Clinical trial NCT03886272
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2019-04-11; Completion date: 2019-06-21
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main objective of Trial Parts 1 and 2 is to investigate the relative bioavailability of two tablet strengths (low dose and high dose) of the intended Commercial Formulation of BI 730357 (Test, T) versus with the corresponding tablet strengths of Trial Formulation 1 (Reference, R).

The main objective of Trial Part 3 is to investigate the relative bioavailability of two iCF side batches of BI 730357 with coarse milled Active pharmaceutical ingredient (API)(Test coarse milled, Tc) and unmilled API (Test unmilled, Tu), respectively, versus the final iCF batch of BI 730357 with regularly milled API (Reference, R).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BI 730357 (Test) intervention 2: BI 730357 (Reference)
Intervention descriptions: intervention 1: tablet intervention 2: tablet

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c26431910 -02
EudraCT No.
2018-004421-91
BI Trial No.
1407-0032
BI Investigational
Medicinal Product
BI 730357
Title
Relative bioavailability of intended commercial formulations
(iCF) of BI 730357 versus BI 730357 trial formulation 1 and 
bioavailability comparison of three different iCF batches 
following oral administration in healthy subjects (an open-label, 
single-dose, randomised, 2-way and 3-way crossover trial)
Lay Title
A study in healthy men and women to test if taking different 
formulations of BI 730357 tablets influences the amount of 
BI 730357 in the blood
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: 
Principal 
Investigator
Phone: 
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 1)
Version and Date
Version: 2.0
Date: 07 March 2019
Page 1 of 66
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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
21 January 2019
Revision date
07 March 2019
BI trial number
1407-0032
Title of trial
Relative bioavailability of intended commercial formulations (iCF) of BI 730357 
versus BI 730357 trial formulation 1 and bioavailability comparison of three 
different iCF batches following oral administration in healthy subjects (an open-
label, single-dose, randomised, 2-way and 3-way crossover trial)
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
Trial Parts 1 and 2:
To define the relative bioavailability of two tablet strengths of Trial Formulation 1 
(TF1) used in previous Phase 1 and Phase 2 trials and of the newly developed 
intended Commercial Formulations (iCF) for Phase 3 in order to bridge 
pharmacokinetic and safety data between the formulations and secure Phase 3 
dosing. The 50 mg tablet formulations will be compared in Part 1, the 100 mg tablet 
formulations in Part 2. 
Trial Part 3:
To determine clinically relevant specifications for BI 730357 particle size in the 
100 mg iCF (coarse milled active pharmaceutical ingredient (API) vs. unmilled API 
vs. regularly milled API) and to show in vivo relevance of the selected in vitro
dissolution method for the iCF. 
Trial objective
Trial Parts 1 and 2:
To investigate the relative bioavailability of two tablet strengths (50 mg and 
100 mg) of the intended Commercial Formulation of BI 730357 (Test, T) versus the 
corresponding tablet strengths of Trial Formulation 1 (Reference, R)
Trial Part 3: 
To investigate the relative bioavailability of two iCF side batches of BI 730357 with 
coarse milled API (Testcoarse milled, Tc) and unmilled API (Testunmilled, Tu), 
respectively, versus the final iCF batch of BI 730357 with regularly milled API 
(Reference, R)
Trial design
Parts 1 & 2: Randomized, open-label, single-dose, 2-way crossover design
Part 3: 
Randomized, open-label, single-dose, 3-way crossover  design


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Trial endpoints
Primary endpoints: AUC0-tz and Cmax of BI 730357 in plasma
Secondary endpoints: AUC0-of BI 730357 in plasma
Number of subjects 
total entered
43 (14 for Trial Part 1, 14 for Trial Part 2, 15 for Trial Part 3)
each treatment
14 (Trial Parts 1 and 2) or 15 (Trial Part 3)
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male and female subjects, age of 18 to 50 years (inclusive), body mass 
index (BMI) of 18.5 to 29.9 kg/m2 (inclusive)
Test product of
Part 1
BI 730357 film-coated tablets 50 mg, iCF, final batch
dose
50 mg
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Reference product of 
Part 1
BI 730357 film-coated tablets 50 mg, TF1
dose
50 mg 
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Test product of
Part 2
BI 730357 film-coated tablets 100 mg, iCF, final batch
dose
200 mg 
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Reference product of 
Part 2
BI 730357 film-coated tablets 100 mg, TF1
dose
200 mg
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Test products of
Part 3
BI 730357 film-coated tablets 100 mg, iCF side batch with coarse milled API;
BI 730357 film-coated tablets 100 mg, iCF side batch with unmilled API
dose
100 mg 
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Reference Product of
Part 3
BI 730357 film-coated tablets 100 mg, iCF final batch with regularly milled API
dose
100 mg
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment
One day (single dose) for each treatment (separated by wash-out phases of at least 
10 days)


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Statistical methods
Relative bioavailability will be estimated by the ratios of the geometric means 
(test/reference) for the primary and secondary endpoints. Additionally, their two-
sided 90% confidence intervals (CIs) will be provided. This method corresponds to 
the two one-sided t-tests procedure, each at a 5% significance level. Since the main 
focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified. The statistical model will be an analysis of 
variance (ANOVA) on the logarithmic scale including effects for ‘subjects’ and 
‘treatment’. CIs will be calculated based on the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART FOR ALL TRIAL PARTS
Period
Visit
Day
Planned time (relative to
BI 730357 administration)
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory 8
PK blood (BI 730357)
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
A
x
x
1/2/37
2/3/47
1
-2:00
06:00 Admission to trial site
x2,5
x2
x2
x2
x2
0:00
08:00 Administration of BI 730357
0:30
08:30
x
1:00
09:00
x
1:30
09:30
x
2:00
10:00 240 mL fluid intake
x
2:30
10:30
x
3:00
11:00
x
3:30
11:30
x
4:00
12:00 240 mL fluid intake, thereafter lunch 3
x
x
5:00
13:00
x
6:00
14:00
x
7:00
15:00 Snack (voluntary)
8:00
16:00
x
10:00
18:00 Dinner
12:00
20:00
x
x
2
24:00
08:00 Breakfast (voluntary) 3, 
discharge from trial site
B
x
x
x
x
34:00
18:00 Ambulatory visit
x
x
3
47:00
07:00 Ambulatory visit
x
x
4
71:00
07:00 Ambulatory visit
x
x
6
119:00
07:00 Ambulatory visit
x
x
8
167:00
07:00 Ambulatory visit
x
x
FU
5
9 to 16
End of trial (EoTrial) examination4
C
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including pregnancy test in 
women and 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.
Pharmacogenetic samples will be collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within 3h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory
(including pregnancy test in women), recording of AEs and concomitant therapies.
5.
Only urine drug screening and alcohol breath test as well as pregnancy test in women will be done at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
Two identical periods / visits in Trial Part 1 and Trial Part 2, or three identical periods / visits in Trial Part 3. All 
periods/visits are separated by wash-out periods of at least 10 days between administrations of BI 730357.
8.  Letter A, B and C define different sets of safety laboratory examinations (see Section 5.2.3)


