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

Brief summary:
To investigate the absolute oral bioavailability of BI 730357 administered as tablet compared with \[C-14\]BI 730357 BS administered as intravenous microtracer

Detailed description:

Arms:
arm 1: Test treatment T followed by Reference treatment R

Interventions: intervention 1: BI 730357 intervention 2: BI 730357 mixed with [C-14] BI 730357 BS
Intervention descriptions: intervention 1: Oral dose intervention 2: Intravenous dose

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c22193484-01
EudraCT No.
2018-003103-19
BI Trial No.
1407-0033
BI Investigational
Medicinal Product
BI 730357
Title
Investigation of pharmacokinetics and absolute oral 
bioavailability of BI 730357 administered as an oral dose with 
an intravenous microtracer dose of BI 730357 BS (C-14) in 
healthy male volunteers
Lay Title
A study in healthy men to measure the amount of BI 730357 in 
the blood when taken as a tablet
Clinical Phase
I
Clinical Trial Leader
Phone: 
Fax:
Principal Investigator
Phone: 
Fax: 
Status
Final Protocol
Version and Date
Version: 1.0
Date: 29 Nov 2018
Page 1 of 64
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
Company name
Boehringer Ingelheim
Protocol date
29 Nov 2018
Revision date
Not applicable
BI trial number
1407-0033
Title of trial
Investigation of pharmacokinetics and absolute oral bioavailability of BI 730357 
administered as an oral dose with an intravenous microtracer dose of BI 730357 BS 
(C-14) in healthy male volunteers
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
This trial is intended to examine the absolute oral bioavailability of BI 730357 as 
tablet formulation for oral administration. The data are considered necessary to 
further understand the pharmacokinetics of BI 730357.
Trial objective
To determine the absolute oral bioavailability of BI 730357 after administration of 
50 mg BI 730357 as tablet and 100 µg BI 730357 BS (C-14) as intravenous 
microtracer
Trial design
Non-randomized, open-label, single period, single arm design
Trial endpoints:
Primary endpoints:
AUC0-[C-14]BI 730357 BS (after i.v. administration)
AUC0-BI 730357 (after p.o. administration)
Secondary endpoints: 
None defined.
Number of subjects 
total entered
6 *
each treatment
6 *
* In case a subject vomits within 12 hours after administration of 50 mg BI 730357 
as tablet on Day 1 or a subject drops out for other reasons, an additional subject 
may be entered and dosed in order to ensure at least 6 subjects completed the trial 
as per protocol. Thus, as up to 2 additional subjects may be entered, the actual 
number of subjects entered may increase up to a maximum of 8 subjects.
Diagnosis
Not applicable


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Main criteria
for inclusion
Healthy male subjects, age of 18 to 65 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product 1 (T)
BI 730357 film-coated tablet (test treatment T)
dose
50 mg
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Test product 2 (R)
BI 730357 BS (C-14) as intravenous solution (reference treatment R)
dose
100 µg infusion consisting of 98.0 µg unlabelled BI 730357 mixed with 2.0 µg 
labelled [C-14]BI 730357 BS in 10 mL i.v. solution (10 µg BI 730357 BS (C-14) /
mL)
The radioactive dose per infusion has been calculated to not exceed 
0.3 µCi = 0.01 MBq.
mode of admin.
Intravenous infusion of 15 min starting at 1.25 hours (i.e. around tmax) after an orally 
administered dose of 50 mg BI 730357 (as tablet)
Duration of treatment
Oral dose (test treatment T):
Single oral dose, Day 1
Intravenous dose (reference treatment R):
Single i.v. infusion of microtracer dose over 15 min, Day 1
Statistical methods
Absolute bioavailability (F) will be estimated by the ratio of the geometric means
(test treatment T / reference treatment R) for the primary endpoints
(dose normalized) AUC0-∞. Additionally, their two-sided 90% confidence intervals
(CIs) will be provided. This method corresponds to the two one-sided t-tests
procedure, each at the 5 % significance level. Since the main focus is on estimation
and not testing, an acceptance range was not specified. The statistical model will be
an ANOVA on the logarithmic scale including the fixed effect for ‘formulation’ and
‘subject’ as a random effect. CIs will be calculated based on the residual error from
ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
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.   Including pharmacogenomics sample
3.   The time is approximate; the 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.   At the end-of-trial visit, the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. 
7.
AEs and concomitant therapies will be recorded throughout the trial; during in-house days subjects will be specifically 
asked for twice daily. 
Visit
Day
Planned time (relative to first drug 
administration) [h:min]
Approximate clock time of actual 
day [h:min]
Event and comment
Safety laboratory
PK plasma BI 730357
PK plasma [C-14]BI 730357 BS 
12-lead ECG
Vital signs (BP, PR)
Local tolerability assessment
Questioning for AEs and 
concomitant therapy7
1
-21 to -2
Screening (SCR)1
x
x
x
2
-1
-18:00
14:00
Admission to trial site
x5
▲
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
▼
-14:00
18:00
Dinner 
-10:30
21:30
Light supper (voluntary)8
1
-2:00
06:00
x2,3
x3
x3
x3
0:00
08:00
Drug administration 
(50 mg BI 730357 as tablet, oral)
1:00
09:00
x
1:15
09:15
Start of IV infusion 
containing BI 730357 BS (C-14)
1:20
09:20
x
1:25
09:25
x
1:30
09:30
Stop of IV infusion
x
x
1:45
09:45
x
x
2:00
10:00
240 mL fluid intake
x
x
x
2:30
10:30
x
x
3:30
11:30
x
x
4:00
12:00
240 mL fluid intake
x
x
5:00
13:00
Lunch4
x
x
7:00
15:00
x
x
11:00
19:00
Dinner
12:00
20:00
x
x
2
24:00
08:00
Breakfast (voluntary)4,
discharge from trial site
x
x
x
x
x
x
4
72:00
08:00
Ambulatory visit9
x
x
6
120:00
08:00
Ambulatory visit9
x
x
x
8
168:00
08:00
Ambulatory visit9
x
x
3
9 to 15
End-of-trial (EoTrial) examination6
x
x
x
x


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8. To be consumed within 30 min to allow 10 h fasting prior to drug administration.
9.
The planned time is approximate; the ambulatory visit and the respective procedures are to be performed within a time 
window of +/- 3 hours to the planned time. 


