Clinical trial NCT03123185
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2017-04-27; Completion date: 2018-02-19
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Investigation of safety, tolerability, pharmacokinetics and pharmacodynamics of single rising doses of BI 705564 and of the food effect on BI 705564 in healthy male subjects

Detailed description:
The primary objective of the single rising dose part under fasting and under fed conditions is to investigate safety and tolerability of BI 705564 in healthy male subjects following oral administration of single rising doses.

Secondary objectives are the exploration of pharmacokinetics (PK) including dose proportionality, and pharmacodynamics (PD) of BI 705564 after single rising doses.

The objective of the food effect part is to explore the relative bioavailability of BI 705564 tablets under fed and fasted conditions following the oral administration of single doses.

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None arm 9: None arm 10: None arm 11: None arm 12: None arm 13: None arm 14: None
Interventions: intervention 1: Placebo intervention 2: BI 705564 (Test) intervention 3: BI 705564 (Reference)
Intervention descriptions: intervention 1: Tablet and solution formulation intervention 2: Fed state intervention 3: Fasting state

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c13141675-05
EudraCT No.:
BI Trial No.:
2017-000324-98
1408-0001
BI Investigational
Product(s):
BI 705564
Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of 
single rising oral doses of BI 705564 (single-blind, partially 
randomised, placebo-controlled parallel group design) and food effect 
on a tablet formulation of BI 705564 (open-label, randomised, single-
dose, two-period, two-sequence crossover design) in healthy male 
subjects
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax:
Principal Investigator:
Phone: 
Fax:
Status:
Final Protocol (Revised Protocol (based on global amendment 4))
Version and Date:
Version: 5.0
Date: 11 SEPTEMBER 2017
Page 1 of 118
Proprietary confidential information
© 2017 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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BI Trial No.: 1408-0001
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Trial Protocol
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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 705564
Protocol date:
Trial number:
Revision date:
11 SEP 2017
15 FEB 2017
1408-0001
Title of trial:
Safety, tolerability, pharmacokinetics and pharmacodynamics of single rising oral 
doses of BI 705564 (single-blind, partially randomised, placebo-controlled parallel 
group design) and food effect on a tablet formulation of BI 705564 (open-label, 
randomised, single-dose, two-period, two-sequence crossover design) in healthy male 
subjects
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
(1) Single rising dose part under fasting conditions: To investigate safety, 
tolerability, pharmacokinetics and pharmacodynamics following single rising 
oral doses of BI 705564
(2) Food effect part: To investigate the relative bioavailability of BI 705564 as tablet
formulation under fed and fasting conditions following oral administration
(3) Single rising dose part under fed conditions: To investigate safety, tolerability,
pharmacokinetics and pharmacodynamics following single rising oral doses of 
BI 705564 under fed conditions
Methodology:
(1) Single rising dose part under fasting conditions: Single-blind, partially 
randomised within dose groups, placebo-controlled, parallel group design
(2) Food effect part: Open-label, randomised, single-dose, two-period, two-sequence 
crossover design
(3) Single rising dose part under fed conditions: Single-blind, partially randomised 
within dose groups, placebo-controlled, parallel group design under fed 
conditions


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 705564
Protocol date:
Trial number:
Revision date:
11 SEP 2017
15 FEB 2017
1408-0001
No. of subjects
planned: 
total entered:
92*
each treatment:
(1) Single rising dose part under fasting conditions: 48
8 per dose group (6 on active drug and 2 on placebo)
(2) Food effect part: 12 (all on active drug)
(3) Single rising dose part under fed conditions: 32*
8 per dose group (6 on active drug and 2 on placebo)
* 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 total number of subjects entered in 
the study may exceed 92 (32 in single rising dose part under fed conditions), but will not exceed 
108 (48 in single rising dose part under fed conditions) subjects entered.
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 50 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
(1) Single rising dose
part under fasting
conditions
Test products:
BI 705564 as solution (powder for oral solution [PfOS], 0.25 mg/mL) and film-coated
tablet (10 mg)
dose:
Solution (PfOS): 1 mg, 3 mg q.d.
Tablet: 10 mg, 20 mg, 40 mg, 80 mg q.d.
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h
Comparator products: Matching placebo as solution (i.e. solvent) and film-coated tablet formulation
dose:
Not applicable
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h
(2) Food effect part
Test product:
Fed: BI 705564 as film-coated tablet formulation (10 mg tablets)
dose:
Tablet: 10 mg q.d.
mode of admin.:
Oral with 240 mL of water after a high-fat, high-calorie meal 


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 705564
Protocol date:
Trial number:
Revision date:
11 SEP 2017
15 FEB 2017
1408-0001
 
