Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 48
Healthy volunteers: yes

Brief summary:
The primary objective of the single-rising dose (SRD) part (trial part 1) is to investigate the safety and tolerability of BI 730460 in healthy subjects following oral administration of single rising doses. The secondary objective is the exploration of the pharmacokinetics (PK) including dose proportionality, and pharmacodynamics of BI 730460 after single dosing.

Detailed description:

Arms:
arm 1: Placebo tablet(s) matching BI 730460 tablet(s) administered orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) - Single rising dose (SRD) part. arm 2: A single dose of 2 mg BI 730460 administered as film-coated tablets orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) - Single rising dose (SRD) part. arm 3: A single dose of 8 mg BI 730460 administered as film-coated tablets orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) - Single rising dose (SRD) part. arm 4: A single dose of 25 mg BI 730460 administered as film-coated tablets orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) - Single rising dose (SRD) part. arm 5: A single dose of 50 mg BI 730460 administered as film-coated tablets orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) - Single rising dose (SRD) part. arm 6: A single dose of 100 mg BI 730460 administered as film-coated tablets orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) - Single rising dose (SRD) part. arm 7: A single dose of 200 mg BI 730460 administered as film-coated tablets orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) - Single rising dose (SRD) part.

Interventions: intervention 1: BI 730460 intervention 2: Placebo
Intervention descriptions: intervention 1: tablets intervention 2: tablets

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c20427822-07
EudraCT No.:
BI Trial No.:
2017-004446-15
1416-0001
BI Investigational
Product:
BI 730460
Title:
A partially randomised, single-blind, placebo-controlled trial to 
investigate safety, tolerability, pharmacokinetics and pharmacodynamics
of single rising doses of BI 730460 administered as tablets to healthy 
subjects, and a randomised, open-label, single-dose, two-way cross-over 
bioavailability comparison of BI 730460 as tablet with and without food
Lay Title:
This study in healthy volunteers determines the amount of BI 730460 in 
the blood when taken as tablet. It looks at how different doses of BI 
730460 are taken up in the body and how well they are tolerated. The 
study also tests how food influences the amount of BI 730460 in the blood.
Clinical Phase:
I
Trial Clinical 
Monitor:
Phone:
Fax: 
Principal 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol based on global amendment 1)
Version and Date:
Version: 7.0
Date: 24 January 2019
Page 1 of 79
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
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 730460
Protocol date:
Trial number:
Revision date:
24 January 2019
04 July 2018
1416-0001
Title of trial:
A partially randomised, single-blind, placebo-controlled trial to investigate safety, 
tolerability, pharmacokinetics and pharmacodynamics of single rising doses of 
BI 730460 administered as tablets to healthy subjects, and a randomised, open-label, 
single-dose, two-way cross-over bioavailability comparison of BI 730460 as tablet 
with and without food
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate the safety, tolerability, pharmacokinetics (PK) including dose 
proportionality, and pharmacodynamics (PD) of BI 730460 (single rising dose [SRD]
part), and the influence of food on the bioavailability of the tablet formulation 
(bioavailability [BA] part).
Methodology:
SRD part:
Single rising dose, partially randomised, single-blind, placebo-controlled, 
parallel group design. 
BA part: 
Single dose, randomised, open-label, intra-individual two-way cross-
over comparisons of the relative bioavailability of tablet fasted versus 
tablet fed
No. of subjects: 
total entered:
841
each treatment:
SRD part:
721 (6 on active drug and 2 on placebo at each of 9 dose levels)
BA part:
12 (all on active drug)
1Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned and 
approved highest dose will not be exceeded. Thus, the actual number of subjects entered may 
exceed 84 (72 in SRD part), but will not exceed 100 subjects (88 in SRD part) entered.
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 45 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 730460
Protocol date:
Trial number:
Revision date:
24 January 2019
04 July 2018
1416-0001
Test products:
SRD part: BI 730460 as film-coated tablet (2 mg, 25 mg, and 100 mg)
BA part:
BI 730460 as film-coated tablet (25 mg) in treatment T
dose:
SRD part: 2, 8, 25, 50, 100, 200, 400, 600 and 800 mg 
BA part:
50 mg2
2 This dose is tentative and can be adapted based on the information obtained 
during the trial as long as this dose will not exceed the highest dose tested in the 
SRD part that has been found to have acceptable safety and tolerability. The 
BA part will only be started if in the SRD part a dose that is at least 4-times 
higher has been found to have acceptable safety and tolerability. 
mode of admin.:
SRD part: Oral with 240 mL of water in fasted state;
BA part:
Oral with 240 mL of water in fed state (high-fat breakfast)
Comparator products: SRD part: Placebo tablets 
BA part:
BI 730460 as film-coated tablet (25 mg) in treatment R
dose:
SRD part:
Not applicable (matching placebo)
BA part: 
50 mg 
mode of admin.:
SRD part:
Oral with 240 mL of water in fasted state 
BA part: 
Oral with 240 mL of water in fasted state
Duration of treatment: SRD part: 1 single dose 
BA part: 
2 single doses separated by a washout period of at least 8 days
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 730460 is the number [N (%)] 
of subjects with drug-related adverse events.
Criteria for
pharmacokinetics:
Secondary endpoints: AUC0-∞and Cmax of BI 730460
Criteria for 
pharmacodynamics:


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 730460
Protocol date:
Trial number:
Revision date:
24 January 2019
04 July 2018
1416-0001
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
SRD part: Dose proportionality will be explored using a regression model. A 95% 
confidence interval for the slope will be computed.
BA part: Relative bioavailability will be estimated by the ratios of the geometric 
means (tablet fed / tablet fasted) for the secondary endpoints. Additionally, their two-
sided 90% confidence intervals (CIs) will be provided. Since the main focus is on 
estimation and not testing, an ac eptance range was not specified. The statistical 
model will be an ANOVA on the logarithmic scale including effects for ‘sequence’, 
‘subjects nested within sequences’, ‘period’ and ‘treatment’.  CIs will be calculated 
based on the residual error from ANOVA.


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FLOW CHART FOR THE SINGLE RISING DOSE PART
Visit
Day
Planned time (relative to 
drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood 
10, 11
12-lead ECG
Continuous ECG 
monitoring
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-21 to -1
Screening (SCR)1
x
x14
x
2
-3 to -1
-72:00
08:00
Ambulatory visit
x7
x
1
-2:00
06:00
Admission to trial site
x2,5
x2
x2
-1:30
06:30
x2,15
x2
-1:15
06:45
x2,15
-1:00
07:00
x2,15
-0:30
07:30
Allocation to treatment2
x2
0:00
08:00
Drug administration
▲
0:30
08:30
x
x9
│
x
x
1:00
09:00
x
x9
│
x
x
1:30
09:30
x
│
2:00
10:00
240 mL fluid intake
x
x9
│
x
x
2:30
10:30
x
│
3:00
11:00
x
x9
│
x
x
4:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
x8
x9
▼
x
x
6:00
14:00
x
x9
x
x
8:00
16:00
Snack (voluntary)3
x
x9
x
x
10:00
18:00
Dinner3
x
x9
12:00
20:00
x
x9
x
x 
2
24:00
08:00
Breakfast (voluntary)3,
discharge from trial site
x
x
x9
x
x
34:00
18:00
Ambulatory visit
x
x9
x
x
3
48:00
08:00
Ambulatory visit
x
x9
x
x
4
72:00
08:00
Ambulatory visit
x
x
x
x
5
96:00
08:00
Ambulatory visit
x
x
x
8
168:00
08:00
Ambulatory visit
x16
x
x
4
9 to 13
End of trial (EOT) examination 4
x
x14
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 (including rhythm strip of at least 15 minutes), 
safety laboratory (including drug screening), demographics (including determination of body height and weight, 
smoking status and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion 
criteria. Pharmacogenetic samples will be collected if needed.
2.
The time is approximate; the respective procedure is to be performed and completed within 3 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed prior 
to (first) drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, vital signs, ECG, safety laboratory, recording of AEs and 
concomitant therapies.
5.
Only urine drug screening and alcohol breath test will be done at this time point.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.


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7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to administration of study drug; this
ambulatory visit including the safety laboratory can be omitted, if the screening examination is performed on 
Days -3, -2 or -1. 
8.
Two blood sample for stability testing will be taken at this time point (refer to Section 5.5.2.4)
9.
The ECG recording has to be performed as triplicate at this time point
10. Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK data) 
including addition of samples and visits as long as the total blood volume taken does not exceed 500 mL per subject
13. Two blood samples should be collected: 4.3 mL in sodium citrate tubes and 4.5 mL in lithium heparin tubes.
14. The ECG will be recorded as single ECG at this time point
15. At baseline (i.e. Day 1, prior to drug administration) 3 triplicate ECGs are recorded within approximately one hour. The 
recordings of each first triplicate ECG should be separated by at least 15 minutes.
16. Only haematology with automatic WBC differential (refer to Table 5.2.3: 1) at this time point.


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FLOW CHART FOR THE BIOAVAILABILITY PART
Visit
Day
Planned time (relative to 
drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood 
8
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-21 to -1
Screening (SCR)1
x
x10
x
2/3*
-3 to -1
-72:00
08:00
Ambulatory visit
x7
x
1
-2:00
06:00
Admission to trial site in visits 2 and 3, 
allocation to treatment in visit 2 only2
x2,5
x2
x10,2
x2
x2
-0:30
07:30
Standardised Breakfast9
0:00
08:00
Drug administration
0:30
08:30
x
1:00
09:00
x
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
x10
x
x
2:30
10:30
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x10
x
x
6:00
14:00
x
x
8:00
16:00
Snack (voluntary)3
x
x
10:00
18:00
Dinner3
x
x10
x
12:00
20:00
x
x 
2
24:00
08:00
Breakfast (voluntary)3, discharge from trial site
x
x
x10
x
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x10
x
x
4
72:00
08:00
Ambulatory visit
x
x
5
96:00
08:00
Ambulatory visit
x
x
8
168:00
08:00
Ambulatory visit
x11
x
x
4
9 to 13
End of trial (EOT) examination4
x
x10
x
x
* Two identical treatment periods separated by a wash-out phase of at least 8 days between drug administrations
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples will be 
collected if needed.
2.
The time is approximate; the respective procedure is to be performed and completed within 3 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed prior 
to the first drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, vital signs, ECG, safety laboratory, recording of AEs and 
concomitant therapies.
5.
Only urine drug screening and alcohol breath test will be done at this time point.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to each administration of study drug; 
this ambulatory visit including the safety laboratory can be omitted, if the screening examination is performed on 
Days -3, -2 or -1. 


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8.
Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK data) 
including addition of samples and visits as long as the total blood volume taken does not exceed 500 mL per subject
9.
Standardised (high-fat, high-calorie) breakfast only in one treatment period under fed condition
10. The ECG will be recorded as single ECG at this time point. However, except for screening and EOT, the number of 
ECGs per time point may be increased to three ECGs based on the preliminary ECG results obtained during the SRD 
part of this trial.
11. Only haematology with, automatic WBC differential (refer to Table 5.2.3: 1) at this time point. 


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART FOR THE SINGLE RISING DOSE PART.........................5
FLOW CHART FOR THE BIOAVAILABILITY PART..............................7
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS.......................................................................................... 13
1.
INTRODUCTION.................................................................................... 16
1.1
MEDICAL BACKGROUND............................................................................16
1.2
DRUG PROFILE...............................................................................................16
1.2.1
Nonclinical pharmacology....................................................................16
1.2.2
Toxicology..............................................................................................17
1.2.3
Nonclinical pharmacokinetics..............................................................20
1.2.4
Prediction of human pharmacokinetics..............................................21
1.2.5
Clinical experience in humans.............................................................21
1.2.6
Drug product.........................................................................................22
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 23
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................23
2.2
TRIAL OBJECTIVES.......................................................................................25
2.3
BENEFIT - RISK ASSESSMENT ...................................................................25
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 29
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................29
3.1.1
Administrative structure of the trial...................................................31
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................32
3.3
SELECTION OF TRIAL POPULATION ......................................................32
3.3.1
Main diagnosis for study entry............................................................33
3.3.2
Inclusion criteria...................................................................................33
3.3.3
Exclusion criteria ..................................................................................33
3.3.4
Removal of subjects from therapy or assessments.............................34
Removal of individual subjects................................................34
3.3.4.1
Discontinuation of the trial by the sponsor..............................35
3.3.4.2
3.3.5
Replacement of subjects .......................................................................36
4.
TREATMENTS........................................................................................ 37
4.1
TREATMENTS TO BE ADMINISTERED....................................................37
4.1.1
Identity of BI investigational product and comparator 
products .................................................................................................37


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4.1.2
Method of assigning subjects to treatment groups ............................38
4.1.3
Selection of doses in the trial................................................................39
4.1.4
Drug assignment and administration of doses for each subject .......39
4.1.5
Blinding and procedures for unblinding ............................................40
Blinding....................................................................................40
4.1.5.1
Procedures for emergency unblinding .....................................41
4.1.5.2
4.1.6
Packaging, labelling, and re-supply ....................................................41
4.1.7
Storage conditions.................................................................................42
4.1.8
Drug accountability ..............................................................................42
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................42
4.2.1
Other treatments and emergency procedures....................................42
4.2.2
Restrictions............................................................................................43
Restrictions regarding concomitant treatment .........................43
4.2.2.1
Restrictions on diet and life style.............................................43
4.2.2.2
4.3
TREATMENT COMPLIANCE.......................................................................43
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 44
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................44
5.1.1
Endpoints of efficacy.............................................................................44
5.1.2
Assessment of efficacy...........................................................................44
5.2
SAFETY..............................................................................................................44
5.2.1
Endpoints of safety................................................................................44
5.2.2
Assessment of adverse events...............................................................44
Definitions of adverse events...................................................44
5.2.2.1
Adverse event collection and reporting ...................................47
5.2.2.2
5.2.3
Assessment of safety laboratory parameters......................................48
5.2.4
Electrocardiogram................................................................................51
12-lead resting ECG.................................................................51
5.2.4.1
Continuous ECG monitoring ...................................................53
5.2.4.2
5.2.5
Assessment of other safety parameters...............................................53
Vital signs ................................................................................53
5.2.5.1
Medical examinations..............................................................53
5.2.5.2
5.3
OTHER...............................................................................................................53
5.3.1
Pharmacogenomic evaluation..............................................................53
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................54
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................54
5.5.1
Pharmacokinetic endpoints..................................................................54
Secondary endpoints................................................................54
5.5.1.1
5.5.2
Methods of sample collection...............................................................55
Plasma sampling for pharmacokinetic analysis.......................55
5.5.2.1