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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
Non-clinical data ...................................................................................13
1.2.1.1
Non-clinical pharmacokinetics and metabolism......................13
1.2.1.2
Safety pharmacology ...............................................................14
1.2.1.3
Toxicology...............................................................................15
1.2.2
Clinical data...........................................................................................17
1.2.2.1
Clinical pharmacokinetics........................................................17
1.2.2.2
Clinical safety ..........................................................................18
1.2.3
Residual Effect Period..........................................................................18
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................19
1.4
BENEFIT - RISK ASSESSMENT ...................................................................19
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......22
2.1.1
Main objectives......................................................................................22
2.1.2
Primary endpoints ................................................................................22
2.1.3
Secondary endpoints.............................................................................22
.....................22
.....................22
.....................22
.....................22
.....................23
.....................23
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 24
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................24
3.3
SELECTION OF TRIAL POPULATION ......................................................25
3.3.1
Main diagnosis for trial entry..............................................................25
3.3.2
Inclusion criteria...................................................................................25
3.3.3
Exclusion criteria ..................................................................................26


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3.3.4
Withdrawal of subjects from treatment or assessments ...................27
3.3.4.1
Discontinuation of trial treatment............................................27
3.3.4.2
Withdrawal of consent to trial participation ............................28
3.3.4.3
Discontinuation of the trial by the sponsor..............................28
3.3.5
Replacement of subjects .......................................................................28
4.
TREATMENTS........................................................................................ 30
4.1
INVESTIGATIONAL TREATMENTS ..........................................................30
4.1.1
Identity of the Investigational Medicinal Products ...........................30
4.1.2
Selection of doses in the trial................................................................31
4.1.3
Method of assigning subjects to treatment groups ............................31
4.1.4
Drug assignment and administration of doses for each subject .......31
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.
ASSESSMENT ......................................................................................... 36
5.1
ASSESSMENT OF EFFICACY.......................................................................36
5.2
ASSESSMENT OF SAFETY............................................................................36
5.2.1
Physical examination ............................................................................36
5.2.2
Vital signs...............................................................................................36
5.2.3
Safety laboratory parameters..............................................................36
5.2.4
Electrocardiogram................................................................................39
5.2.4.1
12-lead resting ECG.................................................................39
5.2.5
Other safety parameters.......................................................................40
5.2.5.1
Local tolerability......................................................................40
5.2.6
Assessment of adverse events...............................................................40
5.2.6.1
Definitions of adverse events...................................................40
Adverse event ............................................................40
5.2.6.1.1
Serious adverse event ................................................40
5.2.6.1.2
AEs considered ‘Always Serious’.............................41
5.2.6.1.3
Adverse events of special interest .............................41
5.2.6.1.4
Intensity (severity) of AEs.........................................42
5.2.6.1.5
Causal relationship of AEs ........................................42
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................43


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AE collection.............................................................43
5.2.6.2.1
AE reporting to the sponsor and timelines ................44
5.2.6.2.2
Information required..................................................44
5.2.6.2.3
Pregnancy ..................................................................44
5.2.6.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................45
5.3.1
Assessment of pharmacokinetics .........................................................45
5.3.2
Methods of sample collection...............................................................45
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................45
5.3.3
Analytical determinations ....................................................................46
5.3.3.1
Analytical determination of analyte plasma concentration......46
5.6
APPROPRIATENESS OF MEASUREMENTS.............................................46
6.
INVESTIGATIONAL PLAN.................................................................. 48
6.1
VISIT SCHEDULE............................................................................................48
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................48
6.2.1
Screening period....................................................................................48
6.2.2
Treatment period ..................................................................................48
6.2.3
Follow-up period and trial completion ...............................................49
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 50
7.1
STATISTICAL DESIGN – MODEL ...............................................................50
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................50
7.3
PLANNED ANALYSES....................................................................................50
7.3.1
Primary endpoint analyses...................................................................51
7.3.2
Secondary endpoint analysis................................................................52
....................................................52
....................................................52
7.3.4
Safety analyses.......................................................................................53
7.4
INTERIM ANALYSES .....................................................................................53
7.5
HANDLING OF MISSING DATA ..................................................................54
7.5.1
Safety......................................................................................................54
7.5.2
Pharmacokinetics..................................................................................54
7.6
RANDOMISATION ..........................................................................................54
7.7
DETERMINATION OF SAMPLE SIZE ........................................................54
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 55


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8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................55
8.2
DATA QUALITY ASSURANCE .....................................................................56
8.3
RECORDS..........................................................................................................56
8.3.1
Source documents .................................................................................56
8.3.2
Direct access to source data and documents.......................................57
8.3.3
Storage period of records.....................................................................57
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................57
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......57
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................58
8.6
TRIAL MILESTONES .....................................................................................58
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................59
9.
REFERENCES......................................................................................... 60
9.1
PUBLISHED REFERENCES...........................................................................60
9.2
UNPUBLISHED REFERENCES.....................................................................61
10. APPENDICES .......................................................................................... 62
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 63
11.1
GLOBAL AMENDMENT 1 .............................................................................63
11.2
GLOBAL AMENDMENT 2 .............................................................................63


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ALCOA
Attributable, legible, contemporaneous, original, accurate
AMS
Accelerator mass spectometry
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BA
Bioavailability
BCS
Biopharmaceutics Classification System
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BS
base
Cmax
Maximum measured concentration of the analyte in plasma after oral 
administration
CA
Competent authority
CI
Confidence interval
CNS
Central nervous system
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CRO
Contract Research Organisation
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager 
CTP
Clinical trial protocol
CTR
Clinical trial report
CTSU
Clinical Trial Supplies Unit


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DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EudraCT
European Clinical Trials Database
FU
Follow-up
GCP
Good Clinical Practice
gMean
Geometric mean
hERG
Human-ether-à-go-go related gene
hLXRα
human liver X receptor α
IB
Investigator’s brochure
iCF
intended clinical formulation
ICRP
International Commission on Radiological Protection
IC50
50% inhibitory concentration
IEC
Independent Ethics Committee
IPD
Important protocol deviation
IQRM
integrated quality and risk management
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NOAEL
No observed adverse effect level
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)


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R
Reference treatment
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
Standard operating procedure
SRD
Single-rising dose
T
Test product or treatment
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
XTC
Ecstasy 


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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.
1.1
MEDICAL BACKGROUND
Retinoic acid-related orphan receptor γt (RORγt) is a nuclear hormone receptor/transcription 
factor expressed in T helper 17 (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].
1.2
DRUG PROFILE
1.2.1
Non-clinical data
1.2.1.1
Non-clinical pharmacokinetics and metabolism


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1.2.1.2
Safety pharmacology


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1.2.1.3
Toxicology
Repeated dose toxicology


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Genetic Toxicology
Phototoxicity


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1.2.2
Clinical data
Up to now, BI 730357 has clinically been tested by Boehringer Ingelheim in a completed 
first-in- human trial, a multiple-rising dose trial (report in preparation) and a human ADME
(hADME) trial (being analyzed) [c09228382; c14109663-03; c22159106-02].

