.
In case concomitant therapy is necessary, drugs that might reasonably influence the results of 
the trial, that might prolong the QT/QTc interval, that are inhibitors or inducers of CYP3A4 
or that might otherwise negatively affect the safety of the subjects, should be avoided if 
possible. 
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. On Day 1, standardised meals will be served at the 
time points described in the Flow Chart. On all other days during in-house confinement, there 
are no special requirements with the exception of the restrictions with respect to grapefruit 
(orange)/Seville orange, methylxanthine- and alcohol containing beverages or food. When 
not fasting, meals and snacks (such as decaffeinated coffee, herbal tea, fruit, and biscuits) will 
be provided according to 
 standard operating procedures (SOPs). A light supper will be 
provided on the evening before those days where fasting is required until lunch-time.
Subjects are to be fasted for at least 10 h prior to dosing. No food is allowed for at least 4 h 
after drug intake. For fasting times before safety laboratory investigations see Section 5.2.3.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water served at 2 h and 4 h post-dose (mandatory
for all subjects). From lunch until 24 h post-dose, total fluid intake is restricted to 3000 mL. 


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During the following days of urine collection, subjects will be advised that total fluid intake 
should be at least 1.5 litres and should not exceed 3.5 litres.
Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products including St. John's wort (Hypericum perforatum) are not 
permitted starting 7 days before first admission to and during in-house confinement at the 
trial site. 
Poppy-seed containing products should not be consumed within 2 days before screening and 
starting 2 days before first admission to trial site until last PK sampling of the trial. 
Alcoholic beverages are not allowed within 48 h before screening and before first admission 
to and during in-house confinement at the trial site. During ambulatory phases alcohol 
consumption is restricted to 2 units per day.
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 h before first admission to and during in-house 
confinement at the trial site. 
Excessive physical activity (such as competitive sport) should be avoided within 96 h before 
screening and starting 96 h before first admission to the trial site until the end-of-trial 
examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
 
 
Adequate contraception is to be maintained throughout the course of the trial and for a 
defined time period afterwards (see Section 3.3.2 for adequate measures).
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured blood and plasma 
concentrations and excretion in urine and faeces will provide additional confirmation of 
compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Safety and tolerability of the investigational drug will be assessed based on:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)
These parameters will be evaluated in a descriptive way only, and are therefore considered to 
be ‘further parameters of interest’. A confirmatory analysis is not planned (see Section 7.3). 
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
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
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’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.2.2, 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
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.2.2.


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The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
an elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.

Severe infections (according to RCTC grading)

Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, 
posttransplant lymphoproliferative disorder (EBV), progressive multifocal 
leucoencephalopathy, bartonellosis (disseminated only), blastomycosis, 
toxoplasmosis, coccidioidomycosis, histoplasmosis, aspergillosis (invasive only), 
candidiasis (invasive or pharyngeal), cryptococcosis, other invasive fungi 
(mucormycosis (zygomycosis, rhizopus, mucor, lichtheimia), 
scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous 
mycobacterium, salmonellosis (invasive only), HBV reactivation, herpes simplex 
(invasive only), herpes zoster, strongyloides (hyperinfection syndrome and 
disseminated forms only), paracoccidioides, penicillium marneffei, sporothrix 
schenckii, cryptosporidium species (chronic only), microsporidiosis, leishmaniasis 
(visceral only), trypanosoma cruzi infection (Chagas’ disease) (disseminated only), 
campylobacteriosis (invasive only), shigellosis (invasive only), vibriosis (invasive due 
to vibrio vulnificus), HCV progression.
Intensity (severity) of AEs
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
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 


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confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 


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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
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for new 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 Sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timelines apply as for the initial 
information.
Information required
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
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 


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(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.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 4 h (at admission on Day -1 only) or at least 10 h (all other time points). Subjects do not
need to have fasted for drug screening and for infectious serology at the discretion of the 
investigator or designee. Overnight fasting is not required at the discretion of the investigator 
or designee for retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis,
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
D
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
Reticulocytes, absol.
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
--
--
--
--
--
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
--
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
--
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands;  Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
X
X
--
--
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
Lipase
Amylase
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
--
X
--
--
--
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
X
--
--
--
Substrates
Glucose (Serum)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
Alpha glycoprotein acid
C-Reactive Protein (Quant)  
Uric Acid
Urea
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
Magnesium
Calcium
X
X
X
X
--
--
--
--
X
X
X
X
X
X
X
X


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
D
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)
A: Parameters to be determined at Visit 1 (screening examination) and at Visit 2 on Day -1
B: Parameters to be determined at Visit 2 on Day 1 (at PTM 2:00, 4:00, 12:00) and Day 2 (at PTM 24:00)
C: Parameters to be determined at Visit 2 on Days 1 (PTM -2:00), 8, 15 and 35 (for time points refer to 
Flow Chart)
D: Parameters to be determined at Visit 3 (end-of-trial examination)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only.
Drug screening will be performed at screening and on Day -1 of the treatment period.
To encourage compliance with alcoholic restrictions, an alcohol test in urine will be 
performed at screening and on Day -1 of the treatment period, and may be repeated at any 
time during the study at the discretion of the Investigator or designee. The results will not be 
included in the CTR.  