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Additional blood sample for stability-testing ..........................57
5.5.2.4
5.5.3
Analytical determinations ....................................................................58
Analytical determination of analyte plasma concentration......58
5.5.3.1
6.
INVESTIGATIONAL PLAN.................................................................. 61
6.1
VISIT SCHEDULE............................................................................................61
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................61
6.2.1
Screening period....................................................................................61
6.2.2
Treatment periods.................................................................................62
6.2.3
End of trial period.................................................................................62
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 63
7.1
STATISTICAL DESIGN – MODEL ...............................................................63
7.1.1
Objectives...............................................................................................63
7.1.2
Endpoints...............................................................................................63
7.1.3
Model......................................................................................................63
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................65
7.3
PLANNED ANALYSES....................................................................................65
7.3.1
Primary analyses...................................................................................65
7.3.2
Secondary analyses ...............................................................................65
7.3.3
Safety analyses.......................................................................................66
7.3.4
Preliminary PK analyses......................................................................67
7.3.5
Pharmacokinetic analyses ....................................................................68
7.4
HANDLING OF MISSING DATA ..................................................................69
7.4.1
Safety......................................................................................................69
7.4.2
Plasma/urine drug concentration - time profiles ...............................69
7.4.3
Pharmacokinetic parameters...............................................................69
7.5
RANDOMISATION ..........................................................................................69
7.6
DETERMINATION OF SAMPLE SIZE ........................................................70
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 72
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................72


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8.2
DATA QUALITY ASSURANCE .....................................................................72
8.3
RECORDS..........................................................................................................73
8.3.1
Source documents .................................................................................73
8.3.2
Direct access to source data and documents.......................................73
8.3.3
Storage period of records.....................................................................73
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................74
8.5
STATEMENT OF CONFIDENTIALITY.......................................................74
8.6
COMPLETION OF TRIAL..............................................................................74
9.
REFERENCES......................................................................................... 75
9.1
PUBLISHED REFERENCES...........................................................................75
9.2
UNPUBLISHED REFERENCES.....................................................................75
10. APPENDICES .......................................................................................... 77
11. DESCRIPTION OF GLOBAL AMENDMENT................................... 78


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BA
Bioavailability
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BW
Body Weight
CA
Competent authority
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central nervous system
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP
Cytochrome P450
DG
Dose group
DILI
Drug induced liver injury
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EEG
Electroencephalograph 
EOT
End of trial


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FIM
First-in-man
gCV
Geometric coefficient of variation
HR
Heart rate
IC50
50% inhibitory concentration
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
ITE
Indirect target engagement
LC-MS/MS
Liquid chromatography tandem mass spectrometry
MACS
Magnetic-activated cell sorting
MedDRA
Medical Dictionary for Regulatory Activities
mRNA
Messenger Ribonucleic Acid
NC
Not calculated
NOA
Not analysed
NOAEL
No observed adverse effect level
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PAD
Pharmacologically active dose
PCR
Polymerase chain reaction
PD
Pharmacodynamic(s)
PE
Polyethylene
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
PUVA
Psoralen Ultraviolet A
QD
Quaque die, once daily
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram


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QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
RNA
Ribonucleic Acid
SAE
Serious adverse event
SCR
Screening
SOP(s)
Operating Procedure(s)
SRD
Single-rising dose
T
Test product or treatment
TDMAP
Trial Data Management and Analysis Plan
Th
T helper type
TMF
Trial master file
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WOCBP
Women of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
BI 730460 has not yet been tested in humans.
1.2
DRUG PROFILE
1.2.1
Nonclinical pharmacology
BI 730460 was profiled in cellular assays in primary human cells central to the pathogenesis 
 
 BI 730460 provided consistent potency across all 
stimuli, cell types, and species tested, including in whole blood conditions. BI 730460 
provided substantial inhibition of disease-relevant biomarker and histology reads in 
mechanistic pre-clinical in vivo mouse models of inflammation. 
BI 730460 showed good off-target selectivity in that it exhibited 
 
 No other off-target activities were 
detected.
General and safety pharmacology studies have been conducted to address the core battery of
CNS, cardiovascular, respiratory, renal, and liver function. The results of BI 730460 general 
and safety pharmacology studies demonstrated an acceptable profile for Phase I clinical trials 
in healthy volunteers.    
the proarrhythmic risk of BI 730460 at clinical dose levels is low.


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1.2.2
Toxicology
The toxicity profile of BI 730460 has been assessed in a comprehensive set of in vitro and in
vivo safety pharmacology studies, genetic toxicology studies, and repeat dose studies in the
rat and dog. Pivotal studies were performed in compliance with GLP. The nonclinical safety
package supports administration of BI 730460 to men for up to 4 weeks duration.
General Tolerability
In repeat dose toxicity studies in rats, doses of 
 in 20 animals/sex resulted in 
mortality with body weight losses in 1 male rate and 2 female rats, and in a dose reduction to 
300 mg/kg/day on dosing day 7. Reduced doses of 
 were then well tolerated.
The NOAEL of a 4-week dosing period was considered to be
 
males and females 
combined).
In dogs doses up to 
 for 4 weeks were well tolerated in repeat dose toxicity 
studies.
 
 
 
 
 
 
Clinical pathology findings
 
These findings were considered non-adverse based on 
the magnitude of the changes and since they were not associated with tissue inflammation.


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Histopathology findings
This finding was considered a non-adverse adaptive
response to hepatic microsomal enzyme induction due to lack of hepatocellular necrosis or
degeneration. It was associated with decreases in plasma exposures upon repeat dosing.


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There was no evidence of vascular injury, erosions or ulcers in the oesophagus, 
stomach or larynx after the 4-week recovery period in dogs so these were all considered to be 
reversible findings [n00255297].
There were no vascular findings in the two-week and four-week rat studies with BI 730460,
suggesting that this might be a dog-specific phenomenon that is of limited relevance to
humans.
Organ System Effects
The immunotoxic potential of BI 730460 was evaluated in 2- and 4-week rat and dog studies
by assessing haematology, peripheral blood immunophenotyping and microscopic evaluation
of lymphoid tissues.


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Genetic Toxicology
The genotoxic potential of BI 730460 was assessed in bacterial and mammalian systems. The 
results of the in vitro and in vivo genetic toxicology studies showed that BI 730460 was free 
of any genotoxic potential [c19477316].
Photosafety
In summary, non-clinical safety data of BI 730460 support clinical Phase I trials in men with 
daily oral administration for up to 28 days. Human exposure up to those achieved at the 
NOAEL of
is considered safe.
1.2.3
Nonclinical pharmacokinetics


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1.2.4
Prediction of human pharmacokinetics
The compound showed equivalent in vitro potency in human, mouse and rat.
 
1.2.5
Clinical experience in humans
This is the first-in-man study. Clinical data are not available up to date for BI 730460. 
To date preliminary results are available at BI from a similar small molecule 
 
 This study was completed on 
15 August 2017 and consisted of 2 parts. The SRD part was a partially randomised, single-
blind, placebo-controlled trial to investigate safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising doses of 
 administered as oral solution (2 mg 
and 8 mg) and film-coated tablets (doses of 25 mg, 50 mg, 100 mg, 200 mg, 400 mg and 
800 mg) to 72 healthy male volunteers. The BA part was a randomised, open label, single-
dose, three-way crossover bioavailability comparison of 25 mg 
 in 12 healthy male 
volunteers to explore the relative bioavailability of tablet fasted versus oral solution fasted 
and the influence of food on the bioavailability of tablet fasted versus tablet fed.  
Safety evaluations included physical examination, vital signs, ECG, laboratory tests, and 
adverse events (AEs) and demonstrated that 
 was safe and well tolerated up to the 
800 mg dose. AEs, which generally reflected commonly-occurring events of short duration, 
and were mostly mild or moderate in severity, were distributed without discernable trend 
among recipients of placebo and rising dose levels of
. No serious AEs were 
reported.


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Following administration of the tablet, 
 was absorbed with a Tmax between about 
2 to 3 hours. Thereafter, plasma concentrations decreased rapidly in a mono- or biphasic 
manner with an estimated terminal half-life (t1/2) ranging from approximately 20 to 27 hours.
The preliminary PK data suggest that the exposure (AUC0-24) to 
 increased in a 
dose-proportional manner for the oral solution between 2 and 8 mg and for the tablet up to 
50 mg, and thereafter increased in a less-than-dose-proportional manner, with approximately 
1.5-fold increase in exposure with each 2-fold increase in dose up to 800 mg. Comparing the 
exposures of tablets in the fasted state, it can be noted that an 8-fold increase in dose from 25 
to 200 mg and a 16-fold increase from 25 to 400 mg only led to AUC increases of 4.4-fold
and 6.6-fold, respectively. After single dosing, the steady-state trough level (C24) of 140 nM 
for the efficacy of 
 was only exceeded in dose groups ≥ 100 mg instead of at 25 mg 
as originally predicted.
Preliminary data of the BA part show an increase in exposure in the fed condition compared 
to the fasted condition suggesting a positive food effect for 
Also other pharmaceutical companies have already tested compounds of this mode of action 
in Phase I or Phase II trials in the past (e.g. ClinicalTrials.gov Identifiers 
 and 
). In the US, safety, tolerability, pharmacokinetics and pharmacodynamics of 
an investigational 
 was investigated in two randomised, double-blind, 
placebo-controlled clinical trials in healthy volunteers. The first study was a SRD trial (7 
dose levels) in 53 subjects. The second study was a multiple rising dose trial (5 dose levels) 
with once daily treatment for 10 days in 40 subjects. For these trials, final results are yet to be 
published and only an abstract is available from the homepage of the Journal of Immunology
(http://www.jimmunol.org/ content/196/1_Supplement/71.4.abstract) [2016, vol. 196 
(1 Supplement) 71.4]. According to this abstract, the investigational compound was shown to 
be safe and generally well tolerated at all dose levels tested.
1.2.6
Drug product
Please refer to Section 4.1. For a more detailed description of the BI 730460 profile, please 
refer to the current Investigator’s Brochure (IB) [c19477316].


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
As a transition from preclinical investigations to clinical development in this first-in-man 
trial, safety, tolerability, and pharmacokinetics of BI 730460 will be assessed in healthy male 
volunteers using single rising oral doses in order to provide the basis for a potential ongoing 
clinical development of BI 730460 in the indication of psoriasis.
Healthy male subjects aged 18 - 45 years will be recruited for this study. They provide a 
relatively stable physiological, biochemical and hormonal basis (steady state) for studying 
drug effects, they show no disease-related variation and they are not taking concomitant 
medication. 
In the single rising dose (SRD) part, within each dose group, all actively treated individuals 
will receive the same BI 730460 dose. The next higher dose will only be administered (to the 
next group) if the treatment in the preceding dose groups was safe and showed acceptable 
tolerability.
In the bioavailability (BA) part, BI 730460 will be administered to the subjects in a two-way-
crossover fashion to gain information about the effect of food on BI 730460 to support 
upcoming clinical efficacy studies.
Dose selection
It is intended to investigate the following dose levels of BI 730460 in the SRD part of this 
trial: 2 mg, 8 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, and 800 mg. The 
background for this dose selection is described in the following paragraphs.
Starting dose in this trial
It is best practice to use different methods for dose selection and to take a starting dose at the 
lower end of the dose range if different methods give different estimates (err on the side of 
caution).
Applying the respective calculation as given in the US FDA Guidance for Industry 
'Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Adult Healthy Volunteers' and assuming a no adverse effect level (NOAEL) of 
 
 a maximum recommended starting dose (MRSD) 
as high as 17 mg could be selected based on the toxicology data. In addition the PAD 
(pharmacologically active dose) approach should be used to support the selection of a safe 
starting dose. The lowest therapeutic dose of BI 730460 is predicted to be 
and was derived from the pharmacodynamic minicircle model. Considering potential but easy 
monitorable and reversible effects of BI 730460 on blood pressure, it is preferable to apply a 
safety factor of 10 to the predicted lowest PAD, which would translate to a starting dose of 
2 mg (for details see Section 5.3.8.2 of the IB). 


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Finally, another commonly used NOAEL-based approach, following ICH guidance M3 (R2), 
is to use a fraction of the NOAEL, e.g. 1/50 or 1/100 (R09-1400). 
 
 
Taken together different approaches give a starting dose in the range of 2 mg 
, and 
2 mg is finally considered as an appropriate and safe starting dose at the lower end of this 
range. The 2 mg dose is
 
 
and is not expected to trigger any relevant or unacceptable biological activity.
Maximum dose and dose escalation
Although, as stated above, a minimum daily dose of about 
 is predicted to achieve 
therapeutic systemic exposure of BI 730460 at steady state
 
for several reasons it is planned to explore higher doses /
exposures. Subsequent clinical studies in patients might show that required therapeutic doses 
and exposures are significantly higher than predicted. Also, higher doses / exposures might
be required for more severe disease states, for induction vs. maintenance treatment, and for
other immunological indications. So while higher doses and exposures might still be well 
tolerated they provide a larger magnitude of therapeutic effects. Further, testing of doses 
higher than 
 is also reasonable to compensate for any bioavailability and half-life 
lower/shorter than expected. If, for example, bioavailability was significantly less than the 
predicted 
 (see section 1.2.4), the therapeutic dose could eventually turn out to be several 
fold higher than currently predicted (e.g. 4-fold higher as observed for BI 730357, refer to 
1.2.5). And eventually, even if the therapeutic dose turns out to be as low
, higher 
than therapeutic doses / exposures are typically explored in the well-controlled clinical 
environment of first-in-man (FIM) studies if supported by non-clinical safety data, in order to 
provide a sufficient safety margin for subsequent studies (e.g. studies with multiple dose and 
accumulation, drug-drug-interaction studies, studies in patients with impaired excretion 
function, etc.), where substantial increases in exposure may be seen.
For this study therefore 800 mg has been selected as maximum dose, but this dose will only 
be administered if predicted geometric mean values of Cmax or geometric mean AUC0-24 do 
not exceed the exposures limits defined below – otherwise dose escalation will be stopped at 
lower doses. Based on the preclinical safety profile of BI 730460 these exposure limits are 
anticipated to be safe and well tolerated.
The maximum human exposure to BI 730460 in this trial will be limited to 2,900 nM for Cmax
and 49,000 nM*h for AUC0-24.
 