In the first-in-human trial BI 730357 was administered in doses ranging from 2 mg 
through 800 mg to a total of 84 healthy male volunteers. The maximum dose given 
under fasted conditions was 400 mg as tablet.

The multiple-rising-dose trial tested administration of BI 730357 over 14 to 28 days 
with daily doses of 25 to 400 mg. The highest dose tested under fasting conditions 
was 200 mg dose for 28 days.

The hADME trial tested the metabolism of a 50 mg dose of radioactively labelled 
BI 730357 BS (C-14) administered as an oral solution.
1.2.2.1
Clinical pharmacokinetics


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1.2.2.2
Clinical safety 
1.2.3
Residual Effect Period
The Residual Effect Period (REP) of BI 730357 is 7 days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.


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1.3
RATIONALE FOR PERFORMING THE TRIAL
This trial is intended to examine the absolute oral bioavailability of BI 730357 using an 
intravenous [C-14]-microtracer approach. The data are considered necessary to further 
understand the pharmacokinetics of BI 730357.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 730357. 
Subjects are exposed to risks of study procedures and risks related to the exposure to the trial
medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of intravenous infusion or blood 
sampling may result in mild bruising, and in rare cases, in transient inflammation of the wall 
of the vein, or nerve injury, potentially resulting in paraesthesia, reduced sensibility, and/or 
pain for an indefinite period. The same risks apply for venepuncture with the purpose of 
blood sampling or safety laboratory assessment.
The solvent for the intravenous infusion containing a mixture of labelled and unlabelled 
BI 730357 is 10% PEG 400 in saline. Therefore, in case of inadvertent paravenous drug 
administration apart from local swelling no tissue damage is expected.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
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 5.2.6.1.4, adverse events of special interest.
Risks related to oral 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, the multiple-
rising-dose trial 1407-0002 and the hADME trial 1407-0031 (see Section 1.2.2):


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Administration of a microtracer dose of 100 µg BI 730357 BS (C-14) as infusion is expected 
to only marginally increase the systemic exposure to BI 730357.
Since preclinical data indicate that BI 730357 has phototoxicity potential, direct exposure to
the sun or exposure to solarium radiation is not allowed during the entire study, and use of 
sunscreens is mandatory in that time (see Section 4.2.2.2).
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,
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.
 
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 intravenous administration of BI 730357 BS (C-14) solution
No intravenous route is planned for therapeutic use of BI 730357. Therefore, in accordance 
with the guideline on non-clinical safety studies on microdose trials (ICH-M3(R2), 
[R15-0594]), the intravenous microtracer dose of 100 µg BI 730357 BS (C-14) is considered 


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to be adequately qualified by the existing oral toxicity studies where adequate exposure 
margins have been reached. An investigation of intravenous local tolerance of the drug 
substance is not recommended in this situation because the administered dose is very low
(100 µg maximum) and no novel i.v. vehicle is used. 
BI 730357 is labelled with isotope [14C] which is necessary for the purpose of this 
microtracer trial in order to distinguish the intravenously administered labelled drug from the 
unlabelled oral drug. The radioactive dose per infusion will be approximately 0.01 MBq. The 
mean radiation burden per subject has been calculated to be 0.001 mSv [c25209040] and 
thereby falls into the ICRP 1 category (trivial level of risk).
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 and up to 800 mg under fed conditions was safe and well tolerated 
[c16462083-01]. In the current trial, it is planned that healthy male volunteers will receive a 
single oral dose of 50 mg BI 730357 as a tablet and an intravenous microdose of 100 µg 
BI 730357 BS (C-14) as infusion. 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 participant will receive only one infusion containing a radioactive dose 
<0.1 mSv (ICRP 1 category, negligible radio burden).
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 1 with 
minor level risk and in WHO Category 1, i.e. within variations of natural background
radioactivity. This is considered to be acceptable.
The investigation of the absolute bioavailability of this BCS class II compound contributes 
substantially to a better understanding of BI 730357’s pharmacokinetics. 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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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the absolute oral bioavailability of 50 mg 
BI 730357 administered as tablet (test treatment, T) compared with 2 µg of [C-14]BI 730357 
BS administered as intravenous microtracer. The total dose administered i.v. is a mixture of 
2 µg labelled [C-14]BI 730357 BS mixed with 98 µg of unlabelled BI 730357 (reference
treatment, R).
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined in plasma for 
[C-14]BI 730357 BS after intravenous administration and for BI 730357 after oral 
administration: 

AUC0-(area under the concentration-time curve of the analyte over the time interval
from 0 to infinity)
2.1.3
Secondary endpoints
No secondary endpoints are defined for this trial.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This Phase 1 study will be performed as a non-randomised, open-label, single period, single 
arm trial in healthy male subjects in order to compare the test treatment (T) to the reference 
treatment (R). Treatment T will be one oral tablet of 50 mg BI 730357 (intended clinical 
formulation (iCF)). Treatment R will be an intravenous microtracer infusion of 100 µg BI 
730357 BS (C-14) consisting of 2 µg labelled [C-14]BI 730357 BS mixed with 98 µg 
unlabelled BI 730357 in 10 mL i.v. solution (10 µg BI 730357 BS (C-14) /mL). Both 
treatments will be given in the fasted state. For details, refer to Section 4.1.
Drug administration in treatment R will start 1.25 hours after drug administration in treatment 
T, i.e. at the time of the expected tmax of treatment T.  
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
To investigate the absolute bioavailability, a single arm, single period trial design using a 
microtracer approach* was considered the favorable design compared to the traditional cross-
over design for the following reasons:

Like with a traditional cross-over design, each subject serves as his own control 
removing inter-subject variability. Additionally, day-to-day variability within a 
subject is also eliminated as potential confounding variable since each subject is 
exposed to the two treatments in parallel, i.e. treatment R will be administered at tmax
of treatment T

Expected favorable safety due to very low exposure levels after an intravenous 
microdose

The radioactive dose per infusion has been calculated not to exceed 
0.3 µCi = 0.01 MBq (radiation burden per subject 0.001 mSv), and thus falls into 
the ICRP 1 category. The radiation burden is negligible [R15-3219]. 