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART FOR ALL TRIAL PARTS ....................................................5
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................13
1.2.1
1.2.2
Clinical data...........................................................................................16
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................18
1.4
BENEFIT - RISK ASSESSMENT ...................................................................18
1.4.1
Expected benefit to the target population...........................................19
1.4.2
Procedure-related risks ........................................................................19
1.4.3
Drug-related risks and safety measures..............................................19
1.4.4
Overall assessment of benefit-risk ratio..............................................20
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 endpoint ..............................................................................22
2.2.2.2
Safety and tolerability..............................................................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


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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 ..................................................................................25
3.3.4
Withdrawal of subjects from treatment or assessments ...................27
3.3.4.1
Discontinuation of trial treatment............................................28
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 .......................................................................29
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................................................................32
4.1.3
Method of assigning subjects to treatment groups ............................32
4.1.4
Drug assignment and administration of doses for each subject .......32
4.1.5
Blinding and procedures for unblinding ............................................33
4.1.6
Packaging, labelling, and re-supply ....................................................33
4.1.7
Storage conditions.................................................................................34
4.1.8
Drug accountability ..............................................................................34
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................34
4.2.1
Other treatments and emergency procedures....................................34
4.2.2
Restrictions............................................................................................35
4.2.2.1
Restrictions regarding concomitant treatment .........................35
4.2.2.2
Restrictions on diet and life style.............................................35
4.3
TREATMENT COMPLIANCE.......................................................................36
5.
ASSESSMENTS....................................................................................... 37
5.1
ASSESSMENT OF EFFICACY NOT APPLICABLE. ................................37
5.2
ASSESSMENT OF SAFETY............................................................................37
5.2.1
Physical examination ............................................................................37
5.2.2
Vital signs...............................................................................................37
5.2.3
Safety laboratory parameters..............................................................37
5.2.4
Electrocardiogram................................................................................39
5.2.5
Other safety parameters.......................................................................40
5.2.6
Assessment of adverse events...............................................................40
5.2.6.1
Definitions of adverse events...................................................40


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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 ........................................43
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................43
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 ..................................................................45
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
5.4
ASSESSMENT OF BIOMARKER(S) .............................................................46
5.5
BIOBANKING ...................................................................................................46
5.6
OTHER ASSESSMENTS .................................................................................46
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................47
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 periods.................................................................................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...................................................................52
7.3.2
Secondary endpoint analyses ...............................................................53
7.3.4
Safety analyses.......................................................................................53
7.4
INTERIM ANALYSES .....................................................................................54
7.5
HANDLING OF MISSING DATA ..................................................................54
7.5.1
Safety......................................................................................................54


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7.5.2
Pharmacokinetics..................................................................................54
7.6
RANDOMISATION ..........................................................................................54
7.7
DETERMINATION OF SAMPLE SIZE ........................................................55
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 58
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................58
8.2
DATA QUALITY ASSURANCE .....................................................................59
8.3
RECORDS..........................................................................................................59
8.3.1
Source documents .................................................................................59
8.3.2
Direct access to source data and documents.......................................60
8.3.3
Storage period of records.....................................................................60
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................61
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......61
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................61
8.6
TRIAL MILESTONES .....................................................................................61
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................62
9.
REFERENCES......................................................................................... 63
9.1
PUBLISHED REFERENCES...........................................................................63
9.2
UNPUBLISHED REFERENCES.....................................................................64
10. APPENDICES .......................................................................................... 65
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 66
11.1
GLOBAL AMENDMENT 1 .............................................................................66


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
API
Active pharmaceutical ingredient 
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 hours
AUC0-96
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 96 hours
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central nervous system
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
CYP
Cytochrome P450
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid


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EEG
Electroencephalogram
EMG
Electromyelogram
EoTrial
End of trial
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
FDA
Food and Drug Administration (US)
FSH
Follicle-stimulating hormone
FU
Follow-up
fu
Fraction unbound
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GLP
Good Laboratory Practice
gMean
Geometric mean
HPC
Human Pharmacology Centre
hPXR
Human pregnane X receptor
IB
Investigator’s Brochure
IC50
50% inhibitory concentration
ICF
Informed consent form
iCF
Intended commercial formulation
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IL
Interleukin
IPD
Important protocol deviation
IQRM
Integrated quality and risk management
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MDR
Multiple rising dose
MedDRA
Medical Dictionary for Regulatory Activities
mRNA
Messenger ribonucleic acid
MRTpo
Mean residence time of the analyte in the body after oral administration


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NOAEL
No observed adverse event level
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
PUVA
Psoralen ultraviolet A
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)
R
Reference treatment
REP
Residual effect period
RCTC
Rheumatology Common Toxicity Criteria
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
T
Test product or treatment
TF1
Trial formulation 1
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vz
Apparent volume of distribution during the terminal phase after 
intravascular administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WOCBP
Woman of childbearing potential
XTC
Ecstasy 


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1.
INTRODUCTION
BI 730357 
It is being 
developed as an oral therapy for the treatment of patients with psoriasis
 
This trial will be performed to investigate the relative bioavailability of BI 730357 in plasma 
when given as different tablet formulations (iCF vs. TF1) and iCF batches of different 
particle size (regularly milled vs. coarse milled vs. unmilled).
1.1
MEDICAL BACKGROUND
 
 
 
 
 
 
 
 
 
1.2
DRUG PROFILE
1.2.1
Nonclinical data
 
 
 
 
 
 
 
 
 
 
 
 


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1.2.2
Clinical data
Up to now, two Phase I trials have been completed, a first-in-human, single-rising-dose
(SRD) trial and a multiple-rising dose (MRD) trial [c09228382]. 

 
 
 


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1.3
RATIONALE FOR PERFORMING THE TRIAL
Parts 1 and 2 of this trial are designed to investigate the relative bioavailability of two tablet 
strengths of a newly developed tablet formulation (iCF batch 1 and batch 2) of BI 730357 
compared to the corresponding strengths of TF1 following oral administration in healthy 
male and female subjects. TF1 has already been administered and investigated in previous 
clinical trials. iCF is the anticipated formulation for Phase 3 and, if applicable, later in clinical 
practice. To allow the prediction of safety and pharmacokinetics in Phase 3 and clinical 
practice, comparable pharmacokinetic data between TF1 and iCF are considered essential. 
PK data from SRD trial 1407.1 and MRD trial 1407-0002 revealed non-linear kinetics of 
BI 730357 with a less-than-dose-proportional increase of AUC0-∞and Cmax. Therefore, in 
accordance with regulatory guidelines [R05-1094; R10-2509] a low dose of 50 mg (with 
50 mg formulations in Part 1), and a high dose of 200 mg (with 100 mg formulations in 
Part 2), corresponding to doses at the bottom and top end of the anticipated dose range to be 
tested in Phases 2 and 3, have been selected. As 50 mg was seen at the top of the dose 
proportional range, results obtained with 50 mg in this trial will also cover lower doses.
The aim of Part 3 is to determine clinically relevant specifications for BI 730357 particle size 
in the 100 mg iCF and to show in vivo relevance of the selected in vitro dissolution method 
for the iCF. The final iCF tablet with regularly milled API showed the fasted dissolution 
behavior whereas the iCF with the unmilled API showed the slowest dissolution. A relative 
bioavailability comparison using these two extremes (i.e. the final batch with regularly milled 
API and a side batch with unmilled API) and a side batch in between (e.g. with coarse milled 
API) would be the best option to achieve this aim.
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. 