 The cause of death in these animals could not be 
determined, but due to the occurrence in only the highest dose group, the mortality was 
attributed to BI 730460 [c19477316].


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To prevent that an exposure beyond the above predetermined safety margins will be achieved 
in this trial, preliminary PK data of preceding dose groups will be provided to estimate the 
expected exposure of the next dose group (see Section 7.3.4). The next higher dose level will 
only be administered, if predicted geometric mean values of Cmax and AUC0-24 do not exceed 
2,900 nM and 49,000 nM*h, the maximum acceptable exposure in this clinical trial.
In order to cover the anticipated dose range, a stepwise and careful dose increase up to a 
maximum dose of 800 mg has been selected for this trial. The escalation schedule has been 
chosen in a way that a decreasing escalation factor will be applied, for example, with a factor 
of 2 for the predicted therapeutic range and higher dose levels and with a factor of 1.5 for the 
last dose. This dose escalation is considered to be adequate and safe, particularly when the 
selected exposure safety margins are taken into consideration.
2.2
TRIAL OBJECTIVES
The primary objective of the SRD part (trial part 1) is to investigate the safety and tolerability 
of BI 730460 in healthy subjects following oral administration of single rising doses. The 
secondary objective is the exploration of the pharmacokinetics (PK) including dose 
proportionality, and pharmacodynamics of BI 730460 after single dosing. 
The objective of the BA part (trial part 2) will be to explore the influence of food on the 
bioavailability of tablet fasted versus tablet fed.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of a new 
orally available drug, which might improve the therapy in patients with psoriasis. The 
subjects are exposed to the risks of the study procedures and the risks related to the exposure 
to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 


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catheter, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venipuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
Drug-related risks and safety measures
As the nature of the target and the mechanism of action of BI 730460 are well understood, 
comparable compounds have been tested by BI and other companies before, and the animal 
models are believed to be predictive for the effects in humans, BI 730460 is not seen as a 
high risk compound. 
The pharmacological effects of BI 730460 are dose dependent and no evidence for prolonged 
or irreversible effects has been observed. Exposures of BI 739460 up to 2,900 nM for Cmax
and 49,000 nM*h for AUC0-24 are supported by preclinical safety data.
The following safety measures will be applied in this study in order to minimize the risk for 
healthy volunteers: 

Careful dose selection as described in Section 2.1. In addition, dose escalation will be 
shallow and both, starting dose and maximum dose/exposure have ample safety 
margins with respect to the preclinical findings. Finally, dose selection was based on a 
sound preclinical package including 4 week toxicological studies (not only 2 weeks).

Preliminary measurement of BI 730460 plasma concentrations and preliminary 
determination of PK parameters (Cmax, AUC0-24 see Section 7.3.4). For precautionary 
reasons, drug plasma concentrations of healthy volunteers in this trial should not 
exceed the geometric mean Cmax of 2,900 nM or geometric mean AUC0-24 of 
49,000 nM*h and will be considered as a preliminary threshold (see Section 2.1).
Further dose progression would only be allowed after a safety interim analysis and 
filing and approval of a substantial CTP amendment.

An extensive safety laboratory will be performed including differentiation of 
lymphocyte subtypes (see Section 5.2.3).

For safety reasons, during the single rising dose part each dose group of 8 subjects 
(6 on active, 2 on placebo) will be divided into two cohorts of 4 subjects each (3 on 
active, 1 on placebo). These two cohorts will be separated by at least 48 hours 
(between 1st subject of each cohort), which based on an anticipated half-life of 
BI 730460 of approximately 14 hours is expected to cover the period of highest risk / 
peak effect. The first cohort will be dosed in a single blinded, fixed sequence fashion 
(active - placebo - active - active) and the drug administration will be separated by at 
least 10 min between the first and second subject, and by at least 3 hours between the 
first and third subject. This design ensures that between first and second active dose 
of each dose level there is a time interval of at least 3 hours, which is expected to be 
sufficient to detect relevant acute effects of BI 730460. If BI 730460 was safe and 
well tolerated during these initial administrations, the remaining subjects of the 
respective dose level could be dosed as close as 10 minutes apart.


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
A thorough ECG monitoring including continuous ECG measurement over 4 hours 
post dose to cover the anticipated period of highest drug exposure and additional 
repeated 12-lead ECGs over 48 hours following drug administration. Dose escalation 
would be stopped as soon as at least 2 subjects at one dose level showed relevant QT 
prolongation (see Section 3.3.4.2 for details).

Although no clinically relevant hypotension is expected at the exposures anticipated 
in this trial (see Section 1.2.1), nevertheless, blood pressure and heart rate will be 
closely monitored for potential hemodynamic effects.

The subjects will stay at the trial site (BI Human Pharmacology Centre) for at least 
24 hours after study drug administration at each dose level. Based on an anticipated 
half-life BI 730460 of approximately 
 this is expected to cover the period of 
highest risk / peak effect.

During in house-confinement the subjects will be under medical observation and 
thoroughly monitored for both expected and unexpected adverse events.

Only if the respective dose of BI 730460 was safe and showed acceptable tolerability 
and if no stopping criterion was met (refer to Section 3.3.4.2), the next higher dose 
will be given at least 6 days later (referring to the 1st subject of each dose group).

The next higher dose will be given after careful assessment of all available safety data 
by the Principal Investigator (or authorised deputy) and the sponsor (see Section 3.1)

The BA part will only be started if in the SRD part a dose that is at least 4-fold higher 
has shown acceptable safety and tolerability.

As reproductive toxicity studies have not yet been conducted, women of child-bearing 
potential will not be enrolled in this study.

 subjects 
will be advised to apply protection measures such as sunscreen, and solarium 
radiation or treatment with ultraviolet light (e.g. PUVA) or medication with known 
phototoxicity potential (e.g. doxycycline) are prohibited during this clinical trial 
within 8 days after administration of trial medication.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety, see also section 5.2.2.1, adverse events of special interest.
In summary, although not tested in humans to date, BI 730460 has the potential to become an 
oral treatment for signs and symptoms of psoriasis. Based upon preclinical data for 
BI 730460 and clinical information from competitor compounds as well as the implemented 
safety measures described above, healthy subjects will not be exposed to undue risks in 
relation to the important information expected from this trial as a basis for further clinical 
development of this compound. Healthy volunteers are not expected to have any direct 
benefit from participation in this FIM clinical trial with BI 730460, as is the usual case in 
such Phase I trials. Considering the medical need of the development of a safer and more 


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effective treatment for patients with psoriasis, the Sponsor considers that the benefit 
outweighs the potential risks and justifies exposure of healthy human volunteers.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This first-in-man trial will be conducted in healthy male volunteers at a single centre. 
A total of 84 healthy male subjects is planned to participate in 9 sequential groups of 
8 subjects each during the SRD part, and in a group of 12 subjects during the BA part. 
However, additional subjects may be entered to allow testing of additional doses on the basis 
of experience gained during trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose of the SRD part will not be exceeded. Thus, the actual number of 
subjects entered may exceed 84, but will not exceed 100 subjects entered. If required for the 
further evaluation of pharmacokinetics such changes may be implemented via non-substantial 
CTP Amendments. However, the addition of further dose groups for the evaluation of safety 
findings is subject to a substantial CTP Amendment requiring approval. Within each dose 
group of the SRD part, 6 subjects will receive the active drug and 2 will receive placebo. In 
the BA part, 12 subjects will receive the active drug. The dose groups to be evaluated are 
outlined in Table 3.1: 1 below.
Table 3.1: 1
Planned dose groups
Trial part
SRD
BA
Dose Group (DG)
1
2
3
4
5
6
7
8
9
Dose (mg) 
2
8
25
50
100
200
400
600
800
2x 50
Number of subjects
8
8
8
8
8
8
8
8
8
12
Subjects receiving placebo
2
2
2
2
2
2
2
2
2
0
Subjects receiving active drug 6
6
6
6
6
6
6
6
6
12
Subject / medication number1
1
Respective reserve subject numbers will be provided. In the SRD part, the medication number matches the subject 
number. In the BA part, the subject numbers 
are assigned to the medication numbers 
 
and 
in ascending order.
SRD part
The first part of the trial, the SRD part, is designed as single-blind, partially randomised, and 
placebo-controlled within parallel dose groups. Only one dose is tested within each dose 
group. The groups will be treated consecutively in ascending order of doses. Each group is 
divided into 2 cohorts of 4 subjects each (3 on active drug and 1 on placebo). On the first 
study day within each dose group, the first cohort will be treated in a single-blind manner in 
the following order: first subject (active) followed at least 10 min later by the second subject 
(placebo) followed at least 2 h 50 min later by the third subject (active) followed at least 
10 min later by the fourth subject (active).
If BI 730460 treatment is safe and showed acceptable tolerability in the first cohort, the 
subjects in the second cohort will be treated not earlier than 2 days later in a single-blind 


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randomised manner. In the second cohort, a time interval of at least 10 min will be 
maintained between each administration of the trial drug to the individual subjects. A time 
interval of at least 6 days will be maintained between the first drug administration in the 
previous dose group and the first drug administration of the subsequent dose group. The 
decision to proceed to the next dose group will be based upon the safety, tolerability, and 
pharmacokinetic data of the preceding dose groups. The next dose will only be given if, in the 
opinion of the Investigator, no safety concerns arose in the preceding dose group (i.e. no 
dose-limiting events occurred) and if none of the pre-specified trial-specific stopping criteria 
were met (refer to Section 3.3.4.2).
A documented Safety Review must take place prior to each dose escalation (see minimum 
data set below). Furthermore, an unscheduled safety review meeting can be requested 
anytime for any reasonable cause by the Principal Investigator (or an authorised deputy) or 
the sponsor of the study, e.g. because of any unforeseen adverse events, etc. Dose escalation 
will only be permitted if no safety concerns exist in the opinion of the Principal Investigator 
(or an authorised deputy) and the trial clinical monitor (or an authorised deputy).
Although no formal Safety Review meeting will take place within a given dose group, safety 
will be continuously monitored during this trial, and an individual will only be dosed in the 
absence of any safety concern (i.e. no dose-limiting events occurred) and if none of the pre-
specified trial-specific stopping criteria have been met (refer to Section 3.3.4.2).
The minimum data set for the Safety Review consists of the following data:

AEs in the current and preceding dose groups up to at least 48h post dosing from at 
least 4 subjects on active drug per dose group, including clinically relevant findings 
from ancillary safety testing listed below (Note: AEs may be ongoing at the time of 
Safety Reviews and AE information may be subject to change prior to Database 
Lock)

Results from 12-lead EGG and continuous ECG monitoring in the current and 
preceding dose groups and from at least 4 subjects on active drug per dose group up to 
at least 48h post dosing.

Vital signs in the current and preceding dose groups and from at least 4 subjects on 
active drug per dose group up to at least 48h post dosing.

Clinical laboratory tests in the current and preceding dose groups and from at least 
4 subjects on active drug per dose group up to at least 24h post dosing.

Preliminary PK data for selected time as per Section 7.3.4.

Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the trial clinical monitor (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs and out-of-range 
laboratory results (if considered clinically significant). Safety Reviews can be conducted 
face-to-face or by video/telephone conference. The trial clinical monitor is responsible for 
organization and minutes of the reviews. Minutes will be signed off by the Principal 
Investigator (or an authorised deputy) and filed in the ISF and TMF.


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The investigator is allowed to alter the scheduled dose levels (e.g. add low and/or
intermediate dose levels) on the basis of experience gained during the study, provided the 
planned and approved highest dose is not exceeded. In this case, the total number of subjects 
in this trial might increase. The investigator and/or the sponsor should stop dose escalation in 
case the safety evaluation leads to concerns that would not allow higher dosing.
BA part
The BA part will be performed in a randomised, open-label, single dose, two-way crossover 
fashion. Subjects will be administered BI 730460 as tablet in a fasting state (reference 
treatment R) and as tablet after a standardised high-fat breakfast (test treatment T). The two
treatments will be separated by a washout period of at least 8 days between study drug
administrations. Subjects will be allocated randomly to one of the two treatment sequences: 
R/T, T/R.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH 
& Co. KG, Biberach, Germany.
The trial will be conducted at the 
 
, under the supervision of the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
.
The analyses of BI 730460 concentrations in plasma and urine will be performed under the 
responsibility of Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, 
Biberach, Germany at a suitable contract research organization (CRO).
The digitally recorded 12-lead ECGs of the SRD part will be sent to a specialised contract 
research organisation (
) for evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs.


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Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For single-rising dose trials, the design described in Section 3.1 is viewed favourable under 
the provision not to expose the subjects involved to undue risks since the main study 
objective is to investigate safety and tolerability of BI 730460 and the risk to subjects will be 
minimized by studying sequentially ascending doses. For safety reasons the first cohort of 
each dose level will be treated in a fixed treatment sequence (Active-Placebo-Active-Active). 
The dose level being investigated at any time will be known to subjects, but single-blind 
conditions regarding each subject’s treatment (active or placebo) will be maintained for both 
cohorts of each dose level.
The disadvantage of this trial design is a possible observer bias with regard to the dose-
depending effects as well as time effects, but it has the virtue of minimizing subject risk by 
sequentially studying ascending doses. As time-effects are expected to be small relative to the 
differences between the doses in the broad range investigated, unbiased comparisons between 
treatments can still be expected.
It is standard in trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety and tolerability. Each dose group consists of 8 subjects with 6 on 
active treatment, and 2 on placebo. The placebo control group includes all subjects of all dose 
groups treated with placebo. 6 subjects per active treatment group are in general considered 
as sufficient for the exploratory evaluation of pharmacokinetics. 
For the BA part comparing bioavailability of BI 730460 following administration as tablet in 
the fasted state versus tablet under fed conditions, the crossover design is viewed favourable 
due to its efficiency: since each subject serves as his own control, the comparison between 
the treatments is based on a comparison within subjects rather than between subjects. Thus 
the inter-subject variability is removed from the comparison between treatments [R94-1529]. 
Blinding is not possible because the treatments are distinguishable.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 84 healthy male will enter the study. The actual number of subjects entered 
may exceed the total of 84 if additional intermediate doses will be tested (see Section 3.1). 
Subjects will be recruited from the volunteers' pool of the trial site. 
Only male subjects will be included into the study because hitherto no data on reproductive 
toxicology are available. With respect to the embryo-fetal risk coming from the treatment of 
male subjects with BI 730460, where it is theoretically possible that relevant exposure to 
BI 730460 may be achieved in women of childbearing potential (WOCBP) from exposure to 
seminal fluid, male contraception (condom or abstinence) should be used in order to avoid 
exposure of an existing embryo/fetus [R16-0373] (see 3.3.3, exclusion criterion 23).