 
Comparator products:
Matching placebo as film-coated tablet formulation
dose:
Not applicable
mode of admin.: Oral with 240 mL of water after a high-fat, high-calorie breakfast
Duration of treatment:
(1) Single rising dose part under fasting conditions: One single dose
(2) Food effect part: Single dose for each treatment (2 single doses in total), 
separated by a washout period of at least 10 days
(3) Single rising dose part under fed conditions: One single dose
Criteria for 
pharmacokinetics:
(1) Single rising dose part under fasting conditions
Secondary endpoints: AUC0-∞and Cmax
Further PK parameters of interest will be calculated as appropriate
(2) Food effect part
Primary endpoints: AUC0-tz and Cmax
Secondary endpoint: AUC0-∞
Further PK parameters of interest will be calculated as appropriate
(3) Single rising dose part under fed conditions
Secondary endpoints: AUC0-∞and Cmax
Further PK parameters of interest will be calculated as appropriate
 


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 705564
Protocol date:
Trial number:
Revision date:
11 SEP 2017
15 FEB 2017
1408-0001
Criteria for safety:
(1) Single rising dose part under fasting conditions
Primary endpoint to assess safety and tolerability of BI 705564 is the number 
[N (%)] of subjects with drug-related adverse events.
Further criteria of interest: Adverse events (AEs) including clinically relevant 
findings from the physical examination, safety laboratory tests, 12-lead 
electrocardiogram (ECG), continuous ECG monitoring, vital signs (blood 
pressure [BP], pulse rate [PR]).
(2) Food effect part
Further criteria of interest: AEs including clinically relevant findings from the 
physical examination, safety laboratory tests, 12-lead electrocardiogram (ECG), 
vital signs (blood pressure [BP], pulse rate [PR]).
(3) Single rising dose part under fed conditions
Primary endpoint to assess safety and tolerability of BI 705564 is the number 
[N (%)] of subjects with drug-related adverse events.
Further criteria of interest: Adverse events (AEs) including clinically relevant 
findings from the physical examination, safety laboratory tests, 12-lead 
electrocardiogram (ECG), continuous ECG monitoring, vital signs (blood 
pressure [BP], pulse rate [PR]).
Statistical methods:
(1) Single rising dose part under fasting conditions
Descriptive statistics will be calculated for all endpoints.
Dose proportionality of BI 705564 will be explored using a regression model. A 
95% confidence interval (CI) for the slope will be computed.
(2) Food effect part
Relative bioavailability will be estimated by the ratios (tablet fed/tablet fasting) 
of the geometric means for the primary and secondary endpoints. Additionally, 
their two-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-tests procedure, each at the 5% significance 
level. Since the main focus is on estimation and not testing, an acceptance range 
was not specified. The statistical model will be an ANOVA on the logarithmic 
scale including effects for ‘sequence’, ‘subjects nested within sequences’, 
‘period’ and ‘treatment’. CIs will be calculated based on the residual error from 
ANOVA. Descriptive statistics will be calculated for all endpoints.
(3) Single rising dose part under fed conditions
Descriptive statistics will be calculated for all endpoints.
Dose proportionality of BI 705564 will be explored using a regression model. A 
95% confidence interval (CI) for the slope will be computed.


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FLOW CHART
(1) Single rising dose part under fasting conditions
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
PK urine
10, 12
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
x
x
2
-3 to -1
-72:007
08:00
Ambulatory visit
x
x
1
-2:00
06:00
Admission to trial site2, 
allocation to treatment2
x5,2
x2
x2
x2,9
x2
x2
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
x8
│
x9
│
x
2:00
10:00
240 mL fluid intake
x
│
x9
│
x
x
3:00
11:00
x
│
x9
│
x
x
4:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
x
┼
│
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
x
│
11:00
19:00
Dinner
│
12:00
20:00
x
┼
x9
x
x
2
24:00
08:00
Discharge from trial site, 
breakfast3 (voluntary)
x
x
▼
x9
x
x
34:00
18:00
Ambulatory visit
x
x
x
3
48:00
08:00
Ambulatory visit
x
x
x9
x
x
4
72:00
08:00
Ambulatory visit
x
x9
x
x
6
120:00
08:00
Ambulatory visit
x15
8
168:00
08:00
Ambulatory visit
x
x
10
216:00
08:00
Ambulatory visit
x
4
11 to 15
End of trial (EOT) 
examination4
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG (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 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.


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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 safety laboratory, can be omitted, if the screening examination is performed on Days -3, -2 
or -1.
8.
One blood sample for stability testing will be taken at this time point in Dose Group 10 mg (tablet) (see Section 5.5.2.4).
9.
The ECG recording has to be performed as triple.
10. Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK/PD
data) including addition of samples and visits as long as the total blood volume taken does not exceed 500 mL per 
subject.
11. Including blood sample for metabolite identification in dose group 40 mg tablet (see Section 5.5.2.2).
12. A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the stated post-dose intervals (◄––│––│––│––►) 0-4, 4-8, 8-12, and 12-24 h.
13. 2 x 8 mL blood at pre-dose (2nd vial as back-up).
 