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Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.
1.4.1
Expected benefit to the target population
 
 
filling an 
unmet medical need for the introduction of new, efficacious oral treatment options in the 
treatment of psoriasis 
1.4.2
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in syncope, 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.
ECG electrodes may cause local and typically transient skin reactions.
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.
1.4.3
Drug-related risks and safety measures
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 of BI 730357 is supported up to 800 mg by preclinical, as well as 
clinical safety data from first-in-human trial 1407.1 (see Section 1.2.2). In trial 1407.1, 
administration of a 800 mg tablet under fed (high-fat) conditions resulted in exposures 
 
This was 2.9-fold and 4.1-
fold below the Cmax and AUC0-24 respectively at the combined NOAEL for male and female 
dogs after 13 weeks of treatment (see Section 1.2.1.3). 
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).
Women of childbearing potential have to use highly effective birth control (see Section 3.3.2). 
In addition, negative pregnancy testing will be required at the screening visit and prior to 
each administration of trial medication.
 
 


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1.4.4
Overall assessment of benefit-risk ratio
BI 730357 
 has been adequately characterised in pre-clinical 
studies. The non-clinical safety package supports clinical trials in males and females with 
administration of BI 730357 for up to 39 weeks. 
Results of the SRD trial 1407.1 indicate good safety and tolerability of single oral doses of 
BI 730357 up to 800 mg (see IB [c09228382]).
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.
 


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All in all, the risk of the participating volunteers is judged to be low considering particularly 
the good tolerability of BI 730357 seen so far and the administration of single doses already 
investigated. With respect to the medical need for an effective and safe treatment of psoriasis, 
the benefit of this trial is assessed to outweigh the potential risks.


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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 Trial Parts 1 and 2 is to investigate the relative bioavailability of two 
tablet strengths (50 mg and 100 mg) of the intended Commercial Formulation of BI 730357
(Test, T) versus with the corresponding tablet strengths of Trial Formulation 1 (Reference, 
R).
The main objective of Trial Part 3 is to investigate the relative bioavailability of two iCF side 
batches of BI 730357 with coarse milled API (Test coarse milled, Tc) and unmilled API 
(Testunmilled, Tu), respectively, versus the final iCF batch of BI 730357 with regularly milled 
API (Reference, R).
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for BI 730357:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for BI 730357:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)


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2.2.2.2
Safety and tolerability
Safety and tolerability of BI 730357 will be assessed based on:  

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The trial consists of three parts, which will be performed in a randomised, open-label, single-
dose, two-way (Parts 1 and 2) or three-way (Part 3) crossover design in healthy male and
female subjects in order to compare the following test treatment and reference treatments:
Part 1
T1 (Test Part 1)
One 50 mg BI 730357 tablet as iCF, final batch
R1 (Reference Part 1)
One 50 mg BI 730357 tablet as TF1
Part 2
T2 (Test Part 2)
Two 100 mg BI 730357 tablets as iCF, final batch
R2 (Reference Part 2)
Two 100 mg BI 730357 tablets as TF1
Part 3
T3c (Test Part 3, coarse milled)
One 100 mg BI 730357 tablet as iCF side batch, coarse milled
T3u (Test Part 3, unmilled)
One 100 mg BI 730357 tablet as iCF side batch, unmilled
R3 (Reference Part 3)
One 100 mg BI 730357 tablet as final iCF batch, regularly milled
In Part 1 and Part 2 the iCF and TF1 will be investigated at two dose levels (at a low dose of 
50 mg and a high dose of 200 mg) due to the non-linear kinetics of BI 730357.
All treatments will be administered to the subjects as single dose in the fasting state. Within 
each trial part the subjects will be randomly allocated to the 2 treatment sequences in Part 1 
(T1/R1 or R1/T1) and Part 2 (T2/R2 or R2/T2) or to the following 3 treatment sequences in 
Part 3 (R3/T3c/T3u or T3c/T3u/R3 or T3u/R3/T3c). Each subject will participate either in Part 1
or Part 2 or Part 3, only.
There will be a washout interval of at least 10 days between the administrations of
BI 730357. For details, refer to Section 4.1.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his/her own control, the comparison between treatments is based 
on an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529].
For this pharmacokinetic bioavailability trial, open-label treatment is acceptable, because the 
primary and secondary endpoints of this trial are pharmacokinetic endpoints derived from 


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measurement of plasma concentrations of BI 730357. These endpoints are not expected to be 
affected by knowledge of treatment.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 14 healthy subjects each (at least 4 of each sex) will enter Trial Parts 1 
and 2, and 15 healthy subjects (at least 4 of each sex) will enter Trial Part 3. They will be 
recruited from the volunteers' pool of the trial site.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (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 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 50 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. Male subjects, or female subjects who meet any of the following criteria from at least 30 
days before the first administration of trial medication until 30 days after trial completion:
-
Use of adequate contraception, e.g. any of the following methods plus condom: 
implants, injectables, combined oral or vaginal contraceptives, intrauterine device
-
Sexually abstinent
-
A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) 
-
Surgically sterilised (including hysterectomy)
-
Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in 
questionable cases a blood sample with levels of FSH above 40 U/L and estradiol 
below 30 ng/L is confirmatory)
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


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2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 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. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 12 g per day for females and 24 g per day for 
males)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) 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)


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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 criteria apply:
23. Male subjects with WOCBP partner who are unwilling to use male contraception 
(condom or sexual abstinence) from time point of first administration of trial medication 
until 30 days after the last administration of trial medication
24. Pulse rate ranging from 45 bpm to 49 bpm (inclusive) in combination either with 
abnormal thyroid function (determined by medical history, physical examination, or 
abnormal TSH) or with signs of diseases associated with bradycardia
25. ALT (alanine transaminase) or AST (aspartate transaminase) or serum creatinine exceeds 
the upper limit of normal (ULN) at screening
Female subjects will not be allowed to participate, if any of the following apply:
26. Positive pregnancy test, pregnancy, or plans to become pregnant within 30 days after 
study completion 
27. Lactation
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.
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. The 
subject is to be followed until she has given birth or until the end of the pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the CTR. For reporting of pregnancy and associated events, refer to Section 
5.2.6.2.4.