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A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry 
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 45 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 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 judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)


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12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
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 30 g per day for males)
16. Drug abuse or positive drug screening
17. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
19. Inability to comply with dietary regimen of trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criteria apply:
23. Male subjects with WOCBP partner who are unwilling to use male contraception 
(condom or sexual abstinence) from the first administration of trial medication until 30 
days after last administration of trial medication
24. ALT (alanine transaminase) or AST (aspartate transaminase) or GGT (gammaglutamyl 
transferase) or serum creatinine exceeds the upper limit of normal (ULN) at screening
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
Removal of individual subjects
3.3.4.1
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events (AEs), or diseases)
4. An AE or clinically significant laboratory change or abnormality occurred that the 
Investigator judges to warrant discontinuation of treatment. This may include cases of 


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sustained symptomatic hypotension or hypertension, or of clinically relevant changes in 
ECG requiring intervention.
5. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
6. The subject experiences a serious adverse event 
7. For BA part only: The subject experiences a drug-related AE of severe intensity
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. Dose escalation in the SRD part or treatments in the BA part will 
be terminated if more than 50% of the respective subjects of one dose level or treatment 
group show drug-related and clinically relevant adverse events of moderate or severe 
intensity, or if at least one drug-related serious adverse event is reported.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP by a trial site or investigator, disturbing the appropriate 
conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
5. Dose escalation in the SRD part or treatments in the BA part will be stopped if at least 
2 subjects on the respective active treatment (at one dose level or in the BA part) have
relevant individual QT prolongations, i.e. absolute QT or QTc greater than 500 ms, as 
confirmed by a repeat ECG recording, or a QTc increase of greater 60 ms from baseline 


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in connection with absolute QT or QTc greater than 500 ms, as confirmed by a repeat 
ECG recording.
6. Dose escalation will be stopped, if the Cmax or AUC0-24 of at least 1 subject of one dose 
group increases above the following exposure thresholds or if the estimated gMean 
exposure is expected to exceed a Cmax of 2,900 nM or an AUC0-24 of 49,000 nM*h. 
Estimation will be done based on preliminary PK results of preceding dose groups (see 
Section 2.1).
7. Occurrence of severe non-serious adverse events considered as drug-related by the 
investigator in 2 subjects of the same cohort (4 subjects), or 2 subjects of the same dose 
group (8 subjects), or 2 subjects of the BA group (12 subjects) 
3.3.5
Replacement of subjects
In case that there are less than 4 subjects on active per dose level in the SRD part or less than 
9 subjects in the BA part, who do not complete the trial, the trial clinical monitor together 
with the trial pharmacokineticist and the trial statistician are to decide if and how many 
subjects will be replaced. A replacement subject will be assigned a unique study subject 
number possessing the same treatment, as the subject 
 replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational products have been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of BI investigational product and comparator products
SRD part 
The characteristics of the test product are:
Substance:
BI 730460
Pharmaceutical formulation:
Film-coated tablet
Source:
BI Pharma GmbH & Co. KG
Unit strength:
2 mg
Posology:
1-0-0 (DG 1), 4-0-0 (DG 2) 
Route of administration:
oral
Duration of use:
Single dose 
Substance:
BI 730460
Pharmaceutical formulation:
Film-coated tablet
Source:
BI Pharma GmbH & Co. KG
Unit strength:
25 mg
Posology:
1-0-0 (DG 3), 2-0-0 (DG 4) 
Route of administration:
oral
Duration of use:
Single dose 
Substance:
BI 730460
Pharmaceutical formulation:
Film-coated tablet
Source:
BI Pharma GmbH & Co. KG
Unit strength:
100 mg
Posology:
1-0-0 (DG 5), 2-0-0 (DG 6), 4-0-0 (DG 7), 6-0-0 (DG 8) or 
8-0-0 (DG 9)
Route of administration:
oral
Duration of use:
Single dose 
The characteristics of the reference product (placebo) are: 
Substance:
Placebo matching in size and weight to 2 mg tablet
Pharmaceutical formulation:
Film-coated tablets
Source:
BI Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
1-0-0 (DG 1), 4-0-0 (DG 2) 
Route of administration:
oral
Duration of use:
Single dose


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Substance:
Placebo matching in size and weight to 25 mg tablet
Pharmaceutical formulation:
Film-coated tablets
Source:
BI Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
1-0-0 (DG 3), 2-0-0 (DG 4)
Route of administration:
oral
Duration of use:
Single dose
Substance:
Placebo matching in size and weight to 100 mg tablet
Pharmaceutical formulation:
Film-coated tablets
Source:
BI Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
1-0-0 (DG 5), 2-0-0 (DG 6), 4-0-0 (DG 7), 6-0-0 (DG 8) or 
8-0-0 (DG 9) 
Route of administration:
oral
Duration of use:
Single dose 
BA part 
The characteristics of test product T and reference product Rare:
Substance:
BI 730460
Pharmaceutical formulation:
Film-coated tablet
Source:
BI Pharma GmbH & Co. KG
Unit strength:
25 mg 
Posology:
2-0-0
Route of administration:
oral
Duration of use:
Single dose 
4.1.2
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects of the SRD part will be contacted in writing and 
informed about the planned visit dates. The subjects willing to participate will be recruited to 
dose groups according to their temporal availability. As soon as enough subjects have been 
allocated to 1 of the 18 dose cohorts (2 cohorts per dose group), the following subjects will be 
allocated to one of the other dose cohorts. Therefore, the allocation of subjects to dose 
cohorts is not influenced by trial personnel, but only by the subjects’ temporal availability. As 
the study includes healthy subjects from a homogenous population, relevant imbalances 
between the dose groups are not expected. 
The randomisation list with study subject numbers and allocated treatments (SRD part) or 
treatment sequences (BA part) will be provided to the trial site in advance. In both parts of 
the trial, the allocation of subjects to study subject numbers will be performed prior to the 
first administration of trial medication. For this purpose, the subjects will be allocated to a 
study subject number by drawing lots. Once a subject number has been assigned, it cannot be 
reassigned to any other subject.


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The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
For the SRD part, oral doses in the range of 2 mg to 800 mg have been selected in order to 
assess the safety and tolerability of BI 730460 in healthy male volunteers, and to investigate 
the PK of this novel 
. The selected doses cover a safe starting dose in the 
sub-therapeutic range, the estimated therapeutic range and potentially supra-therapeutic doses 
within the levels determined by toxicological investigations (see Section 1.2 for details).
The intra-individual comparison of the BA part investigating the relative bioavailability of 
tablet fasted versus tablet fed are planned to be conducted with a dose of 50 mg as it is 
assumed that this dose covers the therapeutic range and might be used in the subsequent 
clinical development.
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Tables 4.1.4: 1 (SRD part) and 4.1.4: 2 (BA 
part) below. The number of units for placebo corresponds to the number of units of the 
respective dose level.
Table 4.1.4: 1
BI 730460 and placebo treatments for the SRD part 
Dose group
Substance
Pharmaceutical form
Unit        
strength
Number of units per 
administration
Total 
dose
1
BI 730460
film-coated tablet
2 mg
1 tablet
2 mg
2
BI 730460
film-coated tablet
2 mg
4 tablets
8 mg
3
BI 730460
film-coated tablet
25 mg
1 tablet
25 mg
4
BI 730460
film-coated tablet
25 mg
2 tablets
50 mg
5
BI 730460
film-coated tablet
100 mg
1 tablet 
100 mg
6
BI 730460
film-coated tablet
100 mg
2 tablets 
200 mg
7
BI 730460
film-coated tablet
100 mg
4 tablets
400 mg
8
BI 730460
film-coated tablet
100 mg
6 tablets
600 mg
9
BI 730460
film-coated table
100 mg
8 tablets
800 mg
1-9
Placebo*
film-coated tablet
--
identical to active treatment
--
*   Subjects receiving placebo are equally distributed across dose groups 
Table 4.1.4: 2
BI 730460 film-tablets for the BA part  
Treatment
Substance
Pharmaceutical 
form
Unit        
strength
Number of units per 
administration
Total 
Dose
T   (tablet fed)
BI 730460
film-coated tablet
25 mg
2 tablets
50 mg
R   (tablet fasted)
BI 730460
film-coated tablet
25 mg
2 tablets
50 mg


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The Investigator can decide at any time to discontinue dosing or to decrease the dose 
escalation by adding intermediate doses in case of intolerability or due to safety concerns.
The trial medication will be administered to the subjects, while in a sitting or standing 
position, as an oral dose together with about 240 mL of water under supervision of the 
investigating physician or an authorised designee in the morning of Day 1. The so-called 
four-eye principle (two-person rule) should be applied for administration of trial medication 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise. Administration will be performed following an overnight fast, which is to start no 
later than 10 h before the scheduled dosing. 
In treatment T (tablet fed) of the BA part, a high-fat, high-calorie meal will be served 30 min 
before drug administration. The meal must be completely consumed prior to drug 
administration. The composition of the standardised high-fat, high-calorie meal will be in 
compliance with the FDA guidance ‘Food-Effect Bioavailability and Fed Bioequivalence 
Studies’ [R03-2269] as detailed in Table 4.1.4: 3.
Table 4.1.4: 3
Composition of the high-fat, high-calorie meal
Ingredients
kcal
Sum1
984
1
The total caloric content was supplied approximately as following: 150 kcal as protein, 
250 kcal as carbohydrate, and 500 to 600 kcal as fat. 
Subjects will be kept under close medical surveillance until at least 24 h following drug 
administration. During the first 4 hours after drug administration subjects of the SRD part 
will be confined to bed with a bed inclination angle of at least 45 degrees unless lower or 
supine positioning is required for trial-related measurements (e.g. recording of 12-lead ECG).
During the first 4 hours after drug administration subjects of the BA part will only be allowed 
to lie down if supine positioning is required for trial-related measurements (e.g. recording of 
12-lead ECG). For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
In the present trial, treatments of the SRD part will be blinded to subjects only. With the 
rising dose design, single-blind conditions regarding the subjects' treatment (active or 
placebo) are maintained within each dose group, however the current dose level will be 
known to subjects and Investigators. Treatments of the BA part will be open-label.


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The database of this trial will be handled open-label, because no bias with regard to data 
cleaning of safety measures is expected. This is considered acceptable because the potential 
for bias seems to be low and does not outweigh practical considerations. The bioanalyst will 
be blinded for the BA part only.
The bioanalyst of analytical laboratory and the trial pharmacokineticist may receive the 
randomisation codes of the SRD part prior to official unblinding to perform the preliminary 
PK analysis. He or she will treat the codes confidentially.
 
He or she will 
confirm in writing that the codes will be treated confidentially.
Within the ECG laboratory, the staff involved with interval measurements and assessments 
will be blinded with respect to the treatment within each dose level and also with regard to 
the recording date and time as well as time the points of the ECGs. The interval 
measurements for a given subject will be performed in a random and blinded sequence by a 
single technician. No more than two different blinded readers will evaluate the ECGs of the 
study.
Procedures for emergency unblinding
4.1.5.2
As this trial will be conducted open-label, the treatment information will be known. 
Therefore, no emergency envelopes will be provided.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. Smaller boxes and/or 
bottles within the clinical trial supply containers will be labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Subject or medication number

Batch number

Visit number (BA part only)
The telephone number of the Sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 


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page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability

The Investigator will receive the investigational drugs delivered by the Sponsor when 
the following requirements are fulfilled:

Approval of the 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 as 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. All unused medication will be disposed locally by the trial site upon 
written authorisation by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The Investigator must maintain records of the product’s delivery to the trial site, the 
inventory at the site, the use by each subject, and the disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
Investigator will maintain records that document adequately that the subjects were provided 
the doses specified by the CTP, and that reconcile all investigational products received from 
the Sponsor. At the time of disposal, the Investigator must verify that all unused or partially 
used drug supplies have been returned by the clinical trial subject and that no remaining
supplies are in the Investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, in case of adverse events in need of treatment, the Investigator can 
authorise symptomatic therapy. In those cases, subjects will be treated as necessary and, if 


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required, kept under supervision at the trial site or transferred to a hospital until all medical 
evaluation results have returned to an acceptable level.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
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.
Restrictions on diet and life style
4.2.2.2
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake (except for the milk served with the 
breakfast in the BA part) is restricted to the water administered with the drug, and an 
additional 240 mL of water served at 2 h and 4 h post-dose (mandatory for all subjects). From 
lunch until discharge from the study centre, liquid intake is restricted to additional 3 litres. 
During the days of urine collection, subjects will be advised to drink at least 1.5 litres per 
day. 
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted starting 4 days before the first administration of trial medication until after the last 
PK sample of each study period is collected.
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 10 h before until 24 h after administration of trial 
medication.
Excessive physical activity (such as competitive sport) should be avoided starting 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 within 8 days after administration of trial medication. The use of sunscreens is 
mandatory in that time.
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 
and/or urinary excretion will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 730460 is the number [N (%)] of 
subjects with drug-related adverse events.
Further criteria of interest:

AEs (including clinically relevant findings from the physical examination)
5.2.2
Assessment of adverse events
Definitions of adverse events
5.2.2.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation  

Requires prolongation of existing hospitalisation,

Results in persistent or significant disability or incapacity

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse. 
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in subsections ‘AE Collection’ and ‘AE reporting to the 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 (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see section 5.2.2.2.