15. May be done up to 26 h earlier. AE questioning to be done at this occasion.


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(2) Food effect 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
x7
x
2/
3*
-3 to -1
-72:009
08:00
Ambulatory visit
x
x
1
-2:00
06:00
Admission to trial site2, allocation to 
treatment2 (Visit 2 only)
x2,5
x2
x2,7
x2
x2
-0:30
07:30
High fat, high calorie breakfast (only in 
treatment ’fed’)
0:00
08:00
Drug administration
0:30
08:30
x
1:00
09:00
x
x7
x
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
x7
x
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x7
x
x
6:00
14:00
x
x
8:00
16:00
Snack (voluntary)3
x
x7
x
x
10:00
18:00
x
11:00
19:00
Dinner
12:00
20:00
x
x 
2
24:00
08:00
Discharge from trial site, breakfast3
(voluntary)
x
x
x7
x
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x
4
72:00
08:00
Ambulatory visit
x
x
4
11 to 15
End of trial (EOT) examination4
x
x7
x
x
* Two identical visits, separated by a wash-out interval of at least 10 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
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.
7.
The ECG will be recorded as single ECG. However, the number of ECGs per time point may be increased to three 
ECGs based on the preliminary ECG results obtained during the single rising dose part.
8.
Sampling times 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.
Safety laboratory to be taken and medically evaluated within 3 days prior to administration of study drug. This 
ambulatory visit, including safety laboratory, can be omitted in visit 2, if the screening examination is performed on 
Days -3, -2 or -1.


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(3) Single rising dose part under fed conditions
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 
9
PK urine
9, 10
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
x
x
2
-3 to -1
-72:007
08:00
Ambulatory visit
x
x
1
-2:00
06:00
Admission to trial site2, 
allocation to treatment2
x5,2
x2
x2
x2,8
x2
x2
x2
-0:30
07:30
High fat, high calorie 
breakfast
0:00
08:00
Drug administration
▲
▲
0:30
08:30
x
│
x8
│
x
x
1:00
09:00
x
│
x8
│
x
x
1:30
09:30
x
│
x8
│
x
2:00
10:00
240 mL fluid intake
x
│
x8
│
x
x
3:00
11:00
x
│
x8
│
x
x
4:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
x
┼
│
x8
▼
x
x
6:00
14:00
x
│
x8
x
x
8:00
16:00
Snack (voluntary)3
x
┼
x8
x
x
10:00
18:00
x
│
11:00
19:00
Dinner
│
12:00
20:00
x
┼
x8
x
x
2
24:00
08:00
Discharge from trial site, 
breakfast3 (voluntary)
x
x
▼
x8
x
x
34:00
18:00
Ambulatory visit
x
x
x
3
48:00
08:00
Ambulatory visit
x
x
x8
x
x
4
72:00
08:00
Ambulatory visit
x
x8
x
x
6
120:00
08:00
Ambulatory visit
x13
8
168:00
08:00
Ambulatory visit
x
x
10
216:00
08:00
Ambulatory visit
x
4
11 to 15
End of trial (EOT) 
examination4
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG (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 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.


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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 safety laboratory, can be omitted, if the screening examination is performed on Days -3, -2 
or -1.
8.
The ECG recording has to be performed as triple.
9.
Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK/PD
data) including addition of samples and visits as long as the total blood volume taken does not exceed 500 mL per 
subject.
10. A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the stated post-dose intervals (◄––│––│––│––►) 0-4, 4-8, 8-12, and 12-24 h.
11. 2 x 8 mL blood at pre-dose (2nd vial as back-up).
 
13. May be done up to 26 h earlier. AE questioning to be done at this occasion.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................6
TABLE OF CONTENTS ................................................................................ 11
ABBREVIATIONS.......................................................................................... 16
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 29
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................29
2.1.1
Starting Dose .........................................................................................29
2.1.2
Maximum Dose and Dose Range.........................................................30
2.1.3
Dose Escalation......................................................................................31
2.1.4
Food effect part .....................................................................................32
2.1.5
Conclusion .............................................................................................32
2.2
TRIAL OBJECTIVES.......................................................................................32
2.3
BENEFIT - RISK ASSESSMENT ...................................................................33
2.3.1
Procedure-related risks ........................................................................33
2.3.2
Drug-related risks and safety measures..............................................33
2.3.2.1
Mode of action.........................................................................33
2.3.2.2
Nature of the target ..................................................................34
2.3.2.3
Relevance of animal species and models.................................34