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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.
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 pregnancy, 
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 overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
if more than 50% of the subjects have drug-related and clinically relevant AEs of 
moderate or severe intensity, or if at least 1 drug-related serious adverse event is reported
3. Violation of GCP or the CTP impairing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational product


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3.3.5
Replacement of subjects
In case more than 2 (Parts 1 and 2) or 3 (Part 3) subjects do not complete the trial part, the 
Clinical Trial Leader together with the Trial Pharmacokineticist and the Trial Statistician are 
to decide, if and how many subjects will be replaced. A replacement subject will be assigned 
a unique trial subject number, and will be assigned to the same treatment as the subject he/she
replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product BI 730357 as film-coated tablet formulation has been 
manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test and reference products of Part 1 are given below:
Test product 
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet, iCF, final batch
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
50 mg
Posology:
1 – 0 – 0 (treatment T1)
Route of administration:
Oral
Duration of use:
1 day 
Reference product
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet, TF1
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
50 mg
Posology:
1 – 0 – 0 (treatment R1)
Route of administration:
Oral
Duration of use:
1 day 
The characteristics of the test and reference products of Part 2 are given below:
Test product
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet, iCF, final batch 
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100 mg
Posology:
2 – 0 – 0 (treatment T2)
Route of administration:
Oral
Duration of use:
1 day 


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Reference product
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet, TF1
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100 mg
Posology:
2 – 0 – 0 (treatment R2)
Route of administration:
Oral
Duration of use:
1 day 
The characteristics of the test and reference products of Part 3 are given below:
Test product 1
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet, iCF side batch with coarse milled 
API
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100 mg
Posology:
1 – 0 – 0 (treatment T3c)
Route of administration:
Oral
Duration of use:
1 day 
Test product 2 
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet, iCF side batch with unmilled API
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100 mg
Posology:
1 – 0 – 0 (treatment T3u)
Route of administration:
Oral
Duration of use:
1 day 
Reference product
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet, iCF final batch with regularly milled 
API
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100 mg
Posology:
1 – 0 – 0 (treatment R3)
Route of administration:
Oral
Duration of use:
1 day 


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4.1.2
Selection of doses in the trial
Results from the SRD trial 1407.1 and the MRD trial 1407-0002 showed non-linear 
pharmacokinetics of BI 730357 with a less-than-dose-proportional increase in AUC and Cmax. 
Based on current guidelines [R05-1094; R10-2509] the planned bioavailability comparison of 
iCF and TF1 in Trial Parts 1 and 2 has therefore to be conducted with doses of 50 mg at the 
bottom and of 200 mg at the top end of the dose range to be tested in Phases 2 and 3. As 50
mg was seen at the top of the dose proportional range, results obtained with 50 mg in this trial 
will also cover lower doses.
For the bioavailability comparison of the three iCF batches with different particle size in 
Part 3, a dose of 100 mg in the middle of the anticipated therapeutic range was selected.
4.1.3
Method of assigning subjects to treatment groups
The randomisation list will be provided to the trial site in advance.
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 2). For this purpose, numbers of the randomisation 
list will be allocated to the subjects by drawing lots. Subjects are then assigned to a treatment 
sequence according to the randomisation list. Once a subject number has been assigned, it 
cannot be reassigned to any other subject. The randomisation procedure is described in 
Section 7.6.
4.1.4
Drug assignment and administration of doses for each subject
This trial consists of two 2-way crossover parts (Trials Parts 1 and 2) and one 3-way 
crossover trial part (Trial Part 3). In Trial Parts 1 or 2, subjects will receive the 2 treatments 
in randomised order. In Trial Part 3, subjects will receive 3 treatments in randomised order. 
The treatments to be evaluated for each trial part are outlined in Tables 4.1.4: 1, 4.1.4: 2 and 
4.1.4: 3 below. 
Table 4.1.4: 1
Dosage and treatment schedule for Part 1
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T1 (Test Part 1)
BI 730357
film-coated tablet, 
iCF final batch
50 mg
1 film-coated 
tablet on Day 1
50 mg
R1 (Reference Part 1)
BI 730357
film-coated tablet, 
TF1
50 mg
1 film-coated 
tablet on Day 1
50 mg
Table 4.1.4: 2
Dosage and treatment schedule for Part 2
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T2 (Test Part 2)
BI 730357
film-coated tablet, 
iCF final batch 
100 mg
2 film-coated 
tablets on Day 1
200 mg
R2 (Reference Part 2)
BI 730357
film-coated tablet, 
TF1
100 mg
2 film-coated 
tablets on Day 1
200 mg


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Table 4.1.4: 3
Dosage and treatment schedule for Part 3
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T3c (Test Part 3, coarse milled)
BI 730357
film-coated tablet, 
iCF side batch  
coarse milled
100 mg
1 film-coated 
tablet on Day 1
100 mg
T3u (Test Part 3, unmilled)
BI 730357
film-coated tablet, 
iCF side batch 
unmilled
100 mg
1 film-coated 
tablet on Day 1
100 mg
R3 (Reference Part 3)
BI 730357
film-coated tablet, 
iCF final batch 
regularly milled
100 mg
1 film-coated 
tablet on Day 1
100 mg
Administration of trial medication will be performed after subjects have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. The investigator (or 
authorised designee) will administer the trial medication as an oral dose together with about 
240 mL of water to subjects who are in a standing position. For drug administration, the so-
called four-eye principle (two-person rule) should be applied. For this, one authorised 
employee of the trial site should witness the administration of trial medication, and – if 
applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
For restrictions with regard to diet, see Section 4.2.2.2.
Subjects will be kept under close medical surveillance until 24 h after drug administration. 
During the first 4 h after drug administration of BI 730357, subjects are not allowed to lie 
down (i.e. no declination of the upper body of more than 45 degrees from upright posture),
except for medical reasons or for recording of 12-lead ECG and vital signs measurements.
The treatments will be separated by a wash-out phase of at least 10 days between 
administrations of BI 730357.
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.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice.
For details of packing and the description of the label, refer to the ISF.


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The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
Clinical Trial Manager (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Approval/notification of the regulatory authority,  e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that 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 Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 


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symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
Poppy-seeds containing foods should not be consumed starting 3 days before the first drug 
administration in each treatment period, in order to avoid false-positive results in the drug 
screen.
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.
No food is allowed within 10 h before and 4 h after intake of BI 730357.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all 
subjects). From lunch until 24 h post-dose, total fluid intake is restricted to 3000 mL.
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 the first administration of trial medication in Period 1 until after the last PK 
sample of the last period is collected.
Alcoholic beverages are not permitted from 2 days before the first administration of trial 
medication in period 1 until after the last PK sample of the last period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 10 h before until 24 h after each administration of trial 
medication.
Smoking is not allowed during in-house confinement while admitted to the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation, treatment with ultraviolet light 
(e.g. PUVA), or medication with known phototoxicity potential (e.g, doxycycline) should be 
avoided from the first administration of trial medication until the EoTrial examination. The 
use of sunscreens is mandatory in that time.
If female subjects of child-bearing potential are included in the trial, adequate contraception 
is to be maintained throughout the course of the trial (see Section 3.3.2 for the definition of 
adequate measures).