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Alcohol
Infectious serology (blood)
Hepatitis B surface antigen (qual)
Hepatitis B core antibody (qual)
Hepatitis C antibodies (qual)
HIV-1 and HIV-2 antibody (qual)
QuantiFERON-TB Gold
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at the safety 
laboratory of 
 
. The drug and alcohol screening tests will be performed using the ADVIA 
Chemistry XPT system.
Laboratory data will be transmitted electronically from the laboratory to the trial site. 
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (Mortara ELI 250 Rx) at the time points given in the 
Flow Chart. Electrode placement will be performed according to the method of Wilson, 
Goldberger and Einthoven.
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.
All ECGs will be recorded as single ECGs for a 10 sec duration as indicated in the 
Flow Chart and after subjects have rested for at least 5 min in a supine position. ECG
recording will always precede all other study procedures scheduled for the same time (except 
for blood drawing from an intravenous cannula that is already in place) to avoid 
compromising ECG quality.
All locally printed ECGs will be evaluated by the Investigator or a designee. ECGs may be 
repeated for quality reasons for instance due to alternating current artefacts, muscle 


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movements, or electrode dislocation. The repeat ECGs are assigned to the respective 
scheduled time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database.
Storage
All ECGs will be stored electronically.
Evaluation
All ECGs will be locally printed and be evaluated by the investigator or a designee.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of cardiac 
safety during the study, the QT and QTcF values generated by the computerised ECG system 
or their manual corrections by the investigators will be used. 
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap CareScape VC150, GE Medical Systems) at the times indicated in the Flow Chart,
after subjects have rested for at least 5 min in a supine position. All recordings should be 
made using the same type of blood pressure recording instrument on the same arm if possible.
5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 
laboratory tests, and a physical examination. At the end-of-trial examination, it will include 
review of vital signs, 12-lead ECG, laboratory tests, and a physical examination.


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5 are 
generally used assessments of drug exposure in human mass balance trials.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the CRFs.
5.5.1
Pharmacokinetic endpoints
5.5.1.1
Primary endpoints
Primary endpoints will be the mass balance recoveries of [14C]-radioactivity in urine and 
faeces:

feurine, 0-t2 (fraction of [14C]-radioactivity excreted in urine as percentage of the 
administered dose over the time interval from 0 to t2 (where t2 is the last quantifiable 
data point across all subjects))

fefaeces, 0-t2 (fraction of [14C]-radioactivity excreted in faeces as percentage of the 
administered dose over the time interval from 0 to t2 (where t2 is the last quantifiable 
data point across all subjects))
Timeframe: The timeframe for determination of these endpoints depends on 
excretion/recovery of radioactivity and may vary between 2-7 weeks, inclusive, after drug 
administration.
5.5.1.2
Secondary endpoints
The following secondary endpoints will be evaluated for [14C]-radioactivity and BI 730357 in 
plasma:


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
Cmax (maximum measured concentration of the analyte)

AUC0-tz (area under the concentration-time curve of the analyte over the time interval 
from 0 to the last quantifiable time point)
5.5.1.3


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5.5.2
Methods of sample collection
5.5.2.1
Sampling of whole blood and plasma
Whole blood and plasma will be collected at time points shown in the Flow Chart:

to determine [14C]-radioactivity concentrations in whole blood and plasma

to determine concentrations of BI 730357


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5.5.2.2
Sampling of whole blood and plasma for [14C]-radioactivity analysis in whole 
blood and plasma and quantification of BI 730357
in plasma
At each time point listed in the Flow Chart, 4 mL (for time points from 1 h up to 72 h post-
dose (inclusive)), or 8 mL (for the pre-dose, at time point 0.5 h and from time point 120 h up 
to 312 h post-dose) or 6 mL (for time points at ambulatory visits) blood will be taken from a 
forearm vein using a commercial vacutainer or monovette collection tube with K2-EDTA as 
anticoagulant. Withdrawal of blood will be done via an indwelling cannula or direct venae 
puncture.
It is planned that aliquots of all time points are prepared for determination of [14C]-
radioactivity in whole blood and plasma.
Aliquots for bioanalysis of BI 730357
in plasma are planned to be prepared for 
up to 312 h after drug administration.
Premature stopping of blood sampling from 168 h onwards
In case [14C]-radioactivity in plasma samples is not detectable (<LLOQ 10 dpm/mL) at two 
consecutive time points for a subject, blood sampling can be stopped for this subject. 
However, all samples until and including the 168 h sample have to be taken.
For detailed description of blood sampling, sample handling, sample preparation, sample
storage, tube labelling and sample shipment refer to the laboratory manual.
5.5.2.3
Sampling of plasma for metabolic profiling 
At each time point listed in the Flow Chart for metabolic profiling sampling, blood will be 
withdrawn from a forearm vein using a commercial vacutainer or monovette collection tube 
with K2-EDTA as anticoagulant. Pre-dose 8 mL of blood will be taken and at all time points 
post-dose the maximum possible volume of blood will be drawn according to what is allowed 
considering the blood samples taken for all other samples except metabolic profiling.
Approximately 8 mL of blood will be taken at 1 h and 2 h post dosing. Approximately 10 
mL, 20 mL, 40 mL, 60 mL, 80 mL and 40 mL will be taken at 4 h, 8 h, 12 h, 24 h, 48 h and 
72 h hours, respectively, after drug administration (Table 5.5.2: 3)
Table 5.5.2: 3
Blood volume to be taken for metabolic profiling
Time after dosing (h)
Blood volume (mL)
Pre-dose
8
1
8
2
8
4
10
8
20
12
40
24
60
48
80
72
40
Total
274