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2.3.2.4
Findings in non-clinical safety studies.....................................35
2.3.2.5
Risks resulting from trial medication auxiliaries.....................35
2.3.2.6
Drug induced liver injury.........................................................36
2.3.2.7
Risk minimization (safety precautions and stopping rules).....36
2.4
OVERALL ASSESSMENT AND CONCLUSION.........................................37
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 39
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................39
3.1.1
Administrative structure of the trial...................................................43
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................44
3.3
SELECTION OF TRIAL POPULATION ......................................................45
3.3.1
Main diagnosis for study entry............................................................45
3.3.2
Inclusion criteria...................................................................................45
3.3.3
Exclusion criteria ..................................................................................46
3.3.4
Removal of subjects from therapy or assessments.............................47
3.3.4.1
Removal of individual subjects................................................47
3.3.4.2
Discontinuation of the trial by the sponsor..............................48
3.3.5
Replacement of subjects .......................................................................48
4.
TREATMENTS........................................................................................ 49
4.1
TREATMENTS TO BE ADMINISTERED....................................................49
4.1.1
Identity of BI investigational product and comparator product......49
4.1.2
Method of assigning subjects to treatment groups ............................52
4.1.3
Selection of doses in the trial................................................................53
4.1.4
Drug assignment and administration of doses for each subject .......53
4.1.5
Blinding and procedures for unblinding ............................................57
4.1.5.1
Blinding....................................................................................57
4.1.5.2
Procedures for emergency unblinding .....................................58
4.1.6
Packaging, labelling, and re-supply ....................................................58
4.1.7
Storage conditions.................................................................................58
4.1.8
Drug accountability ..............................................................................59
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................59
4.2.1
Other treatments and emergency procedures....................................59
4.2.2
Restrictions............................................................................................59
4.2.2.1
Restrictions regarding concomitant treatment .........................59
4.2.2.2
Restrictions on diet and life style.............................................60
4.3
TREATMENT COMPLIANCE.......................................................................60
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 61
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................61
5.1.1
Endpoints of efficacy.............................................................................61
5.1.2
Assessment of efficacy...........................................................................61


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5.2
SAFETY..............................................................................................................61
5.2.1
Endpoints of safety................................................................................61
5.2.2
Assessment of adverse events...............................................................62
5.2.2.1
Definitions of adverse events...................................................62
5.2.2.2
Adverse event collection and reporting ...................................65
5.2.3
Assessment of safety laboratory parameters......................................67
5.2.4
Electrocardiogram................................................................................69
5.2.4.1
12-lead resting ECG.................................................................69
5.2.4.2
Continuous ECG monitoring ...................................................71
5.2.5
Assessment of other safety parameters...............................................71
5.2.5.1
Vital signs ................................................................................71
5.2.5.2
Medical examinations..............................................................71
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................72
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................72
5.5.1
Pharmacokinetic endpoints..................................................................72
5.5.1.1
Primary endpoints....................................................................72
5.5.1.2
Secondary endpoints................................................................73
5.5.2
Methods of sample collection...............................................................74
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................74
5.5.2.3
Urine sampling for pharmacokinetic analysis (single rising dose 
parts under fasting and fed conditions)....................................76
6.
INVESTIGATIONAL PLAN.................................................................. 80
6.1
VISIT SCHEDULE............................................................................................80
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................80
6.2.1
Screening period....................................................................................80


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6.2.2
Treatment periods.................................................................................81
6.2.3
End of trial period.................................................................................81
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 83
7.1
STATISTICAL DESIGN – MODEL ...............................................................83
7.1.1
Objectives...............................................................................................83
7.1.2
Endpoints...............................................................................................83
7.1.3
Model......................................................................................................84
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................84
7.3
PLANNED ANALYSES....................................................................................85
7.3.1
Primary analyses...................................................................................85
7.3.2
Secondary analyses ...............................................................................86
7.3.4
Safety analyses.......................................................................................88
7.3.5
Interim analyses ....................................................................................90
7.3.6
Pharmacokinetic analyses ....................................................................91
7.4
HANDLING OF MISSING DATA ..................................................................92
7.4.1
Safety......................................................................................................92
7.4.2
Plasma/urine drug concentration - time profiles ...............................92
7.4.3
Pharmacokinetic parameters...............................................................92
7.5
RANDOMISATION ..........................................................................................92
7.6
DETERMINATION OF SAMPLE SIZE ........................................................93
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 95
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................95
8.2
DATA QUALITY ASSURANCE .....................................................................95
8.3
RECORDS..........................................................................................................96
8.3.1
Source documents .................................................................................96
8.3.2
Direct access to source data and documents.......................................96
8.3.3
Storage period of records.....................................................................96
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................97
8.5
STATEMENT OF CONFIDENTIALITY.......................................................97
8.6
COMPLETION OF TRIAL..............................................................................97
9.
REFERENCES......................................................................................... 98
9.1
PUBLISHED REFERENCES...........................................................................98
10. APPENDICES ........................................................................................ 104


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10.1
RECONSTITUTION INSTRUCTION(S).....................................................104
10.1.1 Drug Supplies Overview.....................................................................104
10.1.2 Required Equipment and Dosing aids - Overview ..........................104
11. DESCRIPTION OF GLOBAL AMENDMENT(S)............................ 110


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, elimination
AE
Adverse event
AESI
Adverse events of special interest
AMG
Arzneimittelgesetz (German drug law)
ANA
Anti-nuclear antibodies
ANOVA
Analysis of variance
AUC
Area under the concentration-time curve of the analyte in plasma
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
 