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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.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history, 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) will be measured by a 
blood pressure monitor (Dinamap Pro 100, GE Medical Systems, Freiburg, Germany) 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 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required. 
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]
A1
B1
C1
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils Bands;  
Neutrophils Bands, absol.; Eosinophils/Leukocytes; Eosinophils, 
absol.; Basophils/ Leukocytes; Basophils, absol.; Monocytes/ 
Leukocytes; Monocytes, absol.; Lymphocytes/Leukocytes; 
Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time
Prothrombin time 
Prothrombin time - INR (International Normalization Ratio)
X
X
X
--
--
--
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
X
X
X
X
X
X
X
X
X
X
X
X
--
--
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
X
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
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
Electrolytes
Sodium
Potassium
X
X
X
X
X
X
Urinalysis (Stix) 2
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 2
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
1 A, B and C are different sets of laboratory values. The Flow Chart details at which time point which set is to 
be investigated. 
2 Microscopic examination if erythrocytes, leukocytes, nitrite or protein are abnormal in urine


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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 pregnancy tests and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in women will be performed at screening, prior to 
each treatment period, and as part of the end of trial examination. Drug screening will be 
performed at screening and prior to first dosing in each treatment period.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Interferon-γ release assay to tuberculosis (qualitative), e.g. 
QuantiFERON®-TB Gold Test
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
7410, Dräger AG, Lübeck, Germany) will be performed prior to each 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 MVZ Labor 
Ravensburg GbR, Elisabethenstraße 11, 88212 Ravensburg, Germany, with the exception of 
drug screening and pregnancy tests. These tests will be performed at the trial site using 
M-10/14-PDT Multiline test and HCG-K20 test, respectively, or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the times provided in the Flow Chart. 
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.


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All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (GE Medical 
Systems, Freiburg, Germany). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
Not applicable.
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:


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


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The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.

Severe infections (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 polyomavirus-
associated nephropathy, cytomegalovirus, posttransplant lymphoproliferative disorder 
(Epstein-Barr virus), progressive multifocal leukoencephalopathy, 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), hepatitis B virus 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), hepatitis C virus 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


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Causal relationship of AEs
5.2.6.1.6
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

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 


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medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy 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.


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Pregnancy
5.2.6.2.4
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
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
 
 
 
 
 
 


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5.3.3
Analytical determinations
5.3.3.1
Analytical determination of analyte plasma concentration
 
5.4
ASSESSMENT OF BIOMARKER(S) 
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS


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5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Sections 2.1.2, 
2.1.3, 2.2.2.1, and 5.3 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 are to be performed and completed within a 3h-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, ± 45 min on Day 2, and ± 60 min from Day 3 onwards.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. 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.
Starting from 119 hours after BI 730357 administration (and beyond), a time window of 
± 60 min will be allowed for PK blood sampling times.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.3).
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (in Part 1 or Part 2) or 
3 treatment periods (Part 3). At least 10 days will separate drug administrations in the first
and second treatment period as well as in the second and third treatment period.


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On Day 1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration. 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.
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 5.2.2 to 5.2.6.
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 relative bioavailability of two tablet 
strengths (50 mg and 100 mg) of the intended Commercial Formulation of BI 730357 (Test, 
T) versus with the corresponding tablet strengths of trial formulation 1 (Reference, R), and to 
investigate the relative bioavailability of two iCF side batches of BI 730357 with coarse 
milled API (Testcoarse milled, Tc) and unmilled API (Testunmilled, Tu), respectively, versus final 
iCF batch of BI 730357 with regularly milled API (Reference, R) following oral 
administration on the basis of the primary and secondary pharmacokinetic endpoints, as listed 
in Section 2.1.2 and 2.1.3. The trial is designed to allow intra-subject comparisons and will be 
evaluated statistically by use of a linear model for logarithmically transformed PK endpoints. 
A further objective is to evaluate and compare further pharmacokinetic parameters between 
the treatments, see Section 2.2.1. These further pharmacokinetic parameters will be assessed 
by descriptive statistics.
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 relative bioavailability of BI 730357 in plasma after test versus reference treatment will 
be estimated by the ratios of the geometric means (test/reference), and their corresponding 2-
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, a formal hypothesis test and associated acceptance range is not 
specified.
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 or 
secondary 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 
 
contributes only one PK parameter value for one 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 the 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
by means of non-compartmental analysis. Non-compartmental pharmacokinetic parameters 
will be calculated based on actual sampling times using a validated pharmacokinetic software 
(Phoenix® WinNonlin® 6.3). Descriptive statistics will be used to evaluate plasma 
concentration data and PK parameters. The derivation of PK parameters is described in BI 
internal SOP (001-MCS-36-472_RD-01). Further details on analysis will be described in the 
TSAP. 
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


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7.3.1
Primary endpoint analyses
Primary analyses
The primary endpoints (refer to Section 2.1.2) will be calculated according to the BI Standard
Operating Procedure (SOP) ‘Standards and processes for analyses performed within Clinical
Pharmacokinetics/ Pharmacodynamics’ (001-MCS-36-472).
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: sequence, subjects within 
sequences, period and treatment. The effect 'subjects within sequences' will be considered as 
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation, where p=2 for Parts 1 and 2 of the trial and p=3 for Part 3 of the trial:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment  
k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, …, p
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
j = the jth period effect, j = 1,, …, p
k = the kth treatment effect, k = 1,, …, p
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random 
variables.
Point estimates for the ratios 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.


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Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with 
all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, ‘treatment’) 
considered as fixed effects.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.3.2
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will be assessed statistically using the same 
methods as described for the primary endpoints.
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 and end of 
REP (see Section 1.2.3) will be assigned to the treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ’follow-up’. 
In case of two or more treatments, the follow-up will be summarized according to the 
previous treatment. 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-


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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. 
Relevant ECG findings will be reported as AEs.
7.4
INTERIM ANALYSES
No interim analysis is planned.
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
 
 
7.6
RANDOMISATION
Subjects will be randomised to one of the 2 treatment sequences in Part 1 (T1/R1 or R1/T1) or 
Part 2 (T2/R2 or R2/T2) in a 1:1 ratio. For Trial Part 3, subjects will be randomised to one of 
3 treatment sequences (R3/T3c/T3u or T3c/T3u/R3 or T3u/R3/T3c) in a 1:1:1 ratio. The block size 
will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).


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7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter 14 subjects in Part 1, 14 subjects in Part 2 (accounting for up to 2 non 
PK evaluable subjects in each part), and 15 subjects in Part 3 of this trial (accounting for up 
to 3 non PK evaluable subjects), because these sample sizes are considered sufficient to 
achieve the aims of this exploratory trial parts. With this sample size, the following precision 
in estimating the ratio of geometric means (test/reference) can be expected with 95% 
probability. Precision is defined as the ratio of upper CI limit to the relative BA estimate. 
Note that the precision is independent of the actual ratio of geometric means.
The intra-individual coefficient of variation (gCV) is estimated from total gCV from 
pharmacokinetic data of the SRD part of a previous trial (Study 1407.1) using the result of 
50 mg dose, 100 mg and 200 mg doses. Table 7.7:1 below presents, for each dose, the 
observed total gCV in this previous trial, for each primary endpoint, as well as the roughly 
estimated intra-individual gCV.
Table 7.7: 1
Estimated intra-individual gCV depending on observed total gCV in 
trial 1407.1 and assumed within-subject correlation, for Cmax and 
AUC0-tz
Dose
Endpoint
Observed total gCV 
in trial 1407.1
Assumed within-
subject correlation
Estimated intra-
individual gCV
50 mg
Cmax
41.9%
0.6
26%
AUC0-tz
51.5%
0.8
22%
100 mg
Cmax
30.7%
0.6
19%
AUC0-tz
56.8%
0.8
24%
200 mg
Cmax
27.6%
0.6
17%
AUC0-tz
27.8%
0.8
12%
Parts 1 and 2
Assuming a gCV of 22% for BI 730357 and given a sample size of 12 subjects with 
evaluable data for primary analysis, the precision of the two-sided 90% confidence interval of 
the bioavailability ratio will be approximately 1.243, for a greater gCV of 26%, the precision 
would still be approximately 1.292. For a lower gCV (17%), the precision would be 
approximately 1.184. Table 7.7: 2 provides an overview of the achievable precision for 
estimating the ratio of geometric means (test/reference) applicable to Parts 1 and 2 of the trial 
(two-way crossover). For illustrative purposes, the expected 90% confidence intervals with 
95% tolerance probability are displayed for different values of the ratios T/R of geometric 
means.