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The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, and/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.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).


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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. 
Adverse event collection and reporting
5.2.2.2
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A 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.


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
After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
The REP for BI 730460, the time interval when measurable drug levels or PD effects are still 
likely to be present after last administration, is not known for this first-in-human trial at this 
early stage of development. Therefore, all AEs reported until the end of trial examination 
(last per protocol contact) will be considered on treatment; please see Section 7.3.3.
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. 
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no 
further information can be obtained.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h (excluding 4-hour post-dose sample). Overnight fasting is not required at the 
discretion of the Investigator or designee for retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
A1
B2
C3
D4
Haematology
Haematocrit
Haemoglobin
Red blood cells (RBC)
White blood cells (WBC)
Platelets
Reticulocyte count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential 
(relative and absolute)
Neutrophils 
Eosinophils 
Basophils 
Monocytes 
Lymphocytes 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Manual differential WBC 
(if automatic differential 
WBC is abnormal)
Polymorphnuclear neutrophils (segs), band 
neutrophils (stabs), eosinophils, basophils, 
monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin Time (Quick and INR)
X
X
X
X
--
--
X
X
Enzymes
Aspartate aminotransferase (AST/GOT) 
Alanine aminotransferase (ALT/GPT) 
Alkaline phosphatase (AP)
Gammaglutamyl transferase (GGT)  
Lactate dehydrogenase
Lipase
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
X
X
X
X
X
X
Electrolytes
Calcium
Sodium
Potassium
X
X
X
X
X
X
--
--
--
X
X
X
Substrates
Plasma glucose
Creatinine
Total bilirubin 
Direct bilirubin
Total protein
C-Reactive Protein (CRP) 
Urea in serum
Phosphate in serum
Total cholesterol 
Triglycerides
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid stimulating hormone (TSH)
X
--
--
--
1 A: parameters to be determined at visit 1 (screening examination)
2 B: parameters to be determined at visits 2 and 3 on Days -3 to -1 and Days 1 to 4 (for time points, refer 
to Flow Chart)
3 C: parameters to be determined at visits 2 and 3 on Day 8 (for time point, refer to Flow Chart)
4 D: parameters to be determined at visit 4 (end of trial examination)


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Table 5.2.3: 1 Routine laboratory tests (cont.)
Functional lab group
Test name 
A1
B2
C3
D4
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine RBC
Urine WBC
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic examination 
if erythrocytes, leukocytes 
nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (e.g. 
presence of sediment bacteria, casts in sediment, 
squamous epithelial cells, erythrocytes,
leukocytes)
--
1 A: parameters to be determined at visit 1 (screening examination)
2 B: parameters to be determined at visits 2 and 3 on Days -3 to -1 and Days 1 to 4 (for time points, refer 
to Flow Chart)
3 C: parameters to be determined at visits 2 and 3 on Day 8 (for time point, refer to Flow Chart)
4 D: parameters to be determined at visit 4 (end of trial examination)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests at screening only. Drug 
screening will be performed at screening and prior to each administration of trial medication 
on Day 1 (for time points refer to Flow Chart).
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
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed prior to each treatment period at time 


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points indicated in the Flow Chart, 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 Table 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 
the drug screening tests. Drug screening will be performed at the trial site using M-10/14-
PDT Multiline test or comparable tests.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
12-lead resting ECG
5.2.4.1
Recording
Twelve-lead resting 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 time points given in the Flow Chart. 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). Precise electrode placement will be marked 
with an indelible mark on the skin to allow reproducible placement throughout the study.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10-sec duration after subjects have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled 
for the same time (except for blood drawing from an intravenous cannula that is already in 
place) to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database.
Storing
All ECGs will be stored electronically on the Muse Cardiology Information System (GE 
Medical Systems, Freiburg, Germany).
Data transfer
For time points specified in the Flow Chart, ECGs will be transferred electronically to a
central ECG lab (
) for evaluation.


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In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded.
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).
Evaluation
a) Central ECG lab (SRD part only)
For the SRD part, central ECG lab evaluation will be performed post-study for the 
first of three replicate ECGs per time point on Days 1, 2 and 3. For baseline, where 3 
triplicate ECGs are recorded, only the first triplicate ECG (i.e. 3 single ECGs) will be 
evaluated. This will include the determination of cardiac QRS-axis as assessed by the 
ECG machine’s algorithm as well as the intervals RR, PR, QRS and QT measured 
semi-automatically. The remaining second and third replicate ECG will be stored for 
additional analysis if required, e.g. by authorities at a later time point.
Heart rate (HR) and the QT interval corrected for HR (QTc e.g. QTcF and QTcB) will 
be determined by the sponsor (see TSAP for details).
All semi-automatic interval measurements in one subject will be performed on the 
same lead. The intervals will be measured from four cardiac cycles (beats) in lead II. 
If lead II shows a flat T wave or is not measurable for any reason, lead V5 will be 
used, or if that lead is not measurable, then lead I will be used. The lead actually used 
will be reported in the CTR. For automatic interval measurements no lead will be 
provided
For blinding arrangements see Section 4.1.5.1. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular subject should be evaluated by 
a single reader.
Evaluation of ECGs will comply with the ICH E14 guidance document and 
supplements [R07-4722, R16-0366] as well as the FDA requirements for annotated 
digital ECGs [R09-4830].
b) Trial site (SRD part and BA part)
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of 
cardiac safety during the study, the QT and QTcB values generated by the 
computerised ECG system or their manual corrections by the investigators will be 
used. 
In doubtful cases, ECGs may be sent upfront (i.e. prior to the regular data transfer) for
cardiologic assessment by the central lab. In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening) if judged 


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clinically relevant by the investigator.
Any ECG abnormalities will be monitored carefully and, if necessary, the subject will be 
removed from the trial and will receive the appropriate medical treatment. 
Continuous ECG monitoring
5.2.4.2
Cardiac rhythm (including heart rate) will be monitored during the SRD part by means of 
continuous 3-lead ECG recording using the CARESCAPE Monitor B450 (GE Healthcare, 
Freiburg, Germany) for at least 15 min before drug administration (for baseline assessment) 
and for 4 h following drug administration). This continuous ECG monitoring supports the 
early detection of adverse events such as clinically relevant bradycardia, tachycardia, or 
arrhythmia at the trial site. Beyond this clinical evaluation at the trial site, no further data 
collection or analyses are performed based on continuous ECG monitoring.
ECG data from continuous ECG recording will not be transferred to the clinical trial 
database. Abnormal findings during continuous ECG recording will be recorded as AEs if 
judged clinically relevant by the Investigator.
5.2.5
Assessment of other safety parameters
Vital signs
5.2.5.1
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.
Medical examinations
5.2.5.2
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG
(including rhythm strip of at least 15 minutes), 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.
5.3
OTHER
5.3.1
Pharmacogenomic evaluation
Pharmacogenomic investigations explore the role of genetic variation in determining an 
individual’s response to drugs. For this purpose, a sample of at most 10 mL of blood will be 
taken at the screening examination from each subject whose genotype has not been 
previously determined. Separate informed consent for genotyping will be obtained from each 
volunteer prior to sampling.
DNA will be extracted from the blood sample in order to sequence genes coding for proteins 
that are involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs. 


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The gene sequences to be determined include known and likely functional variations of key 
ADME genes and incorporate more than 90% of ADME-related genetic markers identified by 
the PharmaADME group (weblink.pharmaadme.org). It is not intended to include the 
pharmacogenomic data in the final report. However, the data may be part of the report if 
necessary.
5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
 in an appropriate way. The scheduled measurements will allow monitoring of 
changes in vital signs, standard laboratory values, and ECG parameters that might occur as a 
result of administration of trial medication. The safety assessments are standard, are accepted
for evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5 are 
generally used assessments of drug exposure. The 
 measurements outlined in 
Section 5.6 are of exploratory nature only.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Exact time points of plasma sampling will be derived from the study management system 
ClinBase™ and documented in the CRFs by the medical personnel or sent as electronic files 
to the trial data manager. The actual sampling times will be used for determination of 
pharmacokinetic parameters.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK data) including addition of samples and 
visits as long as the total blood volume taken per subject does not exceed 500 mL. Such 
changes would be implemented via non-substantial CTP Amendments.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic endpoints will be determined if feasible:
Secondary endpoints
5.5.1.1

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)


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5.5.2
Methods of sample collection
Plasma sampling for pharmacokinetic analysis
5.5.2.1
For quantification of BI 730460 plasma concentrations, 2.7 mL of blood will be taken from 
an antecubital or forearm vein into an K2-EDTA (dipotassium ethylenediaminetetraacetic 
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venipuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 
2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and stored in 
polypropylene (PP) tubes. The first aliquot should contain at least 0.5 mL plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 90 min, with interim storage of blood samples on crushed ice between 
blood collection and centrifugation. For each aliquot the time when the sample was placed in 
the freezer will be documented. Until transfer on dry ice to the analytical laboratory, the 
aliquots will be stored upright at about -20°C or below at the trial site. The second aliquot 
will be transferred to the analytical laboratory after the bioanalyst has acknowledged safe 
arrival of the first aliquot. At the analytical laboratory the plasma samples will be stored at 
about -20°C or below until analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, and planned sampling time. Further information such as matrix and 
analyte may also be provided. 


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After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years upon the final study 
report has been signed.


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Additional blood sample for stability-testing
5.5.2.4
In order to assess the stability of the analyte in whole blood, two additional blood samples 
will be taken from all subjects of dose group 50 mg. Based on the knowledge gained during 
the trial conduct, e.g. from preliminary PK results, the chosen timing or dose group may be 
changed to a different one. The change will be implemented via a non-substantial CTP 
Amendment.
Approximately 2.4 mL blood will be taken from an antecubital or forearm vein using two 
1.2 mL K2 EDTA-blood drawing tubes at the time indicated in the Flow Chart (immediately 


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after the drawing of a regular blood PK sample, which is to say that no additional venous 
puncture will be necessary).
From each K2-EDTA tube, one aliquot will be generated:

One aliquot (‘stability reference’) will be centrifuged within 10 min after collection. 
Centrifugation will last for about 10 min (at about 2000 g to 4000 g and 4 to 8 °C), 
plasma will be separated and transferred into a freezer

The second aliquot (‘stability test’) will be stored for about 4 h at room temperature 
and ambient light conditions (documentation of storage time necessary) and will then 
be centrifuged and stored according to the first sample. 
At a minimum, the aliquots should be labelled with the following information: BI trial 
number, administered drug, subject number, planned sampling time, ‘stability reference’ or 
‘stability test’.
Until transfer to the analytical laboratory, both aliquots will be stored at about -20 °C or 
below at the trial site. Both aliquots will be provided to the responsible bioanalyst together 
with the information about sample handling (i.e. storage time of ‘test sample’ at room 
temperature). After receipt, the aliquots will be stored at the bioanalytical laboratory at about 
-20°C or below until analysis.
The results of the analysis of these samples will not be reported within this clinical trial but 
will be used for bioanalytical assay validation and therefore included in the corresponding 
method validation report. The remaining sample volume will be discarded upon completion 
of the method validation report at the latest.
5.5.3
Analytical determinations
Analytical determination of analyte plasma concentration
5.5.3.1
BI 730460 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis. The analysis will be performed under the 
responsibility of Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, 
Biberach, Germany at a suitable CRO.
As described in Section 4.1.5, the bioanalyst will be blinded for the BA part only. For the 
SRD part he/she will be unblinded.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration (including blank values for PK 
).
Starting from 72 h post administration a deviation from the scheduled time for PK 
 
 sampling of ±70 min is acceptable.
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 15 min for the first 6 h after trial drug administration and ± 30 min thereafter.
Starting from 72 h post administration a deviation from the scheduled time for vital signs, 
ECG and laboratory tests of ±70 min is acceptable.
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 venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned individual plasma concentration 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 determination of 
pharmacokinetic parameter.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the 
Blinded Report Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.  
Pharmacogenomic genotyping will be performed in those volunteers whose genotypes are not 
known (for details see Section 5.3). 