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For detailed description of blood sampling, sample handling, sample preparation, sample 
storage, tube labelling and sample shipment refer to the laboratory manual. 
5.5.2.4
5.5.2.5
Urine sampling 
During the trial urine will be collected at time points or in intervals as indicated in the 
Flow Chart: 

to determine [14C]-radioactivity 

to determine concentrations of BI 730357
A blank sample will be taken within approximately 14 hours prior to drug administration.
For urine collection, addition of Tween 20 resulting in a final concentration of at least 0.05% 
Tween 20 is required. The weight of the containers has to be determined prior to (empty 
containers) 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 intake of BI 730357 BS (C-14) are planned to be used for determination of
[14C]-radioactivity.
Samples until and including the collection interval 312-336 h are planned to be used for 
analysis of BI 730357.
Samples to be used for metabolic profiling will be selected according to the levels of 
radioactivity in each urine sample. 
For a detailed description of urine sampling, preparation of collection containers, sample
storage, sample handling, labelling, and sample shipment refer to the laboratory manual.


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5.5.2.6
Faeces sampling
Faeces will be collected for the analysis of [14C]-radioactivity and for metabolic profiling in
intervals as indicated in the Flow Chart. A blank sample will be taken within approximately 
48 hours prior to drug administration. If several samples are available, the sample closest to 
drug administration will be used for analyses.
All faeces samples after intake of BI 730357 BS (C-14) are planned to be used for 
determination of [14C]-radioactivity.
Samples to be used for metabolic profiling will be selected according to the levels of 
radioactivity in each faeces sample interval. 
All stools will be collected quantitatively in portions up to 336 hours after drug 
administration. The weight of the faeces and the exact times of faeces collection will be 
recorded in the eCRF.
If subjects are to collect faeces during the ambulatory phase of the study (see Section 3.1 for 
release criteria), subjects are to collect faeces at home within 24 h intervals before admission 
to once-weekly in-house collection intervals. Home collection intervals are (if applicable): 
Days 20-21, 27-28, 34-35, 41-42, and 48-49. If faeces are collected in the subsequent in-
house collection interval, faeces collected at home will be discarded. If no faeces is collected 
in the subsequent in-house collection interval (no defecation), faeces collected at home will 
be used instead for analysis
For a detailed description of faeces sampling, sample preparation, sample storage, labelling,
and sample shipment refer to the laboratory manual.
5.5.2.7
Collection of vomit
If vomiting occurs in a volunteer within 12 h after drug administration, the vomit will be 
collected for determination of weight and [14C]-radioactivity.
For a detailed description of vomit sampling, sample preparation, sample storage, labelling, 
and sample shipment refer to the laboratory manual.
5.5.2.8
Further investigations
Back-up and left-over samples (plasma, urine, faeces; see laboratory manual for details) may 
be used for metabolic profiling if not needed for their primary purpose (bioanalysis and 
radiokinetic). 
After completion of the trial, blood, plasma, urine, faeces samples (and vomit, if applicable) 
may be used for further methodological investigations, e.g. for stability testing of the drug 
and/or drug metabolites, assessment of drug metabolites. However, only data related to the 
analyte and/or its metabolite including anti-drug antibodies (if applicable) will be generated
by these additional investigations. 
The study samples will be discarded after completion of the additional investigations but not 
later than 5 years upon the final study report has been signed.


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5.5.3
Analytical determinations
5.5.3.1
Analytical determinations of BI 730357 and
 plasma and BI 730357 
urine concentrations
Plasma and urine concentrations of BI 730357 
 will be 
determined by a validated LC-MS/MS (liquid chromatography tandem mass spectrometry) 
assay. All details of the analytical method will be available prior to the start of sample 
analysis. 
Analysis will be performed at: 
Since this is an open label study, the bioanalyst will be unblinded during sample analysis. 
5.5.3.2
Metabolic profiling
Determination of the metabolic pattern of BI 730357 in plasma, urine, and faeces including
structure elucidation of the metabolites will be performed at 
Metabolic profiling data will be reported separately from CTR.
5.5.3.3
Radiokinetic and Excretion Balance
Determination of [14C]-radioactivity concentrations in plasma, whole blood, urine, and faeces
(and vomit, if applicable) will be done by means of validated liquid scintillation counting
methods at 
The blood, plasma, urine and faeces concentrations of radioactivity will be determined in
agreement with relevant 
 Standard Operating Procedures (SOPs).


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end-of-trial examination are given in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 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 min on Day 1 and ± 90 min from Day 2 onwards in Visit 2.
If several activities, including ECG and meal intake, are scheduled at the same time point in 
the Flow Chart, ECG should be the first and meal the last activity. Furthermore, if several 
measurements including venipuncture are scheduled for the same time, venipuncture should 
be the last of the measurements due to its inconvenience to the subject and possible influence 
on physiological parameters.
For planned individual plasma/blood concentration sampling times and urine/faeces sampling 
times or collection intervals refer to the Flow Chart. While these nominal times should be 
adhered to as closely as possible, the actual sampling times will be recorded and used for 
determination of pharmacokinetic parameter. If beginning or end of a urine/faeces collection 
interval and a blood sample are scheduled for the same time point, urine/faeces collection 
should be done first, with withdrawal of the blood sample as close to the planned time point 
as possible.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the 
Blinded Report Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
Screening visit is defined as Visit 1.
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.  
6.2.2
Treatment period
Each subject is expected to participate in one treatment period (Visit 2).