Shortened duration of the clinical trial
The open-label treatment is not expected to bias results since the study endpoints are derived 
from measurements of plasma concentrations of the analytes.
_____________
*In this context ‘microtracer’ is defined as an intravenous dose of an isotopically labelled drug in an absolute bioavailability 
study administered as 1% of the pharmacologic dose or 0.1 mg, whichever is lower [R17-1799].


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3.3
SELECTION OF TRIAL POPULATION
It is planned that 6 healthy male subjects will enter the study. They will be recruited from the 
volunteers' pool of the trial site or, if necessary, via advertisement. In case a subject vomits 
within 12 h after administration of treatment T or a subject drops out for other reasons, up to
2 additional subjects may be entered and dosed to assure that 6 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 absolute oral bioavailability of BI 730357. 
Healthy male subjects are an ideal population for the objectives of this trial, since they 
provide relatively stable physiological, biochemical and hormonal conditions, i.e. the absence 
of disease-related variations and relevant concomitant medications.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 65 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
5. Subjects who are sexually active must use, with their partner, highly effective 
contraception from the time of administration of trial medication until 4 months after 
administration of trial medication. Adequate methods are:

Condoms plus use of hormonal contraception by the female partner that started at 
least 2 months prior to administration of trial medication (e.g. implants, injectables, 
combined oral or vaginal contraceptives, intrauterine device) or

Condoms plus surgical sterilization (vasectomy at least 1 year prior to enrolment) or

Condoms plus surgically sterilised partner (including hysterectomy) or

Condoms plus intrauterine device or

Condoms plus partner of non-childbearing potential (including homosexual men)
Subjects are required to use condoms to prevent unintended exposure of the partner to 
the study drug via seminal fluid. Male and female condoms must not be used together. 


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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, whit 
their partner, they must comply with the contraceptive requirements detailed above.
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 139 mmHg, 
diastolic blood pressure outside the range of 45 to 89 mmHg, or pulse rate outside the 
range of 40 to 100 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Clinically significant gastrointestinal (including known or suspected inflammatory bowel 
disease), hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. 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 or loss of more than 100 mL within 60 days of planned administration of 
trial medication or intended blood donation during the trial. Donation or loss of more than 
1.5 litres of blood in the 10 months prior to planned administration of trial medication.
18. Intention to perform excessive physical activities within 4 days prior to the administration 
of trial medication or during the trial


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19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTcF intervals that are 
repeatedly greater than 450 msec in males) or any other relevant ECG finding at 
screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criterion applies:
23. Unwillingness to adhere to the rules of UV-light protection as described in Section 4.2.2.2
24. A positive QuantiFERON-TB Gold Test
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. At the time of 
discontinuation, a complete end-of-trial examination will be performed, if possible, and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.3), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 
and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.
Since the risks of drug exposure of a (pregnant) female partner of a male study participant via 
the seminal fluid are yet unknown, adequate contraception as outlined in Section 3.3.2 is a
prerequisite for participation in the study.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision.
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.


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3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment.
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events (AEs), or diseases).
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF.
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals 
2. 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 1 drug-related serious adverse event is 
reported
3. Violation of GCP, or the CTP, or the contract with BI impairing the appropriate conduct
of the trial
4. The sponsor decides to discontinue the further development of the investigational product
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case a subject vomits within 12 h after oral trial drug administration suggesting an 
incomplete absorption of the tablet or a subject drops out for other reasons, an additional
subject may be entered and dosed to ensure that 6 subjects will complete the study as per 
protocol. In total, no more than 2 subjects will be replaced.


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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 trial subject number.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational unlabelled product for test treatment T has been manufactured by BI 
Pharma GmbH & Co. KG. BI 730357 50 mg film-coated tablets are the intended commercial 
formulation (iCF) and will be administered orally.
Radiolabelled BI 730357 BS (C-14) for reference treatment R is administered as an 
intravenous solution. The powder used for intravenous solution contains radiolabelled 
[C-14]BI 730357 BS and unlabelled BI 730357 and both components are manufactured and 
mixed by BI Pharma GmbH & Co. KG. The intravenous solution from this mixture is made 
by
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the investigational medicinal product (1) for test treatment T are given 
below:
Name:
BI 730357 intended commercial formulation (iCF) 
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
50 mg
Posology:
1-0-0
Route of administration:
oral
Duration of use:
single dose
The characteristics of the investigational medicinal product (2) for reference treatment R are 
given below:
Name:
BI 730357 BS (C-14) intravenous solution
Substance:
BI 730357 mixed with [C-14] BI 730357 BS
Pharmaceutical formulation:
Intravenous solution
Source:
Unit strength:
100 µg BI 730357
-
consisting of 2 µg labelled [C-14]BI 730357 BS mixed 
with 98 µg unlabelled BI 730357 
-
in 10% PEG 400 in saline solution of 10 mL volume 
(concentration of BI 730357 BS (C-14): 10 µg/mL)
Posology:
1-0-0
Route of administration:
intravenous
Duration of use:
single infusion over 15 min


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4.1.2
Selection of doses in the trial
The oral dose of BI 730357 tested in this trial is one single dose of 50 mg. This dose is below 
the highest doses (single dose up to 400 mg under fasted and up to 800 mg under fed 
conditions) already tested in healthy volunteers in previous trials [c16462083-01]. The dose 
of 50 mg was 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.
Using the microtracer approach to investigate the absolute bioavailability, the intravenously 
administered dose is not expected to significantly add to the systemic drug concentrations 
arising from the oral administration [R17-1799]. The oral dose (50 mg BI 730357) is 
500-fold higher than the intravenously infused dose (100 µg). Therefore, exposure of 
BI 730357 resulting from the infusion is considered negligible (see Section 1.4).
The radioactive dose administered via infusion has been calculated to not exceed 
0.3 µCi=0.01 MBq, and thus falls into the ICRP 1 category (negligible radiation burden)
[R18-1905]. 
4.1.3
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.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a non-randomised, open-label, single period, single arm trial. All subjects will 
receive the same treatments. The treatments to be evaluated are outlined in Table 4.1.4: 1
below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T (Test)
BI 730357
Film-coated 
tablet
50 mg
1 tablet as single dose on Day 1
50 mg
R (Reference)
BI 730357 
BS (C-14)
i.v. solution
10 µg/mL
i.v. infusion of 10 mL over 15 min 
on Day 1
100 µg
Administration of treatment T will be performed after subjects have fasted overnight; fasting 
is to start no later than 10 h before the scheduled dosing. 
The oral medication (treatment T) will be administered as a single oral dose together with 
about 240 mL of water to a subject in the sitting/standing position under supervision of the 
investigating physician or an authorised designee. 
From administration of treatment T until 5 hours thereafter, subjects are not allowed to lie 
down (i.e. no declination of the upper body of more than 45 degrees from upright posture) 
except when needed for study assessments or when indicated by the investigator. During the 
intravenous infusion subjects will be in a semi supine position.