 
Β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BA
Bioavailability
BCR
B cell receptor
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
Bpm
Beats per minute
BTK
Bruton’s tyrosine kinase
CA
Competent authority
CD
Cluster of differentiation
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence interval
 
 
 
Cmax
Maximum measured concentration of the analyte in plasma


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CML
Clinical monitor local
CNS
Central nervous system
CRA
Clinical research associate
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CTSU
Clinical Trial Supplies Unit
CV
Arithmetic coefficient of variation
CYC
Cyclophosphamide
CYP
Cytochrome P450
DG
Dose Group
DILI
Drug induced liver injury
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EMA
European Medicines Agency
EOT
End of trial
ESRD
End stage renal disease
F
Absolute bioavailability factor
FcR
Fc receptor
 
GC
Glucocorticoid
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
GLP
Good laboratory practice
gMean
Geometric mean
HED
Human equivalence dose
HP-β-CD
Hydroxypropyl-ß-cyclodextrin
HR
Heart rate
IB
Investigator’s brochure
IC
Informed consent
ICH
International Conference on Harmonisation


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IEC
Independent Ethics Committee
IL
Interleukin
IPV
Important protocol violation
IRB
Institutional Review Board
ISF
Investigator site file
ISN
International Society of Nephrology
KI
Inhibition constant
KO
Knock-out
MedDRA
Medical Dictionary for Regulatory Activities
MIST
Metabolites in safety testing
MMF
Mycophenolate
MRSD
Maximum recommended safe starting dose
 
NOA
Not analysed
NOAEL
No observed adverse effect level
NOEL
No observed effect level
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PAD
Pharmacologically active dose
PD
Pharmacodynamic(s)
PE
Polyethylene
PfOS
Powder for reconstitution of an oral solution
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
q.d.
Quaque die, once daily
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)


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R
Reference treatment
RDC
Remote data capture
REP
Residual effect period
RPS
Renal Pathology Society
SAE
Serious adverse event
SCR
Screening
SOP
Standard Operation Procedure
SRD
Single-rising dose
Ss
(at) steady state
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
Test product or treatment
TDMAP
Trial Data Management and Analysis Plan
TEC
tec protein tyrosine kinase
TLR
toll-like receptors
 
TMF
Trial master file
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
 
 
 
WOCBP
Women of childbearing potential
XLA
X-linked agammaglobulinemia


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
 
 
Healthy male subjects will be recruited for this study. They provide a relatively stable 
physiological, biochemical and hormonal basis for studying drug effects, they show no 
disease-related variation and they are not taking regular concomitant medications.
In the single rising dose parts, within each dose group, all actively treated individuals will 
receive the same BI 705564 dose. The next higher dose will only be administered to the next 
group, if the treatment in the preceding dose group was safe and showed acceptable 
tolerability.
In the food effect part, BI 705564 will be administered to subjects in a randomized two-way-
crossover fashion to understand the effect of food on relative bioavailability and to support 
upcoming clinical studies in respect to better trial designs.
2.1.1
Starting Dose
An estimation was made on the basis of the US FDA Guidance for Industry ‘Estimating the
Maximum Recommended Safe Starting Dose in Initial Clinical Trials for Therapeutics in
Healthy Volunteers’ [R06-1037]:
 
 
 
It is stated in the FDA Guidance that ‘a species might be considered an inappropriate toxicity
model for a given drug, if the dose-limiting toxicity in that species was concluded to be of
limited value for human risk assessment, based on historical comparisons of toxicities in the
animal species to those in humans across a therapeutic class (i.e., the dose-limiting toxicity is
species-specific). In this case, data from that species should not be used to derive the HED.’


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2.1.2
Maximum Dose and Dose Range
 
 
 
 
 
 
Therefore: (1) Systemic exposure of BI 705564 (Cmax, AUC0-24) will be closely monitored 
throughout the study and used to guide dose escalation. (2) A maximum allowable exposure 
is prospectively defined.


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In conclusion, the maximum dose in this first-in-man/ single rising dose study will be limited 
by an exposure threshold (group gMean values) of
 
 whichever is reached first. With the exception of escalation from Dose Group 1 to 
Dose Group 2, the decision for dose escalation at each dose level will be guided by the results 
of PK interim analysis at each dose level and, if necessary, model based estimations. For dose 
escalation from Dose Group 1 to Dose Group 2, availability of interim pharmacokinetic data 
is not required.
2.1.3
Dose Escalation
Dose escalation in the SRD part under fasting conditions
 
 
 
 
 
 
 
 
 
 
 


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2.1.4
Food effect part
Since a 
 of BI 705564 at higher doses might be improved by the application of 
food, the effect of food on the relative bioavailability of BI 705564, as tablet formulation will 
be investigated. The food effect may be dose dependent. 
 
 
 
 
 
2.1.5
Conclusion
The safe starting dose in this study is determined 
 This dose is not expected to 
trigger any relevant or unacceptable biological activities.
 
In the single rising dose part under fasting conditions, the following dose escalation scheme 
is planned: 
 
 
Each dose escalation step in the single rising dose part under fasting conditions will be 
guided by interim PK measurements and projected exposure levels.
 