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On Day -1 of the treatment period study participants will be admitted to the trial site and kept
under close medical surveillance until discharge from the trial site on Day 15. In the morning
of Day 15, the subjects will then be allowed to leave the trial site after formal assessment and
confirmation of their fitness.
Thereafter, until release criteria (see Section 3.1) have been reached, subjects will return to 
the trial site for up to 5 weekly 24-h collection intervals of urine and faeces. For these 
additional 24 h collection intervals, subjects will be admitted to the trial site on Days 21, 28, 
35, 42, and 49. One day later, on Days 22, 29, 36, 43, and 50, respectively, subjects will be 
discharged from the trial site after formal assessment and confirmation of their fitness.
Within 24 h before each once-weekly in-house collection interval, subjects are to collect
faeces at home (beginning of home collections on Days 20, 27, 34, 41, and 48). Faeces
collected in these 24 h home-collection intervals will be used for analysis in case no
defecation occurs in the subsequent 24 h in-house collection interval. E.g., if no defecation
occurs in in-house collection interval Day 21-22, faeces of home-collection interval Day 20-
21 will be used for analysis. If, however, faeces are collected in the subsequent 24 h in-house
collection interval, faeces collected at home will be discarded. Once release criteria are 
reached, home collections will be stopped.
Irrespective of whether release criteria have been met or not after collection interval Days 49-
50, no further collections are planned. 
For details on time points and procedures for collection of blood/plasma/urine/faeces samples
for PK analysis and mass balance assessment, refer to Flow Chart and Section 5.5.2. 
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from screening until the end-of-trial examination.
6.2.3
End-of-trial period 
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end-of-trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end-of-trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the basic pharmacokinetics of BI 730357, 
[14C]-radioactivity, including mass balance, excretion pathways and metabolism following a 
single oral dose of 50 mg BI 730357 BS (C-14) given to healthy male subjects. The 
secondary objective of this trial is to determine PK parameters of [14C]-radioactivity, 
BI 730357
 after single oral dose of BI 730357 BS (C-14) and to determine the 
routes and rates of elimination of BI 730357.
The assessment of safety and tolerability will be an additional objective of this trial, and will 
be evaluated by descriptive statistics. More details will be provided in the Trial Statistical 
Analysis Plan. 
7.1.2
Endpoints
The basic pharmacokinetics of BI 730357 and [14C]-radioactivity, including mass balance, 
excretion pathways and metabolism is to be determined on the basis of the primary and 
secondary pharmacokinetic endpoints (see Section 5.5.1).
Additionally, the PK parameters listed in Section 5.5.1.3 will be calculated and analysed 
descriptively, if feasible. Safety and tolerability will be determined on the basis of the 
parameters specified in Section 5.2.1.
7.1.3
Model
No statistical model will be used.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No confirmatory analysis will be conducted for this study. Data will be reported with 
descriptive statistics only. 
7.3
PLANNED ANALYSES
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol deviations (iPDs) will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.
Plasma/urine/faeces concentration data and parameters of a subject will be included in the
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a
protocol deviation relevant to the evaluation of PK (to be decided no later than in the Report


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Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol 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, urine and faeces concentrations and/or parameters will be considered as non-
evaluable, if for example

a pre-dose concentration  >5% of the Cmax value of that subject

missing samples/concentration data at important phases of PK disposition curve 
The following subject and analysis sets will be defined for this trial:
Treated set (TS):
This subject set includes all subjects who were documented to have received one dose of 
study drug. This is the full analysis set population in the sense of ICH-E9.
PK analysis set (PKS):
The PK analysis set includes all subjects in the treated set who provide at least one value for 
primary or secondary PK endpoint and are not excluded according to the description above. 
Thus, a subject will be included in the PKS, even if he contributes only one PK endpoint 
value for the statistical assessment.
7.3.1
Primary analyses
The analysis of primary and secondary endpoints will be based on descriptive statistics only: 
number, arithmetic mean, standard deviation, minimum, median, maximum, arithmetic 
coefficient of variation, geometric mean, and geometric coefficient of variation. These 
evaluations will be based on the PKS. See Sections 5.5.1 and 7.3.5 for further definitions of 
this analysis. 
7.3.2
Secondary analyses
Refer to Section 7.3.3 for a description of the analysis of safety.
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is,
all subjects who received at least one dose of study drug), will be included in the safety 
analysis. Safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
The analyses will be done by ‘treatment at onset’.