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The microtracer (treatment R) will be administered starting 1.25 h after treatment T as a 
constant intravenous infusion over 15 min to a subject in semi supine position under
supervision of the investigating physician or an authorised designee. Start and end time of the 
infusion will be recorded. For administration of the intravenous microtracer solution an 
indwelling catheter is placed into an arm vein of the subject and will be kept patent with a 
saline infusion. A second indwelling catheter used for collection of blood samples will be 
placed on the contralateral arm. The handling instructions for the intravenous microtracer will 
be filed in the ISF.   
For drug administrations, the so-called four-eye principle (two-person rule) should be 
applied. For this, one authorised employee of the trial site should witness the administration 
of trial medication, and – if applicable – its preparation (e.g. reconstitution), if correct dosage 
cannot be ensured otherwise.
Subjects will be kept under close medical surveillance until 24 h after administration of 
treatment T. The in-house stay can be extended in case considered medically necessary by the 
investigator.
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided because the dose of trial medication is known to 
investigators and subjects.
4.1.6
Packaging, labelling, and re-supply
The investigational product for treatment T (BI 730357, 50 mg tablets) will be provided by 
BI. Drug supply will be packaged and labelled in accordance with local law and the 
principles of Good Manufacturing Practice.
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. The required information according to the Local Drug Law as well as 
Annex 13/EU GMP Guideline will be provided on the containers.
Both components (radiolabeled [C-14]BI 730357 BS mixed with unlabeled BI 730357) used 
for manufacturing of the intravenous solution will be provided to 
 by the Isotope 
Chemistry of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. The final 
container used for administration of the radiolabeled drug product will be a syringe for 
intravenous infusions and will be labeled according to GMP Annex 13/EU GMP Guideline 
and local drug law. 
For details of packaging and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms.
No re-supply is planned.


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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 in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
 pharmacy will receive the investigational medicinal product 1 (50 mg BI 730357 film-
coated tablet) delivered from the sponsor once the below mentioned requirements are 
fulfilled. 
 pharmacy will deliver investigational medicinal products 1 and 2 to the 
investigator upon availability of a valid prescription from the investigator. The investigator 
also will not order the investigational medicinal products from the 
 pharmacy before 
these requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of a signed and dated clinical trial protocol  

Availability of a licence for clinical research using radioactive isotopes
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed 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. In case of AEs 
the volunteers will be treated as necessary and if required will be kept under constant 
supervision at the trial centre or transferred to hospital until all the results of the evaluations 
have returned to a medically acceptable level. 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, 
 
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 will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. When not fasting, meals and snacks (such as decaffeinated 
coffee, herbal tea, fruit, and biscuits) will be provided according to 
 standard operating 
procedures (SOPs).
Subjects are to be fasted for at least 10 h prior to administration of treatment T. No food is 
allowed for at least 5 h after treatment T. For fasting times before safety laboratory 
investigations see Section 5.2.3.
From 1 h before administration of treatment T until lunch, fluid intake is restricted to the 
water administered with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose 
(mandatory for all subjects). From lunch until 24 h after treatment T, total fluid intake is 
restricted to 3000 mL. 


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Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before admission to the trial site until after the last PK is collected.
Poppy-seed containing products should not be consumed within 2 days before screening and 
starting 2 days before admission to the trial site until after the last PK sample is collected.
Alcoholic beverages are not allowed within 48 hours before screening and before admission 
to the trial site and during in-house confinement at the trial site. During ambulatory phases 
alcohol consumption is restricted to 2 units per days.
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 24 h before admission to the trial site 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 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. When exposed to sunlight, study participants should protect skin areas not 
covered by clothes by using sun-protection creams and lip balms with sun protection factor 
30 or higher with protection against UV-A and UV-B. Patients should wear sun glasses when 
exposed to direct sun or other sources of UV-light. These protection measures must be 
applied until the end of 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 plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENT
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported),
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a physical examination. At 
the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, and a physical examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap CareScape VC150, GE Healthcare) 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.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 4 h 
(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. 
Overnight fasting is not required at the discretion of the investigator or designee for re-tests.
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
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
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
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 
INR (International Normalization Ratio)
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 (total)
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
Electrolytes
Sodium
Potassium
Magnesium
Calcium
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
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)
B: parameters to be determined at Visit 2, Day -1, Day 2 and Day 6, and at Visit 3 (end-of-trial examination)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. 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 prior to the treatment period, and may be repeated at 
any time during the study at the discretion of an investigator or designee. The results will not 
be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 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.


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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
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Alcohol
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
QuantiFERON-TB Gold
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 times provided 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 10-second ECGs 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 to avoid compromising ECG 
quality. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons.
Storage
All ECGs will be stored electronically.
Evaluation
All ECGs will be locally printed and be evaluated by the investigator or a designee. 


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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 assessed to be clinically relevant by the investigator. Any ECG abnormalities 
will be carefully monitored and, if necessary, the subject will be removed from the trial and 
will receive the appropriate medical treatment. 
5.2.5
Other safety parameters
5.2.5.1
Local tolerability
Local tolerability will be assessed by the investigator on the basis of swelling, induration, 
heat, redness, pain, and other findings and reported as AE in case of clinical relevant 
findings.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
Adverse event
5.2.6.1.1
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
5.2.6.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation  


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


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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 (grading according to Rheumatology Common Toxicity Criteria 
(RCTC) developed by OMERACT [R13-3515])

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
5.2.6.1.5
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
5.2.6.1.6
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure


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
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
5.2.6.2
Adverse event collection and reporting
AE collection
5.2.6.2.1
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 


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o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
Pregnancy
5.2.6.2.4
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B)
as well as non-trial specific information and consent for the pregnant partner.