With global amendment No 4, a single rising dose part under fed conditions is added.
 
 
Each dose escalation step in the single rising dose part 
under fed conditions will be guided by interim PK measurements and projected exposure 
levels.
2.2
TRIAL OBJECTIVES
The primary objective of the single rising dose parts under fasting and under fed conditions is 
to investigate safety and tolerability of BI 705564 in healthy male subjects following oral 
administration of single rising doses. Secondary objectives are the exploration of 


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pharmacokinetics (PK) including dose proportionality, and pharmacodynamics (PD) of 
BI 705564 after single rising doses.
The objective of the food effect part is to explore the relative bioavailability of BI 705564 
tablets under fed and fasting conditions following the oral administration of single doses.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data, 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 this 
compound which is expected to be superior over other BTK inhibitors being developed in 
non-oncological indications due to its higher selectivity. Subjects participating in this trial are 
exposed to the risks of study procedures and those, related to the exposure of trial medication.
2.3.1
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases, a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. 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, i.e. 500 mL. No health-related risk to healthy subjects is 
expected from this blood withdrawal.
2.3.2
Drug-related risks and safety measures
Factors of risk may derive from particular knowledge or the lack thereof, regarding (1) the 
mode of action, (2) the nature of the target, (3) the relevance of animal models and/or (4) 
findings in non-clinical safety studies.
2.3.2.1
Mode of action
BTK is a well characterized target with known functions in the immune signalling pathways 
of B cells and myeloid cell lineages (see Section 1.1). First clinical experience with the 
approved BTK inhibitor ibrutinib is available (see Sections 1.1 and 1.2.5). In addition, a
‘human model’ with loss of function mutations of the BTK gene is known as syndrome XLA.
The immunodeficiency of XLA patients seems to be limited to the decreased levels of 
circulating antibodies. The resulting (predominant) bacterial infections should be well 
controlled by the application of antibiotics and gammaglobulin substitution, if necessary
[R17-0404].
Ibrutinib treatment in patients with hematologic malignancies is associated with adverse
events including hypertension, thrombocytopenia, and GI complaints (abdominal pain, 


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nausea, diarrhea, and vomiting). As these are not usual features of XLA, they may be related 
to off-target inhibition by ibrutinib of other enzymes besides BTK. Atrial fibrillation has been 
reported in patients receiving ibrutinib. The causal relationship of this finding to ibrutinib is 
not clear. The majority of affected patients had pre-existing cardiovascular disease, and most 
cases resolved quickly [R17-0124]. Other investigational BTK inhibitors (GDC-0853 and
CC-292) were generally well tolerated in Phase 1 and Phase 2 clinical trials in healthy 
volunteers and in patients with rheumatoid arthritis. Serious infections, hypertension, 
thrombocytopenia, and atrial fibrillation were not reported [R17-0165, R17-0166]. All these 
conditions can be well monitored and are accessible to established therapies.
BI 705564 
 (see Section 1.2.1).
 
 
will be the minimum time between treatments in the food effect part (wash-out period) and 
from last administration of study drug until the end of trial examination in all study parts.
2.3.2.2
Nature of the target
The BTK protein is intra-cellular expressed in myeloid and lymphoid cell lines, 
predominantly in the immune system (bone marrow, appendix, lymph nodes, tonsils, and 
spleen), as well as in the lung. [R17-0406] Although on-target effects are unlikely to occur 
after a single dose of BI 705564, they might resemble those seen in XLA patients: Inhibition 
of B-cell differentiation which may manifest as a transient decrease of peripheral B-cell 
numbers, transient decrease of immunglobuline levels and unlikely bacterial infections. Main 
safety measures performed throughout the study will be therefore: (1) Exclusion of subjects 
with a repeated decrease of CD19+ B cell count at screening. (2) Monitoring of white blood 
cell counts and particularly CD19+ B cell counts, as well as immunoglobulin levels for at 
least 10 days after drug administration. (3) Close monitoring for adverse events including 
symptoms of infections. (4) In case of infections, appropriate clinical evaluation and, if 
necessary, adequate treatment thereof.
‘Down-stream’ effects of BTK inhibition are well characterized (see Section 1.2.1). How 
these effects may vary in different populations, e.g. healthy subjects versus diseased patients, 
young versus elderly, different patient populations, etc., is not known. Also, no information 
on BTK polymorphisms in healthy individuals and their potential influence on 
pharmacodynamics effects of BI 705564 or other BTK inhibitors are available.
2.3.2.3
Relevance of animal species and models
Animal models and assays, used during the pharmacological (mice) and toxicological (rats, 
dogs) assessment of BI 705564 were similar, at large, to those used for the development and 
submission of ibrutinib. As such, their relevance for humans was acknowledged by regulatory 
authorities [R17-0403]. For further information, see current version of IB [c12104992-02].