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6.2.2
Treatment periods
Study participants will be admitted to trial site at least 1 hour prior to administration of the 
trial medication. They will be kept under close medical surveillance for at least 24 hours 
following drug administration. Thereafter the subjects will be allowed to leave the trial site 
after formal assessment and confirmation of their fitness. Afterwards the study will be 
performed in an ambulatory fashion until the end-of-study examination.
For the SRD part, each subject will receive one dose of the respective trial medication 
(BI 730460 or placebo) at visit 2. The participants of the BA part will receive the respective 
trial medication (BI 730460) at visit 2 and 3. Details on treatments and procedures of 
administration are described in Section 4.1.4.
For details on time points and procedures for collection of plasma and urine samples for PK 
analysis, refer to Flow Chart and Section 5.5.2. 
The safety measurements performed during the treatment period are specified in Section 5.2. 
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial period 
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
SRD Part:
The primary objective of the first (SRD) part of this trial is to investigate the safety and 
tolerability of BI 730460 by using descriptive statistics for all endpoints comparing active 
dose groups to placebo. The primary endpoint is defined in Section 5.2.1. Inferential statistics 
is not planned (as explained in Section 7.2).
The secondary objective is the exploration of the pharmacokinetics (PK) of BI 730460. 
Endpoints as specified in 5.5.1 will be analysed by descriptive statistics. Secondary endpoints 
as defined in Section 5.5.1.1 will be subjected to analysis of dose proportionality by use of 
the power model.
BA Part:
The primary objective of the second part of the study is to investigate relative bioavailability 
of 50 mg BI 730460 given as tablets after a standardised high-fat breakfast (Test, T) 
compared to 50 mg BI 730460 as tablets in a fasting state (Reference, R)
The secondary objective is the evaluation and comparison of several PK parameters between 
the treatments. The secondary objective will be assessed by descriptive statistics.
7.1.2
Endpoints
The primary endpoint to describe safety and tolerability of BI 730460 will be the number (% 
subjects) with drug-related AEs. The collection of parameters pertaining to these 
investigations is described in detail in Section 5.2.1.
The secondary pharmacokinetic endpoints to be used for the assessment of dose 
proportionality and relative bioavailability are specified in Section 5.5.1.1.
7.1.3
Model
SRD part:
The basic model for the investigation of dose proportionality will be a power model that 
describes the functional relationship between the dose and PK endpoints. 
The model consists of a regression model applied to log-transformed data. The corresponding 
ANCOVA model includes the logarithm of the dose as a covariate. 
ij
i
ij
ε
)
X
exp(
)
exp(Y









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Together with 
and 
, taking natural logarithms converts this model 
to a linear form as follows:
where
logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where i = 1, 2, …, 9, j = 1, 2, …, 6;

intercept parameter;
slope parameter;
logarithm of dose i;
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
This equation can be fit as a linear regression model. Based on the estimate for slope 
parameter (β), a 2-sided 95% CI for the slope will be computed. Perfect dose proportionality 
would correspond to a slope of 1. The assumption of a linear relationship between the log-
transformed pharmacokinetic endpoint and the log-transformed dose will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed.
BA part: Investigation of relative bioavailability
Relative bioavailability is primarily to be determined on the basis of the parameters AUC0-
and Cmax (cf. Section 5.5). Those parameters will be log-transformed (natural logarithm) prior 
to fitting the model.
The statistical model used for the analysis of AUC0-and Cmax will be an ANOVA (analysis 
of variance) model on the logarithmic scale.  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. For tests on subject, period, and treatment effects, 
the denominator sum of squares will be the sum of squares for error; while for tests on 
sequence effects, the denominator will be the sum of squares for subjects. The model is 
described by the following equation
yijkm = + i + sim + j + k + eijkm,  where
yijkm = logarithm of response (endpoint, see Section 7.1.3) measured on subject m in 
sequence i receiving treatment k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2
)
exp(


)
exp(
ε
ij
ij



ij
i
ij
ε
X
β
α
Y




ij
Y
β
i
X
ij
ε


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sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2
k = the kth treatment effect, k = 1, 2
eijkm = the random error associated with the mth subject in sequence i who received 
treatment k in period j.
The difference between the expected means for test treatment and reference treatment log(T)-
log(R), will be estimated by the difference in the corresponding Least Square Means (point 
estimate) and two-sided 90% confidence intervals based on the t-distribution will be 
computed. These quantities will then be back-transformed to the original scale to give the 
point estimator (geometric mean) and interval estimates for the ratio between response under 
test and response under reference.
Pairwise comparisons will be done for tablet fed (Test, T) vs tablet fasted (Reference, R).
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of different dose groups of BI 730460 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will 
be described in their entirety and evaluated by descriptive statistical methods.
In the SRD part, for the evaluation of dose proportionality, a two-sided 95% confidence 
interval (CI) of the slope will be computed. However, the CI will have to be interpreted in the 
perspective of the exploratory character of the study, i.e. as interval estimate for effects in the 
present data.
The relative bioavailability of BI 730460 will be estimated by the ratios of the geometric 
means (test/reference) for the secondary PK endpoints. Additionally, their two-sided 90% 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 on testing, an acceptance 
range was not specified, that is, no hypothesis will be tested.
7.3
PLANNED ANALYSES
7.3.1
Primary analyses
Analysis of safety and tolerability is described in Section 7.3.3.
7.3.2
Secondary analyses
The secondary parameters (see Section 5.5.1) will be calculated according to the relevant 
corporate procedure of the Sponsor ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472, current version). 


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Pharmacokinetic parameters of a subject will be included in the analysis unless the subject 
has an important protocol violation relevant for the evaluation. Whether a protocol violation 
is important will be decided no later than in the Report Planning Meeting. 
Reasons for exclusion of single pharmacokinetic parameters may be:

The subject experiences emesis at or before two times median tmax. Median tmax is to 
be determined for the test product excluding the subjects experiencing emesis.

The subject experiences emesis at any time during the labelled dosing interval.

Time deviations

Use of restricted medications 
The subject set for the evaluation of PK endpoints (PKS) will include all treated subjects that 
provide at least one observation for at least one secondary endpoint without important 
protocol violations with respect to the statistical evaluation of PK endpoints. It will also be 
decided in the Report Planning Meeting which subjects are to be included in the PKS. 
Excluded subjects will be listed with their individual plasma concentrations and individual 
pharmacokinetic parameters, however, will not be included in descriptive statistics for plasma 
concentrations, pharmacokinetic parameters or other statistical assessment.
SRD Part: Assessment of dose proportionality
Dose proportionality of the secondary pharmacokinetic endpoints will be explored based on 
the regression model described in Section 7.1.3. Based on the estimate for slope parameter 
(), a 2-sided 95% CI for the slope will be computed. Perfect dose proportionality would 
correspond to a slope of 1. The assumption of a linear relationship between the log-
transformed pharmacokinetic endpoint and the log-transformed dose will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose ranges, where dose proportionality can be assumed.
BA Part: Assessment of relative bioavailability
Point estimates of bioavailability, the ratios of the geometric means (test/reference) for the 
secondary endpoints (see 5.5.1.1), and their two-sided 90% CIs will be provided.
To this end, the PK endpoints will be log transformed (natural logarithm) prior to fitting the 
ANOVA model (cf. Section 7.1.3). 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 (LeastSquares Means), and a two-sided 90% confidence interval based on the 
t-distribution will be computed. These quantities will then be back-transformed to the original 
scale to provide the point estimate and 90% CIs for each endpoint.
7.3.3
Safety analyses
Safety analyses will be performed in accordance with BI standards. 
All treated subjects (that is, all subjects who received at least one dose of study drug), will be 
included in the safety evaluation. Safety analyses will be descriptive in nature and will be 
based on BI standards.


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Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. The active treatment groups will be compared to the placebo group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
The analyses will be done by ‘treatment at onset’. 
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs). 
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until the end of trial visit 
will be assigned to the treatment period, and those after the end of trial examination will be 
assigned to ‘post-study’. These assignments including the corresponding time intervals will 
be defined in detail in the TSAP.
Additionally, further treatment intervals (analysing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening and post-study intervals). 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA). Frequency, severity and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.2.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.
A centralised evaluation of all 12-lead ECGs recordings (see Section 5.2.4) will be the basis 
for the derivation of further ECG parameters based on the ECG variables QT, HR, QTcF, 
QTcB, PR, QRS, and RR. The baseline value of an ECG variable is defined as the mean of 
the triplicate ECG measurements prior to drug administration. The derivation of the 
quantitative and qualitative ECG endpoints and their analyses will be described in the TSAP.
7.3.4
Preliminary PK analyses
A preliminary analysis of PK parameters (AUC0-24 and Cmax of BI 730460) provided as 
individual values and geometric means of at least the first cohort per dose level, will be 
performed for 

all dose levels up to n-2 before proceeding to dose level n (with n ≤50 mg)

all dose levels up to n-1 before proceeding to dose level n (with n > 50 mg)


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(Note: Data from the first cohorts of the above mentioned dose levels will be sufficient as 
long as the data from at least 2 subjects on active were available)
In contrast to the final PK/PD calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows or not. Therefore, minor deviations of preliminary and final results may occur. 
The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without subject identification. The preliminary 
results will be distributed to the Investigator and the trial team. 
Depending on preliminary data on safety, tolerability, changes of dosing schedule (e.g. 
additional intermediate doses) or planned times for PK
-sampling, additional 
preliminary PK-analysis may be performed based on the request of the trial clinical monitor, 
the Investigator, or trial clinical pharmacokineticist. Preliminary PK data will be distributed 
to the Investigator. No formal interim report will be written.
No inferential statistical preliminary analysis is planned. However, after each dose group the 
Investigator (or 
 deputy) is allowed to postpone further dose progression until a 
preliminary analysis of the data already obtained has been performed.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 730460 will be calculated 
according to the BI SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Subjects who are not included in the PKS (refer to Section 7.3.1.) will be reported with their 
individual plasma / urine concentrations and individual pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for plasma / urine concentrations, 
pharmacokinetic parameters.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of 
the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
Every effort will be made to include all concentration data in an analysis. If not possible, a 
case to case decision is required whether the value should only be excluded from half-life 
estimation or the complete analysis. 

If a concentration is only excluded from half-life determination, it will be used for all 
other calculations (e.g. descriptive statistics) and for graphical presentation.


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
If a concentration value is excluded from all calculations, it will not be presented 
graphically or used for the calculation of descriptive statistics and parameter 
determination. However the excluded concentration itself will be listed in the clinical trial 
report associated with an appropriate flag.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time will not 
be recorded or will be missing for a certain time point, the planned time will generally be 
used for this time point instead. Pharmacokinetic parameters which cannot be determined will 
be identified by "not calculated" (NC).
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma
 drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the predose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.5
RANDOMISATION
SRD part: Each dose group will be divided into two cohorts. The subjects of the first cohort 
will not be randomised to maintain a treatment sequence of active-placebo-active-active due 


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to safety reasons. In the second cohort of each dose level the subjects will be assigned to 
active or placebo treatment using a 3:1 allocation ratio. 
BA part: Subjects will be randomised to one of the two treatment sequences T/R, R/T in a 1:1
ratio. 
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, which 
involves 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 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
SRD part
It is planned to include a total of 72 subjects in this study part. The planned sample size is not 
based on a power calculation. The size of 8 subjects per dose group (6 on active treatment, 
and 2 on placebo) is commonly used in single-rising dose studies of the present type and is in 
general considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics [R95-0013].
Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose will not be exceeded. Thus, the actual number of subjects entered 
may exceed 72, but will not exceed 88 subjects entered in the SRD part.
BA part
It is planned to enter 12 subjects in this trial part, because this sample size is considered 
sufficient to achieve the aims of this exploratory trial.
With this sample size, the following precision of the ratio of geometric means (test/reference)
can be expected. Precision is defined as the ratio of upper limit to relative BA estimate. Note 
that the precision is independent of the actual ratio of geometric means. For this First-in-Man 
trial, no information on intra-subject variability is available. Therefore, Table 7.6: 1 provides 
an overview on the achievable precision for estimating the ratio of geometric means 
(test/reference) for three different gCV. For illustrative purposes, the expected 90% 
confidence intervals with 95% coverage probability are displayed for different values of 
geometric means ratios T/R in the two-period two sequence crossover design.


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Table 7.6: 1
Expected two-sided 90% confidence intervals for different gCVs and 
ratios T/R (N=12)
gCV[%]
Ratio1 [%]
Precision (upper CI 
limit/relative BA)
90% CI [%]
20
80
1.219
(65.61, 97.54)
100
1.219
(82.01, 121.93)
125
1.219
(102.52, 152.41)
150
1.219
(123.02, 181.89)
200
1.219
(164.03, 243.86)
25
80
1.28
(62.52, 102.36)
100
1.28
(78.15, 127.95)
125
1.28
(97.69, 159.94)
150
1.28
(117.23, 191.93)
200
1.28
(156.31, 255.91)
30
80
1.342
(59.63, 107.33)
100
1.342
(74.54, 134.16)
125
1.342
(93.17, 167.71)
150
1.342
(111.80, 201.25)
200
1.342
(149.07, 268.33)
The expected 90% confidence interval limits in the table were derived by
CI limitupper, lower = 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 [R12-0972] using R Version 3.0.3.
1)
Ratio of geometric means (test/reference) for a PL endpoint is defined by exp(μT)/exp(μR)


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


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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 operated 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
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data is entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities, i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last subject/subject out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R03-2269
  Guidance for industry: food-effect bioavailability and fed bioequivalence   
studies. In: U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER); 
2002. p. 1-9.
R09-1400
European Medicines Agency (EMEA). ICH topic M3 (R2) non-clinical 
safety studies for the conduct of human clinical trials and marketing 
authorization for pharmaceuticals: step 4: note for guidance on non-
clinical safety studies for the conduct of human clinical trials and 
marketing authorization for pharmaceuticals (June 2009, 
CPMP/ICH/286/95). http://www.emea.europa.eu; 2009.
R09-4830 
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 
2005). 2005.
R12-0972
Kupper LL, Hafner KB. How appropriate are popular sample size 
formulas? Am Stat 1989;43(2):101-105.
R16-0373
  Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER); 
2002. p. 1-9.
R94-1529
Chow SC, Liu JP. Design and Analysis of Bioavailability and 
Bioequivalence Studies. New York: Marcel Dekker Inc; 1992.
R95-0013
Broom C. Design of first-administration studies in healthy man. In: 
O'Grady J, Linet OI, editors. Early Phase Drug Evaluation in Man. 
London: Macmillan Press; 1990. p. 206-213.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c19477316
 
. Investigator’s Brochure: BI 73046 Psoriasis. P1416.1.
Current version.