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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.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 730357 concentrations in plasma, 3 mL of blood will be drawn from 
an antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetic
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. 
For quantification of [C-14]BI 730357 plasma concentrations, an additional 3 mL K2-EDTA 
tube will be collected as indicated in the Flow Chart. Blood will be withdrawn by means of 
either an indwelling venous catheter or by venepuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged and obtained plasma will be 
split into aliquots. The first aliquots should contain at least 0.5 mL of plasma. The volume of 
the second aliquots may be less than 0.5 mL plasma. The process from blood collection until 
transfer of plasma aliquots into the freezer should be completed in less than 60 min with 
interim storage of blood samples and aliquots on ice water. The time each aliquot was placed
in the freezer will be documented. Until transfer on dry ice to the analytical laboratory, the 
aliquots will be stored frozen and in an upright position at about -20°C or below at the trial 
site. The second aliquot will be transferred to the analytical laboratory after the bioanalyst has 
acknowledged safe arrival of the first aliquot.
For detailed description of blood sampling, sample handling, sample preparation, sample 
storage, tube labelling and sample shipment refer to the laboratory manual. 
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g. for stability testing or assessment of metabolites. However, only data 
related to the analyte and/or its metabolite(s) 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 after the CTR is 
archived.


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5.3.3
Analytical determinations
5.3.3.1
Analytical determination of analyte plasma concentration

Concentrations of unlabelled BI 730357 in plasma will be determined by a validated LC-
MS/MS (liquid chromatography tandem mass spectrometry) assay. The analyses will be 
performed at:

Concentrations of [C-14]BI 730357 BS in plasma will be determined by a validated AMS 
(accelerator mass spectrometry) assay. The analyses will be performed at:
Since this is an open label study, the bioanalyst will be unblinded during sample analysis. 
5.6
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 


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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 and intravenously administered drug, and are 
widely used in clinical trials. The pharmacokinetic parameters and measurements outlined in 
Section 5.4 are generally used assessments of drug exposure.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end-of-trial examination are provided in the 
Flow Chart.
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 ± 180 min on the following days of Visit 2.
If several activities, including 12-lead ECG and meal intake, are scheduled at the same time 
point in the Flow Chart, ECG should be the first and meal intake the last activity.
Furthermore, if several measurements including venepuncture are scheduled for the same 
time, venepuncture should be the last of the measurements due to its inconvenience to the 
subject and possible influence on physiological parameters.
For planned blood sampling times refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
Screening visit is defined as Visit 1.
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.1 to 5.2.5.
6.2.2
Treatment period
Each subject is expected to participate in one treatment period (Visit 2).
On Day -1 of Visit 2, study participants will be admitted to the trial site and kept under close 
medical surveillance for at least 24 h following administration of treatment T. The subjects 
will then be allowed to leave the trial site after formal assessment and confirmation of their 
fitness. On all other study days, subjects will be treated in an ambulatory fashion.


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For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.3
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.1 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate the absolute bioavailability of 50 mg 
BI 730357 administered as tablet (test treatment, T) compared with 2 µg of labelled [C-14]BI 
730357 BS administered as intravenous microtracer (mixed with 98 µg unlabelled BI 
730357), (reference treatment, R) on the basis of the primary pharmacokinetic endpoints, as 
listed in Sections 2.1.2 . The trial is designed to allow intra-subject comparisons and will be 
evaluated statistically by use of an appropriate linear model. 
The assessment of safety and tolerability is a further objective of this trial, and will be
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The absolute bioavailability of 50 mg orally administered BI 730357 compared with 2 µg of 
labelled [C-14]BI 730357 administered as intravenous microtracer (mixed with 98 µg 
unlabelled BI 730357) will be estimated by the ratio of the geometric means (test/reference)
for the dose-normalized primary PK endpoints. Additionally, their 2-sided 90% confidence 
intervals (CIs) will be provided. This method corresponds to the two one-sided t-test 
procedure, each at the 5% significance level. Since the main focus is on estimation and not 
testing, a formal hypothesis test and associated acceptance range is not specified.
Confidence intervals have to be interpreted in the perspective of the exploratory character of 
the study, i.e. confidence intervals are considered as interval estimates for effects.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treated set will be used for safety 
analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary and 
was not excluded due to a protocol deviation relevant to the evaluation of PK or due 
to PK non-evaluability (as specified in the following subsection ‘Pharmacokinetics’).
Thus, a subject will be included in the PKS, even if he contributes only one PK 
parameter value for the study period to the statistical assessment. Descriptive and 
model based analyses of PK parameters will be based on the PKS.


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Adherence to the protocol will be assessed by the trial team. Important protocol deviation
(IPD) categories will be suggested in IQRM plan, IPDs will be identified no later than in the 
Report Planning Meeting, and the IPD categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for drug BI 730357 will be calculated 
according to the relevant SOP of the Sponsor (001-MCS-36-472). 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol 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 concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (median tmax is to be determined excluding the subjects 
experiencing emesis), 

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.3.1
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: ‘subjects’ and ‘formulation’. The 


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effect 'subjects’ will be considered as random, whereas ‘formulation’ will be considered as
fixed. The model is described by the following equation:
ykm = +  sm + k + ekm, where
ykm = logarithm of response (dose normalized primary endpoint, see Section 2.1.2)
measured on subject m receiving formulation k,
= the overall mean,
sm = the effect associated with the mth subject,
m = 1, 2, ..., n
k = the kth formulation effect (either tablet or i.v.), k = 1, 2,
ekm = the random error associated with the mth subject who received
formulation k.
Point estimates for the ratio of the geometric means (test/reference) for the primary endpoints
(see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be provided.  
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means).
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
7.3.2
Secondary endpoint analysis
Not applicable.


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7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.3) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, those between first trial medication intake (test 
treatment) and beginning of reference treatment will be assigned to the test treatment period. 
Those between the start of infusion until the end of REP (see Section 1.2.3) will be assigned 
to the combined test/reference treatment period. Events occurring after the REP but prior to 
next intake or end of trial termination date will be assigned to ’follow-up’. These assignments 
including the corresponding time intervals will be defined in detail in the TSAP. Note that 
AEs occurring after the last per protocol contact but entered before final database lock will be 
reported to Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.4
INTERIM ANALYSES
No interim analysis is planned.