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2.3.2.4
Findings in non-clinical safety studies
Documents supporting the submission of this first-in-man trial with BI 705564 were 
compiled according to Good Clinical Practice (GCP) principles. All pivotal, non-clinical 
safety studies in support of this clinical trial were conducted in compliance with Good 
Laboratory Practice (GLP). For further information, see current version of IB [c12104992-
02].
 
 
 
∀
Toxicology
In the 4-week rat toxicity study (see Section 1.2.3.2), 
 
laboratory 
monitoring will include this parameter during the conduct of the study (see Flow 
Charts and Section 5.2.3).
In the same study, dose independent, 
 
 
 
 
(see Flow Charts and Section 5.2.3).
In the 4-week dog toxicity study (see Section 1.2.3.2), 
 
 
 
 
2.3.2.5
Risks resulting from trial medication auxiliaries
Hydroxypropyl-ß(HP-ß)-cyclodextrin is a standard excipient in pharmaceutical preparations 
and is used also in marketed products. The toxicological profile of HP-ß-cyclodextrin has 
been thoroughly investigated [R01-0682]. Orally administered cyclodextrin is practically 
non-toxic due to lack of absorption from the GI tract. Chronic administration of 16-24 g HP-


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ß-cyclodextrin to healthy volunteers for 14 days led to an increased incidence of soft stool 
and diarrhoea.
In the current trial, HP-ß-cyclodextrin is the main ingredient of the solvent for oral solution. 
 
2.3.2.6
Drug induced liver injury
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.
2.3.2.7
Risk minimization (safety precautions and stopping rules)
The following precautionary measures will be taken in this study in order to minimize the 
risk for healthy volunteers:
∀
Careful starting dose selection, as described in Section 2.1.1.
∀
In the single rising dose part under fasting conditions, decreasing escalation factors
with increasing doses, as described in Section 2.1.3 were chosen. In the single rising 
dose part under fed conditions, escalation factors of 2 were chosen, based on 
experience gained during the trial.
∀
In the single rising dose parts, for safety reasons, 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). The first cohort of each dose group will be dosed in a fixed sequence 
manner (active - placebo - active - active) and each drug administration will be 
separated by at least 60 minutes between the first 3 subjects. This design ensures that 
between first and second active dose of each dose level there is a time interval of at 
least 2 hours. For orally administered drugs, this is usually a sufficient time frame to 
observe acute effects and to obtain a significant proportion of the systemic exposure. 
If BI 705564 is safe and shows acceptable tolerability during these initial 
administrations, the remaining subjects of this dose group can be dosed as close as 
10 minutes apart.
∀
For each dose group, the 2 cohorts will be separated by at least 46 hours (between the 
1st subject of each cohort) which is expected to cover the period of highest risk/ peak 
effect.
∀
Interim measurements of BI 705564 plasma levels will be performed. The expected 
gMean systemic exposure (Cmax, AUC) in the next higher dose group will be 
estimated based on current and preceding doses using a dose proportionality approach 


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or model-based estimations, as applicable. The next higher dose level will only be 
administered, if estimated group gMean values of Cmax and AUC do not exceed the 
maximum acceptable human exposure
whichever is reached first. This should provide a safety margin to the NOAEL of >20 
(see Table 1.2.3.2: 1). In the single rising dose part under fasting conditions, for dose 
escalation from Dose Group 1 to Dose Group 2, availability of interim PK data is not 
required.
∀
If one dose level is safe and shows acceptable tolerability, and if no stopping criterion 
is met (see Section 3.3.4.2), the next higher dose may be given, keeping a minimum
dosing time interval of 10 days between the first subject of the current dose group and 
the first subject of the following dose group.
∀
Extensive standard safety laboratory measurements including serum electrolytes, 
serum amylase and lipase, differential white blood counts, as well as CD19+ B cell 
and platelet counts will be performed before and after study drug administration (see
Flow Charts and Section 5.2.3).
∀
A thorough ECG and heart rate monitoring will be performed, including continuous 
ECG measurements over 4 hours post dose to cover the anticipated period of highest 
drug exposure, and additional repeated single 12-lead ECGs.
∀
Prior to each dose escalation, a documented safety review will be performed by the
Principal Investigator (or an authorized deputy) and the Trial Clinical Monitor (or an
authorized deputy). For details, see Section 3.1.
∀
In the food effect part, the 10 mg dose will be tested first and thereafter the 40 mg 
dose will be tested*. The 10 mg dose will only be given, if, in the single rising dose 
part, doses of up to 40 mg are safe and of acceptable tolerability. The 40 mg dose will 
only be given, if, in the single rising dose part, doses of up to 160 mg are safe and of 
acceptable tolerability and, if, based on available preliminary PK data, the systemic 
exposure (group gMean Cmax, AUC0-24) is not expected to exceed the maximal group 
gMean values reached in the single rising dose part*.
* Global Amendment No 4: In the food effect part, the 40 mg dose is not tested.
∀
Subjects will be confined under close observation for at least 24 hours after drug 
administration at the trial site and will be discharged only after a formal assessment 
and confirmation of fitness by an investigator or qualified designee. During in-house 
confinement subjects will be under medical observation and thoroughly monitored for 
both, expected and unexpected adverse events.
2.4
OVERALL ASSESSMENT AND CONCLUSION
BI 705564 is an inhibitor of BTK to be developed for the treatment of LN, SLE and 
rheumatoid arthritis. Clinical experience has been gained with another BTK inhibitor, 
ibrutinib, which was approved for the treatment of hematologic malignancies (chronic 