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Table 7.7: 2
Precision that can be expected with 95% tolerance probability and 
illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T/R) for different gCVs in a two-way crossover 
trial with 2 treatments and 2 sequences and 2 periods (N=12)
gCV [%]
Precision upper CL / 
relative BA estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
17
1.184
50
42.23
59.21
17
1.184
100
84.45
118.41
17
1.184
150
126.68
177.62
17
1.184
200
168.90
236.82
22
1.243
50
40.22
62.16
22
1.243
100
80.44
124.32
22
1.243
150
120.66
186.47
22
1.243
200
160.88
248.63
26
1.292
50
38.70
64.59
26
1.292
100
77.41
129.18
26
1.292
150
116.11
193.77
26
1.292
200
154.82
258.36
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
Part 3
Assuming a gCV of 22% for BI 730357 and given a sample size of 12 subjects with 
evaluable data for primary analysis, the precision of the two-sided 90% confidence interval of 
the bioavailability ratio will be approximately 1.211, for a greater gCV of 26%, the precision 
would still be approximately 1.253. For a lower gCV (17%), the precision would be 
approximately 1.161. Table 7.7: 3 provides an overview of the achievable precision for 
estimating the ratio of geometric means (test/reference) applicable to part 3 of the trial (three-
way crossover). For illustrative purposes, the expected 90% confidence intervals with 95% 
tolerance probability are displayed for different values of the ratios T/R of geometric means.


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Table 7.7: 3
Precision that can be expected with 95% tolerance probability and 
illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T/R) for different gCVs in a three-way crossover 
trial with 3 treatments and 3 sequences and 3 periods (N=12)
gCV [%]
Precision upper CL / 
relative BA estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
17
1.161
50
43.08
58.03
17
1.161
100
86.16
116.06
17
1.161
150
129.24
174.09
17
1.161
200
172.32
232.12
22
1.211
50
41.27
60.57
22
1.211
100
82.54
121.15
22
1.211
150
123.82
181.72
22
1.211
200
165.09
242.29
26
1.253
50
39.90
62.66
26
1.253
100
79.80
125.32
26
1.253
150
119.70
187.98
26
1.253
200
159.59
250.64
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The expected 90% confidence interval limits in the table were derived by
CI limit,  = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 3.0.3.


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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 
regulation 536/2014, 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. As a general rule, no trial results should be 
published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (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.
ClinBaseTM
In the Human Pharmacology Centre (HPC) – Boehringer Ingelheim's Phase I unit – the 
validated ClinBaseTM system is used for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as data base. Instead of being entered into CRFs, selected data are directly 
entered into the system.
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.


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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

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.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data are entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
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(s) must retain the source and essential documents (including ISF) according to 
the local requirements valid at the time of the end of the trial.


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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. 
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, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

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 
biobanking 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.


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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 ethics committee/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.
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 the 
 
 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 Clinical Trial Leader (CT Leader), 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 (CT Manager), 
Clinical Research Associates, and investigators of participating trial sites
The trial medication (BI 730357) will be provided by the Clinical Trial Supplies Unit, BI 
Pharma GmbH & Co. KG, Biberach, Germany.
Safety laboratory tests will be performed by the local laboratory of the trial site (MVZ Labor 
Ravensburg GbR, Ravensburg, Germany).
Analyses of BI 730357 concentrations in plasma will be performed 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 
organization 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
R05-1094
Guidance for industry: bioavailability and bioequivalence studies for 
orally administered drug products - general considerations (revision 1). In: 
Rockville: U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER); 
2003.
R10-2509
European Medicines Agency (EMEA). Committee for Medicinal Products 
for Human Use (CHMP): guideline on the investigation of bioequivalence 
(London, 20 January 2010, doc. ref.: CPMP/EWP/QWP/1401/98 rev. 
1/corr). http://www.emea.europa.eu; 2010.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
 
 
 
 
 
R13-3515
Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, 
Tsuji W, et.al. Standardizing assessment and reporting of adverse effects 
in rheumatology clinical trials II: the Rheumatology Common Toxicity 
Criteria v.2.0. J Rheumatol 34:6. 1401-1414. 2007.
 
  
 
R94-1529 
Chow SC, Liu JP. Design and Analysis of Bioavailability and 
Bioequivalence Studies. New York: Marcel Dekker Inc; 1992.


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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472
Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
001-MCS-36-472_RD-01 Noncompartmental Pharmacokinetic/Pharmacodynamic Analyses 
of Clinical Studies. Current version.
c09228382
Investigator Brochure BI 730357. Psoriasis - 1407.P01; Current 
version.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
07 March 2019
EudraCT number
EU number
2018-004421-91
BI Trial number
1407-0032
BI Investigational Medicinal 
Product(s)
BI 730357
Title of protocol
Relative bioavailability of intended commercial 
formulations (iCF) of BI 730357 versus BI 730357
trial formulation 1 and bioavailability comparison of 
three different iCF batches following oral 
administration in healthy subjects (an open-label, 
single-dose, randomised, 2-way and 3-way crossover 
trial)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1) 3.3.3 (exclusion criterion 24)
2) 3.3.3 (exclusion criterion 25)
3) 3.3.3 (exclusion criterion 15)
4) 1.4.2
Description of change
1) Exclusion of pulse rates ranging from 45 to 49 
bpm (inclusive) in combination with abnormal 
thyroid function or signs of diseases associated 
with bradycardia
2) Exclusion of ALT, AST and serum creatinine 
exceeding upper limit of normal 
3) Limits for alcohol consumption were lowered
4) Syncope was added as risk for using an 
indwelling venous catheter or venepuncture
Rationale for change
1-4)
Recommended/requested by Competent 
Authority and IEC

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
C28264105-01
BI Trial No.:
1407-0032
Title:
Relative bioavailability of intended commercial formulations (iCF) 
of BI 730357 versus BI 730357 trial formulation 1 and 
bioavailability comparison of three different iCF batches following 
oral administration in healthy subjects (an open-label, single-dose, 
randomised, 2-way and 3-way crossover trial) including Global 
Protocol Amendment 1 [c26431910-02]
Investigational
Products:
BI 730357 film-coated tablets 50 mg iCF and trial formulation 1 
(TF1), 100 mg iCF and TF1, and 100 mg iCF final batch with 
regularly milled API and iCF side batches with coarse milled or 
unmilled API.
Responsible trial 
statisticians:
Phone: 
         Fax: 
Phone: 
   Fax:
Date of statistical 
analysis plan:
30 JUL 2019 SIGNED
Version:
final
Page 1 of 27
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2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINT(S).....................................................................................................10
5.1
PRIMARY ENDPOINT(S) ................................................................................10
5.2
SECONDARY ENDPOINT(S) ..........................................................................10
5.2.1
Key secondary endpoint(s).................................................................................10
5.2.2
Secondary endpoint(s) ........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENT(S)................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................19
7.4
PRIMARY ENDPOINT(S) ................................................................................19
7.5
SECONDARY ENDPOINT(S) ..........................................................................20
7.5.1
Key secondary endpoint(s).................................................................................20
7.5.2
(Other) Secondary endpoint(s) ..........................................................................21
7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse events.....................................................................................................21
7.8.2
Laboratory data ..................................................................................................24
7.8.3
Vital signs.............................................................................................................24
7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................24
8.
REFERENCES....................................................................................................25