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7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Randomisation is not applicable in this open-label, single arm study. All subjects will receive 
the same treatment. Consecutive subject numbers will be assigned via the EDC system.
7.7
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. In case of observing dropouts, the sample size may 
increase to a maximum of 8 to have at least 6 subjects who completed the trial as per 
protocol.
For replacement rules, refer to Section 3.3.5.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC and other relevant regulations. Investigators and site staff must adhere to these 
principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract.
As a general rule, no trial results should be published prior to archiving of the CTR.
The terms and conditions of the insurance coverage will be described in the ICF and also 
stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (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 retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and
should be conducted according to the sponsor’s instructions.


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


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


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


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The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at 
 
, under the supervision of the Principal Investigator. Relevant documentation 
on the participating (Principal) Investigators (e.g. their curricula vitae) will be filed in the 
ISF.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

ensure appropriate training and information of Clinical Trial Manager (CTM), 
Clinical Research Associates, and investigators of participating trial sites
The non-labelled trial medication (intended commercial formulation (iCF) of 50 mg BI 
730357) will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma GmbH & 
Co. KG, Biberach, Germany.
The radio-labelled trial medication (intravenous microtracer solution) will be provided by 
.
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
).
The analyses of unlabelled BI 730357 concentrations in plasma will be performed at the 
Department of Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, 
Biberach, Germany.
The analyses of labelled [C-14]BI 730357 BS concentrations in plasma via AMS analysis 
will be conducted 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 or a contract research 
organisation appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
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.
R13-3515
Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, Tsuji 
W, Stevens R, Fries J, Witter J, Johnson K, Lassere M, Brooks P. 
Standardizing assessment and reporting of adverse effects in rheumatology 
clinical trials II: the Rheumatology Common Toxicity Criteria v.2.0. J 
Rheumatol 2007;34(6):1401-1414.
R15-0594
European Medicines Agency (EMA). ICH guideline M3(R2) on non-
clinical safety studies for the conduct of human clinical trials and marketing 
authorization for pharmaceuticals: step 5 (December 2009, 
EMA/CPMP/ICH/286/1995). 
website.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/
2009/0 9/WC500002720.pdf (access date: 5 February 2015) ; London: 
European Medicines Agency (EMA); 2009.
R15-3219
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%20Publication%20103%20(Use
rs%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.
R17-1799
Lappin G. Approaches to intravenous clinical pharmacokinetics: recent 
developments with isotopic microtracers. J Clin Pharmacol 2016;56(1):11-
23.
R18-1905
International Commission on Radiological Protection (ICRP). Factors 
related to project evaluation. Ann ICRP 1992;22(3):11-13.


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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c09228382
 
Investigator Brochure 1407.P1 Version 5.0 - BI 
730357 RORgamma Inhibitor - Psoriasis (ankylosing spondylitis, psoriatic 
arthritis, asthma, inflammatory bowel disease). 06 Aug 2018.
c14109663-03
 Phase Ib evaluation of the safety and tolerability and 
effect on midazolam metabolism of the administration of multiple rising 
doses of BI 730357 to healthy volunteers. 1407.2. 12 Jan 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.
c22159106-02
 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. 1407-0031. 25 Sep 
2018.
c25209040
 radiation-burden-calculation-report-v-2. 1407-0031. 2018 
Jul 05. 


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10.
APPENDICES
Not applicable.  


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Medicinal 
Product(s)
Title of protocol
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Description of change
Rationale for change
11.2
GLOBAL AMENDMENT 2
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Medicinal 
Product(s)
Title of protocol
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 


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Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c22193484
1.0
clinical-trial-protocol
Investigation of pharmacokinetics and absolute oral bioavailability of BI 730357
administered as an oral dose with an intravenous microtracer dose of BI 730357 BS
(C-14) in healthy male volunteers
Author-Clinical Trial 
05 Dec 2018 07:45 CET
Author-Trial Statistician
05 Dec 2018 08:15 CET
Author-Trial Clinical
Pharmacokineticist
05 Dec 2018 09:03 CET
Approval-Team Member Medicine
05 Dec 2018 14:12 CET
Approval-Therapeutic Area 
05 Dec 2018 18:57 CET
Verification-Paper Signature
Completion
10 Dec 2018 07:52 CET


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c22193484
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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c26809055-01
BI Trial No.:
1407-0033
Title:
Investigation of pharmacokinetics and absolute oral bioavailability 
of BI 730357 administered as an oral dose with an intravenous 
microtracer dose of BI 730357 BS (C-14) in healthy male 
volunteers
Investigational
Product(s):
BI 730357
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
17 APR 2019 SIGNED
Version:
“Final”
Page 1 of 23
Proprietary confidential information
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 ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINT .................................................................................9
5.3
FURTHER ENDPOINTS.....................................................................................9
5.3.2
Safety parameters .................................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................12
...........................................................................................13
6.5
POOLING OF CENTRES .................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................13
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................14
7.
PLANNED ANALYSIS......................................................................................15
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........16
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................16
7.3
TREATMENT COMPLIANCE........................................................................16
7.4
PRIMARY ENDPOINT .....................................................................................16
7.5
SECONDARY ENDPOINT ...............................................................................17
7.6
FURTHER ENDPOINTS...................................................................................17
7.6.1
Safety parameters ...............................................................................................17
7.7
EXTENT OF EXPOSURE.................................................................................17
7.8
SAFETY ANALYSIS..........................................................................................17
7.8.1
Adverse events.....................................................................................................17
7.8.2
Laboratory data ..................................................................................................19
7.8.3
Vital signs.............................................................................................................19
7.8.4
ECG......................................................................................................................19
7.8.5
Others...................................................................................................................19
8.
REFERENCES....................................................................................................21


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......................................................................22
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 6.1: 2
Overview of treatments for intra-individual comparison .................................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
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ANOVA
analysis of variance
AST
Aspartate aminotransferase
AUC0-
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
BS
base
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBLM
Database lock meeting
gCV
geometric coefficient of variation
ICH
International Conference On Harmonisation
iPD
Important Protocol Deviations
IQRMP
Integrated Quality and Risk Management Plan
MedDRA
Medical Dictionary For Regulatory Activities
NOA
Not analysed
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetic(s)
PKS
Pharmacokinetc set
Q1
Lower Quartile
Q3
Upper Quartile
RAGe
Report appendix generator
REP
Residual effect period
RPM
Report Planning Meeting
SAE
Serious adverse event
SD
Standard Deviation


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Term
Definition / description
SOC
System Organ Class
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal