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Tabulations of frequencies/proportions will be used for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyse continuous 
(quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
the treatment (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until end of the residual 
effect period (see Section 1.2) will be assigned to the treatment period. Events after the 
residual effect period but prior to end-of-trial examination will be summarized as ‘follow-up’.
These assignments including the corresponding time intervals will be defined in detail in the 
TSAP.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.2.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.
Relevant ECG findings as judged by the investigator will be reported as AEs.
7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 will be calculated according to the BI 
SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-472].
Subjects who are not included in the PKS (refer to Section 7.3) will be reported with their 
individual plasma/urine/faeces concentrations and individual pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for plasma/urine/faeces
concentrations, pharmacokinetic parameters or other statistical assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
The following descriptive statistics will be calculated for concentration-time data as well as
for all pharmacokinetic parameters: number, arithmetic mean, standard deviation, minimum,


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median, maximum, arithmetic coefficient of variation, geometric mean, and geometric
coefficient of variation. Descriptive statistics of pharmacokinetic parameters will be
calculated using the individual values with the number of decimal places as provided by the
evaluation program. Then the individual values as well as the descriptive statistics will be
reported with three significant digits in the Clinical Trial Report.
If a pre-dose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a pre-dose concentration is above BLQ, but less than or equal to 5% 
of the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Blood/plasma/urine/faeces drug or [14C]-radioactivity concentration - time 
profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
[001-MCS-36-472].
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the pre-dose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
[001-MCS-36-472].
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.5
RANDOMISATION
Randomisation is not applicable in this open-label, single arm study. All subjects will receive
the same treatment. Consecutive subject numbers will be assigned via the EDC system.


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7.6
DETERMINATION OF SAMPLE SIZE
For this clinical trial, no prospective calculations of statistical precision or power have been
made. The planned sample size of 6 subjects is judged as being adequate to get reliable
results regarding the trial objectives.
The sample size of 6 subjects accounts for moderate PK variability, the potential of the drug
to induce vomiting and potential drop-outs. For replacement rules, refer to Section 3.3.5.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP), and relevant BI SOPs.
The Investigator should inform the Sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the Investigator or the trial site and 
the Sponsor. As a general rule, no trial results should be published prior to finalisation of the 
CTR.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his personal trial-related data will be used by Boehringer 
Ingelheim in accordance with the local data protection law. The level of disclosure must also 
be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the Sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 
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.


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The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the Sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The Investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The Investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The Sponsor must retain the essential documents according to the Sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.


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Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities, i.e. the competent authority 
(CA).
8.6
COMPLETION OF TRIAL
The EC/CA in each participating EU member state needs to be notified about the end of the 
trial (last subject/subject out, unless specified differently in Section 6.2.3 of the CTP) or early
termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R13-2643
Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, 
Higgins PDR, Wehkamp J, Feagan BG, Yao MD, Karczewski M, 
Karczewski J, Pezous N, Bek S, Bruin G, Mellgard B, Berger C, Londei M, 
Bertolino AP, Tougas G, Travis SPL, Secukinumab in Crohn's Disease 
Study Group. Secukinumab, a human anti-IL-17A monoclonal antibody, for 
moderate to severe Crohn's disease: unexpected results of a randomised, 
double-blind placebo-controlled trial. Gut 2012;61(12):1693-1700.
R15-3219
International Commission on Radiological Protection (ICRP). 2007 
Recommendations of the International Commission on Radiological 
Protection (users edition): abstract. 
website.icrp.org/publication.asp?id=ICRP%20Publ 
ication%20103%20(Users%20Editi on) (access date: 24 June 2015) ; (ICRP 
Publication; 103 (Users Edition)) International Commission on 
Radiological Protection (ICRP); 2007.
R16-2630
Ueda E, Kurebayashi S, Sakaue M, Backlund M, Koller B, Jetten AM. High 
incidence of T-cell lymphomas in mice deficient in the retinoid-related 
orphan receptor RORgamma. Cancer Res 2002;62(3):901-909.
R16-3149
Onishi RM, Gaffen SL. Interleukin-17 and its target genes: mechanisms of   
interleukin-17 function in disease. Immunology 2010;129:311-321.
R16-3166
Miossec P. Clinical implications of Th17/IL-17: diseases that may benefit 
from manipulating the Th17 pathway. Eur J Immunol 2009;39:667-669.
R18-1905
International Commission on Radiological Protection (ICRP). Factors 
related to project evaluation. Ann ICRP 1992;22(3):11-13
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c09228382-06
 
Investigator Brochure 1407.P1 Version 4.0 - BI 
730357 RORgamma Inhibitor - Psoriasis (ankylosing spondylitis, psoriatic 
arthritis, asthma, inflammatory bowel disease). 20 Jul 2018.
c16462083-01
. A partially randomised, single-
blind, placebo-controlled trial to investigate safety, tolerability, 
pharmacokinetics and pharmacodynamics of single rising doses of BI 
730357 administered as oral solution and tablets to healthy human subjects, 
and a randomized, open-label, single-dose, three-way cross-over 
bioavailability comparison of BI 730357 as tablet versus oral solution and 
tablet with. 1407.1. 13 Jul 2018.


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n00258749-01
 Excretion of radioactivity in urine, faeces and bile after oral and 
intravenous administration of [14C]BI 730357 to rats. A194/16FU. B5718. 
03 Nov 2017.
n00260847-01
 Quantitative whole-body autoradiography in male pigmented rats 
after single intravenous or oral administration of [14C]BI 730357. 
A117/17JS. B6163. 27 Mar 2018.