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10.
HISTORY TABLE..............................................................................................27


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................12
Table 6.3: 1
Subject sets analysed........................................................................................15
Table 10: 1
History table .....................................................................................................27


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANOVA
Analysis of variance
API
Active pharmaceutical ingredient
AST
Aspartate transaminase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BI
Boehringer Ingelheim
BMI
Body mass index
BP
Blood pressure
BWC
Bioavailability/Bioequivalence, within-subject design, time-controlled
CI
Confidence interval
CL/F
Apparent clearance of the analyte in the plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CRA
Clinical research associate
CRF
Case report form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DILI
Drug induced liver injury
ECG
Electrocardiogram 
EDC
Electronic data capture
EudraCT
European Union Drug Regulating Authorities Clinical Trials
gCV
Geometric coefficient of variation
gMean
Geometric mean


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Term
Definition / description
iCF
Intended commercial formulation
ICH
International Conference on Harmonisation
iPD
Important Protocol Deviation
ISF
Investigator site file
IQRM
Integrated quality and risk management
λz
Terminal rate constant in plasma
LLT
Lower level term
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MRT,po
Mean residence time of the analyte in the body after oral administration
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PK
Pharmacokinetics
PKS
PK parameter analysis set
PR
Pulse rate
PT
Preferred term
Q1
1st quartile
Q3
3rd quartile
R
Reference treatment
RAGe
Report Appendix Generator system
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual effect period
RPM
Report planning meeting
SASTM
Statistical Analysis System
SD
Standard deviation
SOC
System organ class
SOP
Standard operating procedure
T
Test treatment
t1/2
Terminal half-life of the analyte in plasma


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Term
Definition / description
TF1
Trial formulation 1
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WHO-DD
World Health Organization Drug Dictionary
XPKISTAT
Library of SAS® Macros for PK analysis


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This Trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP). 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 RAVE EDC system.
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or higher, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including 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).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP. No changes compared to the protocol were made.


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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT(S)
Section 2.1.2 of the CTP: The following pharmacokinetic parameters will be determined for 
BI 730357: 

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoint(s)
Pharmacokinetic (PK):
Section 2.1.3 of the CTP: The following pharmacokinetic parameter will be determined for 
BI 730357:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
There are two methods by which AUC0-∞is calculated:

AUCINF_obs: Area under the plasma concentration time curve from time zero to time 
infinity with extrapolated area from time tz to infinity based on last observed 
concentration at time tz

AUCINF_pred: Area under the plasma concentration time curve from time zero to 
time infinity with extrapolated area from time tz to infinity based on the concentration 
predicted by regression for the time tz
In this study, both types will be derived and both will statistically be evaluated.


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Safety:
Section 2.2.2.2 of the CTP: Safety and tolerability of BI 730357 will be assessed based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on investigational products, assignment of treatment sequences, 
and selection of doses, please see CTP, Sections 3 and 4.
The study will be performed as a randomised, open-label, two-way and three-way crossover 
trial with 3 parts.
Part 1 is a two-way crossover trial with two treatments (T1 and R1) and two treatment 
sequences (T1-R1 or R1-T1).
Part 2 is a two-way crossover trial with two treatments (T2 and R2) and two treatment 
sequences (T2-R2 or R2-T2).
Part 3 is a three-way crossover trial with three treatments (T3c, T3u, and R3) and three 
treatment sequences (T3c-T3u-R3 or T3u-R3-T3c or R3-T3c-T3u).
In total, it was planned to assign 43 healthy male and female subjects: 14 subjects to the two 
treatment sequences of Part 1 and 2 in a 1:1 ratio, and 15 subjects to the three sequences of 
Part 3 in a 1:1:1 ratio.
For details of dosage and formulation see Table 6.1: 1 below:
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
Short label for footnote
T1
BI 730357, 50 mg tablet, iCF, final 
batch, qd
BI 50mg  iCF
BI 730357 50mg iCF 
R1
BI 730357, 50 mg tablet, TF1, qd
BI 50mg TF1
BI 730357 50mg TF1
T2
BI 730357, 2*100 mg tablet, iCF, 
final batch, qd
BI 200mg iCF
BI 730357 200mg iCF
R2
BI 730357, 2*100 mg tablet, TF1, 
qd
BI 200mg TF1
BI 730357 200mg TF1
T3c
BI 730357, 100mg tablet, iCF side 
batch coarse milled API, qd
BI coarse
BI 730357 100mg coarse 
milled API
T3u
BI 730357, 100mg tablet, iCF side 
batch unmilled API, qd
BI unmilled
BI 730357 100mg 
unmilled API
R3
BI 730357, 100mg tablet, iCF final 
batch reg milled API, qd
BI regular
BI 730357 100mg 
regularly milled API
The following separate study phases will be defined for the analyses of AEs:


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Screening (ranging from 0:00 h on day of informed consent until first administration 
time of study drug)
On treatment (separately for each treatment described in Table 6.1: 1 above, including 
residual effect period (REP); i.e. ranging from the time of administration of the 
respective treatment until 7 days after administration of the respective treatment)
Follow-Up (ranging from end of on-treatment phase until end of follow-up or time of 
administration of the next treatment)
Two types of AE displays will be provided in the report for each of the parts:
A) Section 15.3 and Appendices 16.1.13.1.8.2 and 16.1.13.1.8.3 (for ClinicalTrials.gov and 
EudraCT) of the CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the 
study treatment (short label)). Screening and follow-up will not be included in this 
analysis. 
The following total will be provided in addition (Section 15.3 only):
a total over all on treatment phases included in this analysis ("Total on treatment")
B) Section 15.4 and Appendix 16.1.13.1.8.1 (except for ClinicalTrials.gov and EudraCT) of 
the CTR displays:
Screening 
On treatment (labelled with the name of the study treatment (short label))
Follow-up
In Section 16.1.13.1.8 AE tables, the following total will be provided in addition:
a total over all study phases ("Total")
Tables of vital signs and laboratory values will present results by the above mentioned on 
treatment phase.
For detailed information on the handling of the treatments in the BRAVE views refer to 
Technical TSAP ADS plan and Data Reviewers guide. 