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c11248385-04
 A partially randomised, single-blind, 
placebo-controlled trial to investigate safety, tolerability, pharmaco-
kinetics and pharmacodynamics of single rising doses of BI 730357 
administered as oral solution and tablets to healthy subjects, and a 
randomized, open-label, single-dose, three-way cross-over bioavailability
comparison of BI 730357 as tablet versus oral solution and tablet with and 
without food. CTP. 1407.1. 05-May-2017.
n00255510-01
 Prediction of BI 730460 Pharmacokinetics and 
Therapeutic Dose in Human. Nonclinical Expert Statement. BI 730460. 
05 Oct 2017.
n00255297
 BI 730460: Four-Week Oral (Gavage) Toxicity and
Toxicokinetics Study in the Dog Followed by a Four-Week Recovery 
Period. Nonclinical Report. 17R014. Draft report available.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT
Number of global amendment
1
Date of CTP revision
17 July 2018
EudraCT number
2017-004446-15
BI Trial number
1416-0001
BI Investigational Product
BI 730460
Title of protocol
A partially randomised, single-blind, placebo-
controlled trial to investigate safety, tolerability, 
pharmacokinetics and pharmacodynamics of single 
rising doses of BI 730460 administered as tablets to 
healthy subjects, and a randomised, open-label, single-
dose, two-way cross-over bioavailability comparison 
of BI 730460 as tablet with and without food
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
Title Page & Synopsis
Description of change
Change of Principal Investigator
Rationale for change
Due to change of staff


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Number of global amendment
2
Date of CTP revision
24 January 2019
EudraCT number
2017-004446-15
BI Trial number
1416-0001
BI Investigational Product
BI 730460
Title of protocol
A partially randomised, single-blind, placebo-
controlled trial to investigate safety, tolerability, 
pharmacokinetics and pharmacodynamics of single 
rising doses of BI 730460 administered as tablets to 
healthy subjects, and a randomised, open-label, single-
dose, two-way cross-over bioavailability comparison 
of BI 730460 as tablet with and without food
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
CTP Synopsis (test products, comparator products) 
and Sections 3.1, 4.1.1, 4.1.2, 4.1.3, 4.1.4 and 7.1.1
Description of change
The tentative dose of the BA part of 100 mg (1 tablet 
of 100 mg BI 730460) was changed to 50 mg 
(2 tablets of 25 mg BI 730460).
Rationale for change
In accordance with the CTP, the tentative dose of the 
BA part of 100 mg was adapted to 50 mg. This 
based on the preliminary PK information obtained 
during the trial and indicating that 200 mg probably 
will be the maximum dose of the SRD part, and on 
the condition that the BA part may only start if an at 
least 4-fold dose has been assessed to have 
acceptable safety and tolerability in the SRD part.  
In contrast to the SRD part, where the subject 
number matches the medication number, the 
medication and subject numbers of the BA part do 
not match.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c20427822
7.0
clinical-trial-protocol-version-7-revision-2
A partially randomised, single-blind, placebo-controlled trial to investigate safety,
tolerability, pharmacokinetics and pharmacodynamics of single rising doses of BI
730460 administered as tablets to healthy subjects, and a randomised, open-label,
single-dose, two-way cross-over bioavailability comparison of BI 730460 as tablet
with and without food
Approval-Therapeutic Area 
25 Jan 2019 12:19 CET
Author-Clinical Trial Leader
25 Jan 2019 14:00 CET
Approval-Team Member Medicine
25 Jan 2019 14:01 CET
Author-Clinical Pharmacokineticist
25 Jan 2019 14:25 CET
Author-Trial Statistician
25 Jan 2019 17:19 CET
Verification-Paper Signature
Completion
28 Jan 2019 09:36 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c20427822
7.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c27412368-01
BI Trial No.:
1416-0001
Title:
A partially randomised, single-blind, placebo-controlled trial to
investigate safety, tolerability, pharmacokinetics and
pharmacodynamics of single rising doses of BI 730460
administered as tablets to healthy subjects, and a randomised, open-
label, single-dose, two-way cross-over bioavailability comparison 
of BI 730460 as tablet with and without food
Including Protocol Amendment 1 [c20427822-07]
Investigational
Product:
BI 730460
Responsible trial 
statisticians:
Phone:
Fax:
Phone: 
Fax: 
Date of statistical 
analysis plan:
06 MAY 2019 SIGNED 
Version:
Final
Page 1 of 38
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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.


Boehringer Ingelheim
TSAP for BI Trial No: 1416-0001
Page 2 of 38
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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.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINT .....................................................................................10
5.2
SECONDARY ENDPOINTS.............................................................................10
5.2.1
Key secondary endpoints....................................................................................10
5.2.2
Secondary endpoints...........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................13
6.1
TREATMENTS...................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................15
6.3
SUBJECT SETS ANALYSED...........................................................................17
6.5
POOLING OF CENTRES .................................................................................18
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................18
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................19
7.
PLANNED ANALYSIS......................................................................................22
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........24
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................24
7.3
TREATMENT COMPLIANCE........................................................................24
7.4
PRIMARY ENDPOINT .....................................................................................24
7.5
SECONDARY ENDPOINTS.............................................................................25
7.5.1
Key secondary endpoints....................................................................................25
7.5.2
Secondary endpoints...........................................................................................25
7.7
EXTENT OF EXPOSURE.................................................................................27
7.8
SAFETY ANALYSIS..........................................................................................27
7.8.1
Adverse events.....................................................................................................27
7.8.2
Laboratory data ..................................................................................................29
7.8.3
Vital signs.............................................................................................................29
7.8.4
ECG......................................................................................................................30
7.8.5
Others...................................................................................................................32
8.
REFERENCES....................................................................................................33


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10.
HISTORY TABLE..............................................................................................38


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR (SRD part) ......................................13
Table 6.1: 2
Labels for treatments for use in the CTR (BA part).........................................13
Table 6.2: 1
Important protocol deviations ..........................................................................16
Table 6.3: 1
Analysis sets for endpoints/data description ....................................................18
Table 6.7: 1
Time schedule of 12-lead ECG recordings (SRD part)....................................20
Table 10: 1
History table .....................................................................................................38


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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 Aminotransferase
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
AST
Aspartate Aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index
BP 
Blood pressure
BWC
Bioavailability/Bioequivalence, Within-Subject Design, Time-Controlled
CARE
Clinical Analysis and Reporting Environment
CDR
Clinical Data Repository
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic Coefficient of Variation
DB
Dose Proportionality, Between-Subject Design
DBLM
Database Lock Meeting
DILI
Drug induced liver injury
ECG
Electrocardiogram
ECGPCS
ECG Pharmacokinetic Concentration Set
eCRF
Electronic Case Report Form
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
HR
Heart rate


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Term
Definition / description
ICH
International Conference On Harmonisation
ISF
Investigators Site File
iPD
Important Protocol Deviation
LLT
Lower Level Term
Max
Maximum
MedDRA
Medical Dictionary For Regulatory Activities
Min
Minimum
mRNA
Messenger Ribonucleic Acid
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
PK analysis set
POC
Percent of Control
PR
Pulse rate
PT
Preferred Term
Q1
1st quartile
Q3
3rd quartile
QD
Quaque die, once daily
RAGe
Report Appendix Generator system
REP
Residual Effect Period
RPM
Report Planning Meeting
S
Reference treatment
SAS®
Statistical Analysis System
SD
Standard Deviation
SOC
System Organ Class
SP
Sample Point
SRD
Single rising dose


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Term
Definition / description
TMCP
Translational Medicine and Clinical Pharmacology
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
U
Test treatment
ULN
Upper Limit of Normal
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), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
Study data will be stored in a Clinical Data Repository (CDR).
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or higher, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated Clinical Analysis and 
Reporting Environment (CARE), including SAS® (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 
adverse event (AE) data or laboratory data; Report Appendix Generator system (RAGe) for 
compilation/formatting of the Clinical Trial Report (CTR) appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in the TSAP are outlined in the CTP. The following changes 
compared to the protocol will be made:
According to the Reference Document 3 of the Boehringer Ingelheim (BI) Statistical Position 
Paper on Statistical Methods for PK (14), the 90% confidence intervals (CI) should be 
considered for the assessment of dose proportionality. Therefore, the 90% CI will be used 
instead of the 95% CI.
The trial was prematurely discontinued on 21 March 2019 after completion of dose group 6 
(200 mg) of the SRD part, and without starting the originally-planned BA part of this trial. 
The TSAP will therefore only describe the analysis of the SRD part.
All subjects up to and including the 200 mg dose group have completed their follow-up 
period. The maximum exposure (Cmax) observed in the SRD part following doses of 200 mg 
BI 730460 was 1,864 nM (gMean). Administration of the originally planned next 2-fold 
higher dose of 400 mg was not possible due to a higher predicted estimated Cmax of 3,728 nM 
which is above the allowed exposure limit of 2,900 nM. Therefore, the SRD part was stopped 
as with the next planned dose group (400 mg) the pre-defined stopping rule was met. Due to 
the above mentioned exposure limitation, BI also decided to stop the BA part of trial 1416-
0001.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Section 5.2.1 of the CTP:
Primary endpoint to assess safety and tolerability of BI 730460 is the number [N (%)] of
subjects with drug-related adverse events.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 5.5.1.1 of the CTP: 

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
It was planned that in total 84 volunteers participate in this study.
72 healthy male subjects will enter the SRD part, according to 9 sequential dose groups 
comprising 8 subjects per dose group (6 on active and 2 on placebo) and 12 healthy males 
will enter the BA part (one dose group, all on active).
For details of dosage and formulation see Tables 6.1: 1, and 6.1: 2 below.
Table 6.1: 1
Labels for treatments for use in the CTR (SRD part)
Dose 
group
Treatment
Short label
1-6
N*
Placebo film-coated tablet
Placebo 
1
A
2mg BI 730460 film-coated tablet
BI 2mg 
2
B
8mg BI 730460 film-coated tablet
BI 8mg 
3
C
25mg BI 730460 film-coated tablet
BI 25mg 
4
D
50mg BI 730460 film-coated tablet
BI 50mg 
5
E
100mg BI 730460 film-coated tablet
BI 100mg 
6
F
200mg BI 730460, film-coated tablet
BI 200mg 
7
G**
400mg BI 730460 film-coated tablet
BI 400mg 
8
H**
600mg BI 730460 film-coated tablet
BI 600mg 
9
I**
800mg BI 730460 film-coated tablet
BI 800mg 
*: The placebo group in the safety evaluation will consist of all placebo treated subjects, 
regardless of the dose group in which they were treated.
**: These dose groups were cancelled.
Dose escalation was stopped after the 200mg dose group, as the results of the preliminary PK 
analysis indicate that Cmax for 400 mg (dose group 7) will very likely exceed the CTP 
stopping criterion. Therefore, all analyses will be performed for the first six dose groups only.
Table 6.1: 2
Labels for treatments for use in the CTR (BA part) 
Treatment
Short label
S
50mg BI 730460 film-coated tablet, fasted
BI 50mg fast
U
50 mg BI 730460 film-coated tablet, fed
BI 50mg fed
The trial was stopped after the 200 mg dose group, skipping also the BA part.


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The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from 0:00h on day of informed consent until administration time 
of study drug (BI or Placebo))

On treatment
o
BI/Placebo treatment (separately for each treatment, ranging from the time of 
administration of BI 730460 or Placebo until 0:00h on the day after trial 
termination date (whatever occurs first))
Please note that all AEs reported between start of trial drug administration and the trial 
termination date will be considered on treatment (i.e. no follow-up period is considered in 
this trial).
Two types of AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT) of the CTR 
displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening will not be included in this analysis. 
The following totals will be provided in addition:

a total over all BI treated phases (“BI Total”)

a total over all on treatment phases included in this analysis ("Total on treatment") 
(Section 15.3 only)
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of 
the CTR displays:

Screening 

On treatment (labelled with the name of the study treatment (short label))
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:

a total over all BI treated phases (“BI Total”)

a total over all study phases ("Total")
Tables of vital signs, ECG and laboratory values will present results by the above mentioned 
on treatment phase.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewer`s 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 Report Planning Meeting 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/DBLM minutes via an accompanying Excel spreadsheet (3). The following table
contains the categories which are considered to be iPDs in this trial. If the data show other
iPDs, this table will be supplemented accordingly by the time of the RPM/DBLM at the
latest.
The iPDs will be summarised and listed.


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Table 6.2: 1
Important protocol deviations
Category
/Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C2
Randomisation not followed
C3
Non-compliance
C4
Incorrect intake of trial medication
C5
Improper washout between treatments
D
Concomitant medication
D1
Concomitant medication with the potential to affect the assessment of the trial 
medication
E
Missing data
E1
Certain violations of procedures used to measure secondary data
F
Incorrect timing1
F1
Certain deviations from time schedule used to measure secondary data
G
Other trial specific important deviations
G1
Appropriate fasting condition not met 
G2
Other protocol deviations affecting safety and rights
1 Time deviations will only be flagged as iPD, when leading to exclusion of the entire subject from an analysis set


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6.3
SUBJECT SETS ANALYSED

Treated set (TS): 
This subject set includes all subjects who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.
This is the full analysis set population in the sense of ICH-E9 (1). It is used for 
demographics, baseline characteristics, and safety analyses.
The ECG analyses are performed on the TS, except for the exposure-response analyses, 
which are performed on the ECGPCS defined below.
Section 7.3.2 of the CTP: Pharmacokinetic parameters of a subject will be included in the
analysis unless the subject has an important protocol deviation relevant for the evaluation. 
Whether a protocol deviation is important will be decided no later than in the Report 
Planning Meeting.
Reasons for exclusion of single pharmacokinetic parameters may be:

The subject experiences emesis at or before two times median tmax. Median tmax is to 
be determined for the test product excluding the subjects experiencing emesis.

The subject experiences emesis at any time during the labelled dosing interval.

Time deviations

Use of restricted medications

PK analysis set (PKS):
The PK analysis set (PKS) includes all subjects from the TS receiving BI 730460 who 
provide at least one secondary PK parameter that was not excluded according to the 
description above.
It is used for assessment of dose proportionality and the descriptive analyses of PK 
parameters.
The descriptive analysis of PK concentrations will be based on the ADS ADPC. 

ECG Pharmacokinetic Concentration Set (ECGPCS):
This subject set includes all subjects from the TS for whom at least one pair of a valid 
drug plasma concentration of BI 730460 and a corresponding (i.e. time-matched) ECG 
endpoint to be used in the exposure-response analyses was provided. For placebo 
subjects, the plasma concentration is set to zero and hence always considered as valid. 
The decision whether a time deviation between PK blood sampling and ECG recording is 
acceptable (and thus whether the pair of values will be used) is to be made no later than 
at the DBLM/RPM before database lock.


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Table 6.3: 1
Analysis sets for endpoints/data description
Endpoint/data description
Analysis set
TS
PKS
ECGPCS
Primary and further safety endpoints 
(incl. ECG) 
X
ECG endpoints and plasma concentrations 
used in exposure-response analysis
X
Secondary PK endpoints
X
Demographic/baseline data
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 7.4.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (5).
If single cardiac cycles of an ECG (out of the generally four) are missing, the arithmetic 
mean for this single ECG will be computed with the reduced (1, 2 or 3) number of cardiac 
cycles.