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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 CTP, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 "Statistical Methods and Determination of 
Sample Size". Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
Study data will be stored in a trial database within the 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 Phoenix 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
5.3
FURTHER ENDPOINTS
5.3.2
Safety parameters
Further safety parameters of interest will be used as defined in Section 2.2.2.2 of the CTP:
CTP:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignments of dose groups, 
and selection of doses, cf. Section 4 of the CTP.
All subjects were planned to be treated with 

one non-radiolabelled film-coated tablet of 50 mg BI 730357 on Day 1
and

a single iv infusion of the microtracer 100 μg BI 730357 BS (C-14) on Day 1
The microtracer (reference treatment) will be administered starting 1.25 h after the 
administration of the table (test treatment) as a constant intravenous infusion over 15 min.
For statistical analysis of AEs, safety laboratory data and vital signs, the following analysis 
phases are defined for each subject:
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety laboratory 
data and vital signs
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first administration 
of BI 730357
On-treatment
BI 730357
Date/time of first 
administration of BI 730357
Date/time of last administration of 
BI 730357 + REP (7 * 24 h)
Follow-up
F/U BI 730357
Date/time of last 
administration of BI 730357 + 
REP (7 * 24 h)
12:00 a.m. on day after subject's 
trial termination date
It will not be differentiated between intravenous or oral administration of the drug.
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.
CTR Appendix 16.1.13.1.8.1 displays will present results for the screening, on-treatment and 
follow-up phases. Additionally to 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 (screening + on-treatment + follow-up)


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The following labels will be used for the comparison of treatments:
Table 6.1: 2
Overview of treatments for intra-individual comparison
Treatment
Short label
T
BI 730357, tablet, 50 mg, qd
BI 50 mg tab
R
BI 730357, 98μg + 2μg (C-14) BI 730357 in 10 ml solution
BI 100 ug iv
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all subjects enrolled in 
this trial.
Consistency check listings (for identification of deviations from 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 medical quality review meeting, the blinded report planning 
and database lock meeting (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 important 
protocol deviation (iPD). For definition of iPDs, and for the process of identification of these, 
refer to the Boehringer Ingelheim (BI) SOP "Integrated Quality and Risk Management 
Process" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM minutes via an accompanying excel spreadsheet. Categories which are 
considered to be iPDs in this trial are defined in the integrated quality and risk management 
plan (IQRMP). If the data show other iPDs, the definition in the IQRMP will be 
supplemented accordingly by the time of the RPM/DBLM.
iPDs will be summarised and listed.
6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
The following subject sets will be defined for statistical analysis:

Treated set (TS):
This subject set includes all subjects who received at least one dose of study drug. 
This is the full analysis set population in the sense of ICH-E9 (1). It will be used for 
analysis of safety, demographic data and baseline characteristics.

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects in the TS who provide at least one primary PK 


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parameter that was not excluded because of protocol deviations relevant to the 
statistical evaluation of PK endpoints as defined in Section 7.3 of the CTP.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to analysis sets will be made at latest at the RPM/DBLM.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Disposition
X
Exposure
X
iPDs
X
Demographic/baseline endpoints
X
Safety parameters
X
Primary PK endpoint
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: It is not planned to impute missing values for safety parameters.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).
Missing data and outliers of PK data are handled according to BI standards (4) and (6).


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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" (5).
The individual values of all subjects will be listed. Listings will generally be sorted by dose 
group, subject number and visit (if visit is applicable in the respective listing). AE listings will 
be sorted by assigned treatment (see Section 7.8.1 below for details). The listings will be 
contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical to the data 
format of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR. These will be based on the 
TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary.
Only descriptive statistics are planned for this section of the CTR based on the TS.
A medication will be considered concomitant to a treatment, if it

is ongoing at the time of first administration of the respective treatment or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete intake will be addressed in the RPM/DBLM (cf. Section 6.2) and described in the 
CTR.
7.4
PRIMARY ENDPOINT
The analysis of secondary endpoints will be based on the PKS.
Analysis of absolute oral bioavailability of dose normalised primary endpoints will be 
performed as defined in Section 7.1 and 7.3.1 of the CTP.
The statistical model for the primary analysis defined in the CTP is an analysis of variance 
(ANOVA) model on the logarithmic scale.
Primary PK endpoints will also be assessed descriptively. The analysis of standard PK 
parameters is performed according to BI standards (4) [001-MCS-36-472_RD-01].
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 


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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" (4) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (6).
7.5
SECONDARY ENDPOINT
Not applicable
7.6
FURTHER ENDPOINTS
7.6.1
Safety parameters
Safety and tolerability will be analysed as described in Section 7.8 of this TSAP.
7.7
EXTENT OF EXPOSURE
Only descriptive statistics are planned for this section of the CTR.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse events
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For analysis, multiple AE occurrence data on the eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended)


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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" (7) and "Handling of missing and incomplete AE 
dates" (3).
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 on-treatment phase 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 (8) 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: 
○
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
○
Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN.
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (8), AEs classified as "other significant" need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological or other lab abnormalities, or
(ii) which were reported with "action taken = discontinuation" or "action taken = reduced", or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting. 
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related will be 
summarised separately. Separate tables will also be provided for subjects with SAEs, subjects 
with AESIs and subjects with other significant AEs (according to ICH E3 (8)). The frequency 
of subjects with AEs and the frequency of subjects with AEs considered by the investigator to 
be drug related will also be summarised by maximum intensity, primary SOC and preferred 
term.
The system organ classes and preferred terms within system organ classes will be sorted by 
descending frequency overall treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will also 
be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.


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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 standards 
"Display and Analysis of Laboratory Data" (9).
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the RPM/DBLM at the latest. It is the Investigator's 
responsibility to decide whether a lab value is clinically significant abnormal or not. Standard 
or project-specific rules for flagging clinically significant values in an automated manner will 
not be applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and
will be analysed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see 
Section 6.7) will be provided.
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.4
ECG
Abnormal findings in 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
Local tolerability
Clinically relevant findings from the local tolerability assessment will be reported as AEs.


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Physical examinations
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of first study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9; 
Note For Guidance on Design, Conduct, Analysis and Evaluation of Clinical Trialss, 
current version
2
001-MCS-40-135: “Integrated Quality and Risk Management Process”, current version;
IDEA for CON
3
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version; 
IDEA for CON
4
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies", current version; IDEA for CON
5
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current version; 
IDEA for CON
6
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD Data 
Files", current version; IDEA for CON
7
001-MCG-156: "Analysis and Presentation of Adverse Event Data from Clinical Trials", 
current version; IDEA for CON
8
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version
9
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
17-APR-19
None
This is the final TSAP without any 
modification