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10.
APPENDICES
10.1
RADIO BURDEN CALCULATION


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
25 September 2018
EudraCT number
2018-001837-41
BI Trial number
1407-0031
BI Investigational Product(s)
BI 730357
Title of protocol
A phase I, open-label, single-dose trial to 
investigate metabolism and pharmacokinetics of 
BI 730357 BS (C-14) administered as oral 
solution in healthy male volunteers
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as 
changes involve logistical or 
administrative aspects only
Section to be changed
3.3.5
5.2.3
5.2.5.1
5.5.2.5
Exclusion Criteria
Assessment of safety laboratory parameters
Vital signs
Urine sampling
Description of change
3.3.5
5.2.3
5.2.5.1
5.5.2.5
Deleted the number before sentence “In 
addition, the following trial-specific exclusion 
criteria apply”
Deleted the sentence “(please specify which)”
and deleted the timepoint Day 1, 1:00 in the 
footnote for lab set C in table 5.2.3: 1
Changed the type of monitor used for blood 
pressure measurements
Added “at least” in front of “0.05 % Tween 20”
Rationale for change
3.3.5
The incorrect numbering in the list of exclusion 
criteria was corrected. The exclusion criteria per 


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Number of global amendment
1
5.2.3
5.2.5.1
5.5.2.5
se were not changed.
The type of alcohol test is specified in the next 
paragraph; the deleted sentence was a leftover 
from protocol drafting process
Inconsistency in the footnote: Timepoint Day 1, 
1:00 for safety lab is not in the Flow Chart since 
it is not necessary for safety reasons.
Site has changed the equipment since old 
monitor has become obsolete
The concentration of Tween 20 in the urine 
container is now allowed to be 0.05% or higher.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c22159106
2.0
clinical-trial-protocol-revision-01
A phase I, open-label, single-dose trial to investigate metabolism and
pharmacokinetics of BI 730357 BS (C-14) administered as oral solution in healthy
male volunteers
Author-Trial Clinical
Pharmacokineticist
25 Sep 2018 16:56 CEST
Author-Clinical Trial Leader
25 Sep 2018 17:41 CEST
Approval-Team Member Medicine
25 Sep 2018 17:58 CEST
Approval-Therapeutic Area 
27 Sep 2018 16:36 CEST
Verification-Paper Signature
Completion
28 Sep 2018 13:09 CEST
Author-Trial Statistician
01 Oct 2018 10:05 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c22159106
2.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c26502696-01
BI Trial No.:
1407-0031
Title:
A phase I, open-label, single-dose trial to investigate metabolism and
pharmacokinetics of BI 730357 BS (C-14) administered as oral
solution in healthy male volunteers
Investigational
Product(s):
BI 730357
Responsible trial 
statistician(s):
Phone: 
Fax: 
Phone: 
Fax: 
Date of statistical 
analysis plan:
10 JAN 2019 SIGNED 
Version:
Final
Page 1 of 23
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2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENT.....................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................11
6.3
SUBJECT SETS ANALYSED...........................................................................12
6.5
POOLING OF CENTRES .................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................13
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................14
7.
PLANNED ANALYSIS......................................................................................15
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........15
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................16
7.3
TREATMENT COMPLIANCE........................................................................16
7.4
PRIMARY ENDPOINTS...................................................................................16
7.5
SECONDARY ENDPOINTS.............................................................................17
7.5.1
Key secondary endpoint .....................................................................................17
7.5.2
Secondary endpoints...........................................................................................17
7.7
EXTENT OF EXPOSURE.................................................................................17
7.8
SAFETY ANALYSIS..........................................................................................17
7.8.1
Adverse events.....................................................................................................17
7.8.2
Laboratory data ..................................................................................................19
7.8.3
Vital signs.............................................................................................................19


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7.8.4
ECG......................................................................................................................20
7.8.5
Others...................................................................................................................20
8.
REFERENCES....................................................................................................21
10.
HISTORY TABLE..............................................................................................23


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety 
laboratory data and vital signs..........................................................................11
Table 6.2: 1
Important protocol deviations...........................................................................12
Table 6.3: 1
Subject sets analysed ........................................................................................13
Table 10: 1
History table .....................................................................................................23


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADPC
Proper name of the analysis dataset containing PK concentrations per time-
point or per time-interval
ADPP
Proper name of the analysis dataset containing calculated PK parameters
ADS
Analysis dataset
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data point
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body Mass Index
BP
Blood Pressure
BRPM
Blinded Report Planning Meeting
Cmax
Maximum measured concentration of the analyte in plasma
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
EDC
Electronic Data Capture
FAS
Full Analysis Set
fefaeces, 0-t2
fraction of [14C]-radioactivity excreted in faeces as percentage of the
administered dose over the time interval from 0 to to t2 (where t2 is the last 
quantifiable data point across all subjects)
feurine, 0-t2
fraction of [14C]-radioactivity excreted in urine as percentage of 
theadministered dose over the time interval from 0 to t2 (where t2 is the last 
quantifiable data point across all subjects)
gCV
geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
IPD
Important Protocol Deviation


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Term
Definition / description
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary For Regulatory Activities
NOA
Not analysed
NOP
No peak detectible
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter set
PR
Pulse Rate
PT
Preferred Term
Q1
Lower Quartile
Q3
Upper Quartile
SA
Statistical Analysis
SD
Standard Deviation
SOC
System Organ Class
TCM
Trial Clinical Monitor
ToC
Table of Contents
TMW
Trial Medical Writer
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP, 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, randomization.
Study data will be stored in a trial database within the Medidata Rave system.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version 6.3, Certara 
USA Inc., Princeton, NJ, USA).