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6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the combined report planning and database lock meeting 
(RPM/DBLM). At this meeting, all manual deviations identified at the sites by the CRAs and 
deviations too complex to program will be reviewed by the trial team to decide which are 
considered important. For definition of important protocol deviations (iPD), and for the 
process of identification of these, refer to the Boehringer Ingelheim (BI) SOP "Identify and 
Manage Important Protocol Deviations (iPD)" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM minutes via an accompanying Excel spreadsheet (3). 
For a description of categories which are considered to be iPDs in this trial, please refer to the 
IQRM plan. 
6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP:
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were 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 or 
secondary 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 one period to the statistical assessment. Descriptive and 
model based analyses of PK parameters will be based on the PKS.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken


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
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
 
The following Table 6.3: 1 contains the information which subject is used for which class of 
endpoint:
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Analyses of primary and secondary PK endpoints 
X
Safety endpoints 
X
Demographic/baseline endpoints
X
Important protocol deviations
X
Disposition
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exception where imputation might be necessary for safety evaluation is AE dates. 
Missing or incomplete AE dates are imputed according to BI standards 


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Missing data and outliers of PK data are handled according to BI standards 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For vital signs, baseline for each study period is defined as the pre-treatment measurement at 
-2:00 h. 
For overall analysis, the screening visit will be used as baseline for laboratory measurements.
Section 6.1 of the CTP: Exact times of measurements outside the permitted time windows 
will be documented. The acceptable time windows for screening and the end of trial 
examination are provided in the Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication
administration are to be performed and completed within a 3h-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, ± 45 min on Day 2, and ± 60 min from Day 3 onwards.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. 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.
Starting from 119 hours after BI 730357 administration (and beyond), a time window of ±
60 min will be allowed for PK blood sampling times.
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Section 7.4 and Section 7.5.2) will 
also be performed by 
and will be presented in Section 15.5 of 
the CTR and in Appendix 16.1.13.3.
 
 
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of Clinical Trials and Project Summaries” [001-MCG-159] (6) with the 
exception of those generated for PK-calculations (7).
The three parts will be reported in separate tables, listings, and figures. 
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number, visit and actual treatment (if appropriate). 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations 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
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
 
 
 
 


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Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment sequence/group. Percentages will be rounded to one decimal place and will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not. The category 'missing' will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
Exclusion of PK parameters
 
 
 
Exclusion of PK concentrations
 
 
 
 
 
 
 
 
 
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised by treatment sequence and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 


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Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM. 
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: 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.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM/DBLM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINT(S)
Relative bioavailability of BI 730357 is to be determined on the basis of the primary and 
secondary pharmacokinetic endpoints (see Section 5.1). 
Section 7.3.1 of the CTP:
Primary analysis
The statistical model used for the analysis of primary and secondary 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: sequence, subjects within 
sequences, period and treatment. The effect ‘subjects within sequences’ will be considered as 
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation, where p=2 for Part 1 and 2 of the trial and p=3 for Part 3 of the trial:
yijkm = + ζi + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment 
k in period j,
= the overall mean,
ζi = the ith sequence effect, i = 1, …, p
sim = the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., ni


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j = the jth period effect, j = 1, …, p
k = the kth treatment effect, k = 1, …, p
eijkm = the random error associated with the mth subject in sequence i who received 
treatment k in period j.
where  ~ (0, 
) i.i.d.,  ~ (0, 
 ) i.i.d. and sim, eijkm are independent random 
variables.
The implementation for this analysis will be accomplished by using the XPKISTAT macro, 
based on PKS, and option BWC (Bioavailability/Bioequivalence, within-subject design, time-
controlled).
Section 7.3.1 of the CTP: 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. 
Further exploratory analyses
As a sensitivity analysis, this ANOVA will be repeated for the primary and secondary 
endpoints with all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, 
‘treatment’) considered as fixed effects. This analysis will be done using PROC GLM.
The following SAS code can be used to fit the model:
PROC GLM DATA=indata; 
CLASS subject treatment sequence period; 
MODEL logkp = treatment sequence period subject(sequence); 
LSMEANS treatment / PDIFF=CONTROL(“Ref_trt”) CL ALPHA=0.1; 
RUN;
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.


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7.5.2
(Other) Secondary endpoint(s)
The secondary PK parameter AUC0-∞will be assessed using the same methods as described 
for the primary endpoints.
 
 
 
Safety:
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability.
7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
The safety data for treated subjects who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials” [001-MCG-156] (8).


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The standard AE analyses 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 case report form (CRF) will be collapsed 
into one AE provided that all of the following applies:

All AE attributes are identical (lower level term (LLT), intensity, action taken, 
therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest)

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
two occurrences is given if the second occurrence started within one hour after end of 
the first occurrence).
For further details on summarization of AE data, please refer to [001-MCG-156] (8,4).
Section 5.2.6.1.4 of the CTP: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-
fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure these parameters are analysed, if necessary in an unscheduled blood test. 
Should the results meet the criteria of hepatic injury alert, the procedures described 
in the DILI checklist should be followed.

Severe infections (grading according to Rheumatology Common Toxicity Criteria
(RCTC) developed by OMERACT)

Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including
polyomavirusassociated nephropathy, cytomegalovirus, posttransplant
lymphoproliferative disorder (Epstein-Barr virus), progressive multifocal 
leukoencephalopathy, bartonellosis (disseminated only), blastomycosis,
toxoplasmosis, coccidioidomycosis, histoplasmosis, aspergillosis (invasive only), 


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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), hepatitis B virus 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), hepatitis C virus progression.
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events.
Section 1.2.3 of the CTP: The Residual Effect Period of BI 730357 (REP, i.e., the period 
after the last dose with measurable drug levels and/or pharmacodynamic effects still likely to 
be present)
All adverse events occurring before first drug administration will be assigned to ‘screening’, 
those between intake of trial medication and prior to next drug administration or termination 
date will be assigned to the corresponding treatment (‘on treatment’) as long as they occur 
within the REP. Adverse events with onset outside of the REP but prior to next drug 
administration or termination will be assigned to “follow-up”.
Section 7.3.4 of the CTP: Note that AEs occurring after the last per protocol contact but 
entered before database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
For more detail see the TSAP ADS plan.
According to ICH E3 (9), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken with trial drug = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant
therapy as identified by the Clinical Monitor/Investigator at the Report Planning Meeting. 
An overall summary of AEs (including AESIs) will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with other 
significant AEs according to ICH E3 (9), for subjects with serious AEs, for subjects with 
drug-related AEs, for subjects with drug related serious adverse events and for subjects with 
AESIs.
The SOC and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.


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In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT, additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
Descriptive statistics will be calculated for screening and end-of-trial visits as well as for the 
difference from screening. The summary statistics will be provided in total.
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possible 
clinically significant will be flagged in the data listings.
It is the investigator's responsibility to decide whether a lab value is clinically significantly
abnormal or not (at the RPM/DBLM at the latest).
The analyses of laboratory data will be based on BI standards [001-MCG-157] (10).
7.8.3
Vital signs
Descriptive statistics will be calculated for screening and end-of-trial visits. The summary 
statistics will be provided in total. Furthermore, for each treatment, summary statistics at pre-
treatment visit and 24:00 h including change from pre-treatment visit will be provided.
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening) or will be reported as AEs (when they 
occurred during treatment).
7.8.5
Others
This section is not applicable as no other variables have been specified in the protocol.


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8.
REFERENCES


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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
30-JUL-19
None
This is the final TSAP without 
any modification