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If replicate ECG recordings are missing, the arithmetic means per time point will be 
computed with the reduced number (1 or 2) of recordings.
For the classification of the on treatment QTc/QT intervals into “no new onset” / “new onset” 
categories, a missing value is obtained only in case that
(i)
all on treatment values are missing and
(ii)
the baseline value is less than or equal to 500 msec, or missing.
If condition (i) is fulfilled but the baseline value is greater than 500 msec, this case will be 
categorized as ‘no new onset’. If baseline is missing and the maximum on treatment 
QTc interval is greater than 450 msec (or 500 msec for QT interval, respectively), this is 
classified as a ‘new onset’ in the respective category. If baseline is missing and the maximum 
QTc interval is less than or equal to 450 msec (or 500 msec for QT interval, respectively), 
this will be categorized as ‘no new onset’. If baseline is missing, a QTc/QT interval 
> 500 msec at any time on treatment will be a notable finding.
For placebo subjects, the missing plasma concentration values will be replaced by 0 for the 
exposure-response analyses. For subjects on active drug, missing plasma concentration values 
with ‘BLQ’ in the comment field will be replaced by ½ LLOQ.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before administration of BI 730460 or 
Placebo.
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 end of trial examination 
are given in the CTP Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration (including blank values for PK
Starting from 72 h post administration a deviation from the scheduled time for PK 
 sampling of ±70 min is acceptable.
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests
will be ± 15 min for the first 6 h after trial drug administration and ± 30 min thereafter.
Starting from 72 h post administration a deviation from the scheduled time for vital signs,
ECG and laboratory tests of ±70 min is acceptable.
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.
Unscheduled measurements of laboratory data or vital signs will be assumed to be repeat 
measurements of the most recent scheduled measurement (e.g. for follow-up or confirmation 


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of a particular value). Therefore, unscheduled measurements will be assigned to the planned 
time point of the previous scheduled measurement.
There will be a centralised evaluation of the 12-lead ECG recordings at the time points and 
for the ECG recordings specified in the Table 6.7: 1 below:
Table 6.7: 1
Time schedule of 12-lead ECG recordings (SRD part)
Visit
Day
Planned time [hh:mm]
(relative to drug 
administration)
Study phase
Central evaluation
1
-21 to -1
Screening
NA
2
1
-1:30
Predose
first of three replicate ECG
-1:15
Predose
first of three replicate ECG
-1:00
Predose
first of three replicate ECG
0:30
On treatment
first of three replicate ECG
1:00
first of three replicate ECG
2:00
first of three replicate ECG
3:00
first of three replicate ECG
4:00
first of three replicate ECG
6:00
first of three replicate ECG
8:00
first of three replicate ECG
10:00
first of three replicate ECG
12:00
first of three replicate ECG
2
24:00
first of three replicate ECG
34:00
first of three replicate ECG
3
48:00
first of three replicate ECG
3
9 to 13
End of trial
examination
NA
At Visits 1 and 3, single ECGs will be recorded.
At Visit 2, triple ECGs will be recorded (three single ECGs within 180 sec).
Prior to study drug administration, 3 triplicate ECGs (9 single ECGs) will be recorded. The 
vendor will analyse the first single ECG per triplicate for all on treatment timepoints. 
The baseline value of an ECG variable is defined as the mean of the first triplicate ECG 
measurement at -01:30 prior to drug administration.
Section 5.2.4.1 of the CTP: For the SRD part, central ECG lab evaluation will be performed 
post-study for the first of three replicate ECGs per time point on Days 1, 2 and 3. For 
baseline, where 3 triplicate ECGs are recorded, only the first triplicate ECG (i.e. 3 single 
ECGs) will be evaluated. This will include the determination of cardiac QRS-axis as assessed 
by the ECG machine’s algorithm as well as the intervals RR, PR, QRS and QT measured


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semi-automatically. The remaining second and third replicate ECG will be stored for
additional analysis if required, e.g. by authorities at a later time point.
For the exposure response analyses, pairs of ECG variables and corresponding plasma 
concentrations will be built using the same planned time points, e.g. HR change from 
baseline and the plasma concentration measured at planned time 1:00 will build one pair. 
Whether a time deviation between PK blood sampling time and corresponding ECG 
recording is too big and the pair has to be excluded from the analysis will be decided no later 
than at the RPM. This critical time deviation depends on the PK properties. When plasma 
concentrations are expected to change only little around a given time point, the acceptable 
time deviation between ECG recording and PK blood sampling may be bigger.


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7.
PLANNED ANALYSIS
The placebo group will consist of all placebo treated subjects, regardless of the dose group in 
which they were treated.
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 7.5.2) will also be performed 
by 
 and will be presented in Section 15.5 of the CTR and in 
Appendix 16.1.13.3.
Descriptive data analysis of PK parameters and concentrations will be performed by 
department Translational Medicine and Clin. Pharmacology (TMCP) and will be presented in 
Section 15.6 of the CTR.
Descriptive and inferential statistical analyses of PD endpoints (refer to Sections 7.6) will be 
performed by 
 and will be presented in Section 15.7 of the CTR 
and in Appendix 16.1.13.6. 
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.
The individual values of all subjects will be listed, sorted by treatment group, subject number, 
and visit. 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation


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For PK parameters, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment 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
The ADS ADPP (PK parameters) contains column variables APEXC and APEXCO 
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for
exclusion, that is APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’, the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’, the value can be used for further analyses based on actual times. If ACEXCO 
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.


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Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (7).
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 group 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 latest version of the coding system of the 
Medical Dictionary for Drug Regulatory Activities (MedDRA). Medications will be coded 
using the latest version of the World Health Organization Drug Dictionary (WHO-DD). The 
coding version number will be displayed as a footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
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 and/or urinary excretion 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 and described in the CTR.
7.4
PRIMARY ENDPOINT
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 730460.


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been specified in the 
protocol.
7.5.2
Secondary endpoints
Assessment of dose proportionality – SRD part
Dose proportionality of the secondary PK endpoints AUC0-∞and Cmax in plasma of 
BI 730460 will be explored using the power model that describes the functional relationship 
between dose and PK endpoints based on the PKS. The basic model consists of a regression 
model applied to log-transformed data (log-transformation refers to using the natural 
logarithm). The corresponding ANCOVA (Analysis of Covariance) model includes the 
logarithm of the dose as a covariate.
The model is described by the following equation:
Yij = α + β*Xi + εij
where
Yij
logarithm of the PK endpoint for subject j at dose level i; 
where i = 1, 2, …, 6, j = 1, 2, …, 6,
α
intercept parameter;
β 
slope parameter;
Xi
logarithm of dose i;
εij
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
Section 7.1.3 of the CTP: This equation can be fit as a linear regression model. Based on 
the estimate for slope parameter (β), a 2-sided 90% CI for the slope will be computed.
Perfect dose proportionality would correspond to a slope of 1. The assumption of a linear 
relationship between the log-transformed pharmacokinetic endpoint and the log-transformed 
dose will be checked.
According to the Reference Document 3 of the Boehringer Ingelheim (BI) Statistical Position 
Paper on Statistical Methods for PK (14), the 90% confidence intervals (CI) should be 
considered for the assessment of dose proportionality. Therefore, the 90% CI will be used 
instead of the 95% CI.
This analysis will be accomplished by using the XPKISTAT macro (design DB), based on 
the PKS.


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If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed.
Graphical displays:
To support the analyses of dose proportionality, a regression plot will be performed, where 
the logarithm of dose is depicted versus logarithm of PK endpoint, including the estimated 
regression line from the power model and reference line of perfect proportionality (β=1).
 


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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.
If not stated otherwise, the safety results will be sorted by treatment group.
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] (9).
The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs). 


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For analysis, multiple AE occurrence data on the electronic case report form (eCRF) will be 
collapsed into an 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 (AESI))

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] (9).
Section 5.2.2.1 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 aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, and/or
o
Aminotransferase (ALT and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the 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.
The analysis of adverse events will be based on the concept of treatment emergent AEs. 
Section 5.2.2.2 of the CTP: The REP for BI 730460, the time interval when measurable drug 
levels or PD effects are still likely to be present after last administration, is not known for this 
first-in-human trial at this early stage of development. Therefore, all AEs reported until the 
end of trial examination (last per protocol contact) will be considered on treatment […].
For more details see the TSAP ADS plan.
According to ICH E3 (10), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = 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 RPM at the latest.
An overall summary of AEs (including AESIs) will be presented.


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The frequency of subjects with AEs will be summarized by treatment, primary system organ 
class (SOC) and preferred term (PT), as well as by treatment, worst intensity, primary SOC 
and PT. Separate tables will be provided for subjects with other significant AEs according to 
ICH E3 (10), 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.
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
The analyses of laboratory data will be descriptive in nature and will be based on 
BI standards [001-MCG-157] (11).
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 significant 
abnormal or not (at the RPM/DBLM at the latest).
Descriptive statistics of laboratory data will be calculated by planned time point based on the 
worst value of the subject at that planned time point (or assigned to that planned time point).
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (BP, PR).
Descriptive statistics will be calculated by planned time point based on the last value of the 
subject at that planned time point (or assigned to that planned time point).


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7.8.4
ECG
Continuous safety ECG monitoring (by investigator)
Clinically relevant abnormal findings will be reported as AEs.
No separate listing or analysis of continuous ECG monitoring will be prepared.
12-lead ECG
Abnormal findings, irrespective of whether they originate from central or local evaluation,
will be reported as baseline conditions (at screening) or as AEs (during the trial) if judged 
clinically relevant by the investigator. 
All evaluations of ECG data will be based on the TS, except the exposure-response analyses, 
which are based on the ECGPCS set.
The following ECG analyses will only be performed:
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR only listings will be provided. Occurrences of notable findings will be flagged.
Comments regarding the ECGs will be listed.
Categorical endpoints
For the categorical endpoints, frequency tables will be provided.
For all subjects with any notable finding in ECG intervals, a separate listing will be created as 
end-of-text display (based on the same display template as in Appendix 16.2), and the 
corresponding time profiles will be shown.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the changes from 
baseline over time of QTcF, HR, QT, PR and QRS. The time profiles of mean and SD for the 
changes from baseline on treatment will be displayed graphically by treatment.
For QTcF and HR changes from baseline, the relationship to the corresponding plasma 
concentrations will be evaluated using a random coefficient model. For subjects in the 
ECGPCS, all time points with available ECG endpoints and valid time-matched drug plasma 
concentrations will be included. For the handling of missing values, see Section 6.6.
The response variable will be the change from baseline in QTcF (QTcF). The placebo 
subjects will be included in the analysis, setting their plasma concentrations to zero.


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As a first step, it is investigated if there is a potential delayed or accelerated (e.g. due to 
metabolites) effect of the drug on QTcF. A general visual impression will be provided by 
overlaying time profiles of plasma concentrations and QTcF changes from baseline (QTcF). 
These figures will be generated for each subject (presented in Statistical Appendix of the 
CTR), as well as for means per active treatment (presented in the End-of-Text part of the 
CTR).
The relationship between BI 730460 plasma concentrations and QTcF changes from baseline 
will be investigated in an exploratory manner using a random coefficient model to estimate 
the difference in means between BI 730460 and placebo of QTcF change from baseline and 
its 90% confidence interval at the geometric mean of Cmax for each dose. Additionally, the 
estimated overall slope with its 90% confidence interval will be provided. The used random 
coefficient model is based on a white paper from Garnett et al. (12) with QTcF as response 
variable, centered baseline QTc and plasma concentration as continuous covariates, treatment 
and time as fixed categorical effects, and a random intercept and slope for each subject. For 
more details refer to Section 9.3.
For visualization, a scatterplot of the BI 730460 plasma concentration against the following 
individual QTcF values will be provided: For each subject on active treatment and each time 
point, subtract the mean value of all individual observed ΔQTcF values from the placebo 
group for this time point from the individual observed ΔQTcF value for this subject and time 
point. This results in estimates for “individual ΔΔQTcF” values, which should only be used 
for plotting purposes. The corresponding regression line and its pointwise confidence bands 
as well as and the geometric mean of Cmax for each dose will additionally be displayed in the 
plot.
To check model assumptions, the conditional residuals will be plotted and presented in the 
Statistical Appendix of the CTR. In case of non-linearity or if there is evidence for a delayed 
effect, further models will be explored in order to better characterise the PK-ECG 
relationship (e.g. effect compartment models, non-linear models, etc.).
All of the above described graphical and statistical analyses will be also performed for HR in 
place of QTcF.
Appropriateness of heart rate correction methods of QT interval
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of QTcF interval versus RR interval (values log-transformed using the natural 
logarithm) will be estimated by applying the random coefficient model described in 
Section 9.1 using all time points. A scatterplot of QTcF vs RR including the overall
regression line will be included in the Statistical Appendix of the CTR. The resulting (fixed 
effect) slope together with two-sided 95% confidence intervals will be included in the 
footnote for this plot.


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7.8.5
Others
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. 
No separate listing or analysis of physical examination findings will be prepared.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, BIRDS
3.
BI-KMED-COPS-TMP-0001: "iPD log", current version; KMED
4.
001-MCG-156_RD-01: "Handling of Missing and Incomplete AE Dates", current 
version; IDEA for CON.
5.
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic
Analyses of Clinical Studies”, current version; IDEA for CON.
6.
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current version; 
IDEA for CON.
7.
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.
8.
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
9.
001-MCG-156: “Analysis and Presentation of Adverse Event Data from Clinical Trials”, 
current version; IDEA for CON.
10. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version
11. 001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.
12. Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. J Pharmacokin Pharmacodyn (2017) [R18-0143].
13. Ring A. Statistical models for heart rate correction of the QT interval. Stat Med (2010)
[R10-2920].
14. BI Statistical Position Paper - Statistical Methods for PK - Reference Document 3: 
Regulatory recommendations for BA/BE trials and implementation instructions in 
clinical trial documents, version 1.0 (2017).


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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
06-MAY-2019
None
This is the final TSAP without any 
modification


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c27412368
1.0
8-01-tsap-core
A partially randomised, single-blind, placebo-controlled trial to investigate safety,
tolerability, pharmacokinetics and pharmacodynamics of single rising doses of BI
730460 administered as tablets to healthy subjects, and a randomised, open-label,
single-dose, two-way cross-over bioavailability comparison of BI 730460 as tablet
with and without food
Author-Trial Statistician
09 May 2019 07:32 CEST
Approval-Medical Writer
09 May 2019 09:28 CEST
Author-Clinical Trial Leader
09 May 2019 09:59 CEST
Approval-Clinical Pharmacokinetics
09 May 2019 14:33 CEST
Approval-Project Statistician
09 May 2019 14:37 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c27412368
1.0