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


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary endpoints are PK endpoints of mass balance recovery of [14C]-radioactivity as 
defined in Section 5.5.1.1 of the CTP:

feurine, 0-t2 (fraction of [14C]-radioactivity excreted in urine as percentage of the
administered dose over the time interval from 0 to t2 (where t2 is the last quantifiable 
data point across all subjects))

fefaeces, 0-t2 (fraction of [14C]-radioactivity excreted in faeces as percentage of the
administered dose over the time interval from 0 to t2 (where t2 is the last quantifiable 
data point across all subjects))
CTP: Timeframe: The timeframe for determination of these endpoints depends on
excretion/recovery of radioactivity and may vary between 2-7 weeks, inclusive, after drug
administration.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable
5.2.2
Secondary endpoints
Secondary PK endpoints will be defined as in Section 5.5.1.2 of the CTP for [14C]-
radioactivity and BI 730357 in plasma:

Cmax (maximum measured concentration of the analyte)

AUC0-tz (area under the concentration-time curve of the analyte over the time interval
from 0 to the last quantifiable time point)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT
For basic study information on treatments to be administered, assignments of dose groups, 
and selection of doses, cf. Section 4 of the CTP.
All subjects were planned to be treated with a single dose of 50 mg BI 730357 BS (C-14) (BI 
730357 mixed with [C-14]BI 730357 BS)
For statistical analysis of AEs, safety laboratory data and vital signs, the following analysis 
phases are defined for each subject:
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety laboratory 
data and vital signs
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of administration 
of study drug
On-treatment
BI 730357
Date/time of administration 
of study drug
12:00 a.m. on day after end 
of REP
(REP ends 7 days after date 
of administration of study 
drug)
Follow-up
F/U
12:00 a.m. on day after end 
of REP
12:00 a.m. on day after trial 
completion date
CTR Section 15, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phase only. Appendix 16.1.13.1.8.1 will present results for 
the screening, on-treatment and follow-up phase.
Additionally, the following total will be provided in CTR Section 16.1.13.1.8.1 AE tables:

"Total", defined as the total over all study phases (incl. screening, on-treatment, and 
follow-up)
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of violations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the RPM/DBLM. At this meeting, it will be decided whether a 
discrepant data value can be used in analyses or whether it must be corrected in the clinical 
database. Each protocol deviation must be assessed to determine whether it is an IPD. For 
definition of IPDs, and for the process of identification of these, refer to the BI reference 
document "Identify and Manage Important Protocol Deviations (iPD)" (2).


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If any IPDs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM minutes via an Excel spreadsheet (3). The table below contains the 
categories which are considered to be IPDs in this trial. If the data show other IPDs, this table 
will be supplemented accordingly by the time of the RPM/DBLM.
IPDs will be summarised and listed.
Table 6.2: 1
Important protocol deviations 
Category 
/ Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Non-compliance
C2
Incorrect dose of trial medication
D
Concomitant medication
D1
Prohibited medication use
E
Missing data
None1
G
Other trial specific important violations
G1
Certain violations of procedures used to measure primary or secondary PK data
Deviations C1, C2 and G1 can only be detected at the trial site.
1 Missing visits, evaluations, and tests will be considered missing data, not IPDs
Source: BI reference document "Identify and Manage Important Protocol Deviations (iPD)" (2).
6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
The following subject sets will be defined for statistical analysis:

Treated set (TS):
This subject set includes all subjects who were documented to have received one dose 
of study drug. This is the full analysis set population in the sense of ICH-E9. It will be 
used for analysis of safety, demographic data and baseline characteristics.

Pharmacokinetic parameter analysis set (PKS):
This subject set includes all subjects in the TS who provide at least one value for 
primary or secondary PK parameter that was not excluded because of iPDs relevant to 


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the statistical evaluation of PK endpoints as defined in Section 7.3 of the CTP. The 
discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to analysis sets will be made at latest at the RPM/DBLM
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Disposition
X
Exposure
X
IPDs
X
Demographic/baseline data
X
Safety parameters
X
Primary PK endpoints
X
Secondary PK endpoints
X
Further PK endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects who were withdrawn from the trial prior to first administration of 
any study drug will not be reported in the CTR.
Data of subjects who failed to complete all periods of the study (dropouts or withdrawals) will 
be reported in the CTR as far as their data are available. All withdrawals will be documented 
and the reason for withdrawal recorded in the CTR.
CTP: With respect to safety evaluations, it is not planned to impute missing values.
The only exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (4) [001-MCG-
156_RD-01].
Missing data and outliers of PK data are handled according to BI standards (5).
Blood/ Plasma/ Urine/ Faeces drug concentration or [14C]-radioactivity-time profiles


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CTP: Drug concentration data identified with NOS (no sample available), NOR (no valid 
result), NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no peak
detectable) will be displayed as such and not replaced by zero at any time point (this rule also
applies also to the lag phase, including the predose values).
Pharmacokinetic parameters 
CTP: For the non-compartmental analysis, concentration data identified with NOS, NOR or 
NOA will generally not be considered. Concentration values in the lag phase identified as 
BLQ or NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The 
lag phase is defined as the period between time zero and the first time point with a 
concentration above the quantification limit.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The last non-missing value determined prior to the first study drug administration will be 
defined as baseline. 
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM/DBLM.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (6).
The individual values of all subjects will be listed, sorted by dose group, subject number and 
visit. AE listings will be sorted by assigned treatment (see Section 7.8.1 below for details). 
The listings will be contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N
number of non-missing observations
Mean
arithmetic mean
SD
standard deviation
Min
minimum
Median
median
Max
maximum
For plasma concentrations as well as for all PK parameters, the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment. Percentages will be rounded to one decimal place. The category missing 
will be displayed if and only if there actually are missing values. Percentages will be based on 
all subjects in the respective subject set whether they have non-missing values or not.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. These will be based on the 
TS.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to MedDRA, version 21.1. Concomitant 
medication will be coded according to the World Health Organisation – Drug Dictionary, 
version of March 2018.
Only descriptive statistics are planned for this section of the report.
A medication will be considered concomitant to a dose group, if it

is ongoing at the time of first administration of this treatment, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a definition 
of treatments and analysis phases).
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint (cf. Section 5.4.2). Any 
deviations from complete intake will be addressed in the RPM/DBLM (cf. Section 6.2) and 
described in the CTR.
7.4
PRIMARY ENDPOINTS
Only descriptive statistics are planned for this section of the CTR. These will be based on the 
PKS. The analysis of standard PK parameters is performed according to BI standards (5)
[001-MCS-36-472_RD-01].
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
Exclusion of plasma/urine concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (5) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (7).


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the CTP.
7.5.2
Secondary endpoints
Secondary PK endpoints will be assessed descriptively. This will be based on the PKS.
The analysis of standard PK parameters is performed according to BI standards (5) [001-
MCS-36-472_RD-01].
See Section 7.4 of this TSAP for details regarding exclusion of PK parameters and plasma 
concentrations.
7.7
EXTENT OF EXPOSURE
Treatment exposure will only be listed by means of the date and time of drug administration.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For analysis, multiple AE occurrence data on the electronic case report form (eCRF) will be 
collapsed into an AE event provided that all of the following applies:

All AE attributes are identical (LLT, intensity, action taken, therapy required, seriousness, 
reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended).


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For further details on summarization of AE data, please refer to "Analysis and presentation of 
adverse event data from Clinical Trials" (8) and "Handling of missing and incomplete AE 
dates" (4).
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to the screening or treatment phases as defined in Section 6.1. AEs 
will be analysed based on actual treatments, as defined in Table 6.1: 1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 and for the class of 
AESIs.
CTP: The following are considered as AESIs:

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

Severe infections (according to RCTC grading)

Opportunistic and mycobacterium tuberculosis infections
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (9), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological or other lab abnormalities, or
(ii) which were reported with ‘action taken with study treatment’ other than ‘dose not 
changed’, or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class and preferred term. AEs which were considered by the investigator to be drug related 
will be summarised separately. Separate tables will also be provided for subjects with SAEs, 
subjects with AESIs and subjects with other significant AEs (according to ICH E3 (9)). AEs 
will also be summarized by maximum intensity.
The system organ classes will be sorted by total frequency, preferred terms will be sorted by 
total frequency (within system organ class).
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will also 
be summarised.


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For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standard
"Display and Analysis of Laboratory Data" (10). Alpha-1 Acid Glycoprotein values will only 
be listed.
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
Unscheduled measurements of laboratory 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. Descriptive statistics will be calculated by planned time 
point based on the worst value of the subject at that planned time point (or assigned to that 
planned time point).
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator’s comments on the eCRF or at the RPM/DBLM at the latest. It is the 
Investigator's responsibility to decide whether a lab value is clinically significant abnormal or 
not. Standard or project-specific rules for flagging clinically significant values will not be 
applied in this study.
Clinically relevant findings in laboratory data will be reported as AEs and will be analysed as 
part of AE analysis.
7.8.3
Vital signs
The analysis of vital signs will be descriptive in nature. Descriptive statistics of vital signs 
over time and for the difference from baseline (see Section 6.7) will be provided.
Unscheduled measurements of vital signs will be assigned to planned time points in the same 
way as described above for laboratory data. However, for vital signs, descriptive statistics will 
be calculated 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 data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.


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7.8.4
ECG
Abnormal findings in 12-lead ECG will be reported as baseline conditions (at screening) or as 
AEs (during the trial) if judged clinically relevant by the investigator, and will be analysed as 
such. No separate listing or analysis of ECG data will be prepared.
7.8.5
Others
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of first study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version
2.
001-MCS-40-413_1.0: "Identify and Manage Important Protocol Deviations (iPD)", 
current version; IDEA for CON
3.
"Template Domain DV", current version; Section "Resources and Key User Emails" on
ICBI homepage
4.
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version; 
IDEA for CON
5.
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies", current version; IDEA for CON
6.
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current version; 
IDEA for CON
7.
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD Data 
Files", current version; IDEA for CON
8.
001-MCG-156: "Analysis and Presentation of Adverse Event Data from Clinical Trials", 
current version; IDEA for CON
9.
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, current 
version
10. 001-MCG-157: "Display and Analysis of Laboratory Data", current version; IDEA for 
CON


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