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lymphocytic leukaemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia).
Treatment with ibrutinib in patients with hematologic malignancies is associated with adverse 
events including hypertension, thrombocytopenia, and GI complaints which may be related to 
off-target effects. In contrast, BI 705564 is considered to be a more selective BTK inhibitor
and may have a more favourable safety profile.
Considering preclinical data of BI 705564, the well characterised target structure and its 
physiologic role in B cell differentiation and function, and taking into account the safety 
measures described above, participation in this single dose regimen does not represent an 
undue risk to healthy subjects.
Inhibition of BTK in patients with LN and SLE is expected to block the stimulation of 
autoantibody-producing B cells, and the release of inflammatory cytokines from monocytes 
and macrophages. By diminishing these harmful effects, BI 705564 may slow or halt disease 
progression. Considering the medical need for a better LN/ SLE treatment and taking into 
account the potential advantage of a highly selective BTK inhibitor, the expected benefit of 
this trial is likely to outweigh the potential risks and justifies exposure of healthy volunteers.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
Global Amendment No 4 – major changes in Section 3:
Originally, the study was planned to consist of two study parts: (1) SRD part under fasting
conditions consisting of 8 dose groups (1 to 160 mg) à 8 volunteers (64 volunteers in total) 
and (2) food effect part investigating the effect of a high-fat, high-calorie breakfast on doses 
of 10 mg and 40 mg in 12 volunteers each, i.e. in 24 volunteers total. 
Data obtained during the trial indicate that no relevant increase of exposure was to be
expected with dose groups 120 mg and 160 mg in the SRD part under fasting conditions. 
Therefore, the two highest dose groups of the SRD part under fasting conditions (120 mg and 
160 mg) are not dosed. Data of the food effect part 10 mg indicate that relative bioavailability 
of BI 705564 tablet may be increased by food. The food effect part 40 mg is not dosed. 
Instead, a third study part is added. A SRD part under fed conditions is added to the study and
is designed to investigate single rising oral doses of BI 705564 after a high-fat, high-calorie 
breakfast. It is planned to apply BI 705564 to 4 dose groups à 8 volunteers per group (32 
volunteers in total) with the possibility to add up to 2 interim dose groups in the SRD part 
under fed conditions (see Section 3.1, “Single rising dose part under fed conditions”).
See Appendix 11 for details.
3.1
OVERALL TRIAL DESIGN AND PLAN
A total of 92 healthy male subjects is planned to participate in the trial, thereof 48 in the 
single rising dose part under fasting conditions, 12 in the food effect part, and 32 in the single 
rising dose part under fed conditions. Additional subjects may be entered in the single rising 
dose part under fed conditions (see below). Thus, the actual number of subjects may exceed 
92 but not 108 subjects entered.
Single rising dose part under fasting conditions
This part is designed single-blind, partially randomised, and placebo-controlled within 
parallel dose groups.
A total of 48 healthy male subjects is planned to participate in the single rising dose part
under fasting conditions, resulting in 6 sequential groups comprising 8 subjects each. 
Within each dose group, 6 subjects will receive the active drug and 2 will receive placebo. 
Only one dose is tested within each dose group. Dose groups will be treated consecutively in 
ascending order of doses. Each dose group will consist of 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 1 hour later by the 
second subject (placebo) followed at least 1 hour later by the third subject (active) followed 
at least 10 minutes later by the fourth subject (active).


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If BI 705564 treatment is safe and showed acceptable tolerability in the first cohort, subjects 
in the second cohort will be treated not earlier than 2 days later (at least 46 h between the 
1st subject of each cohort) in a single-blind, randomised manner. In the second cohort, a time 
interval of at least 10 minutes will be maintained between administrations of trial drug to the 
individual subjects.
A time interval of at least 10 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 
dose groups to be evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups in the single rising dose part under fasting conditions
Dose Group
1
2
3
4
5
6
Dose (mg) q.d.
1
3
10
20
40
80
Formulation
PfOS
PfOS
Tab
Tab
Tab
Tab
Number of subjects
8
8
8
8
8
8
Subjects with placebo
2
2
2
2
2
2
Subjects with active drug
6
6
6
6
6
6
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 (see Section 3.3.4.2).
A documented Safety Review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested at any time 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).
The minimum data set for review consists of the following data:
∀
AEs in the current and preceding dose groups up to at least 48 h post dosing,
including clinically relevant findings from ancillary safety testing, as 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 ECG and continuous ECG monitoring in the current and 
preceding dose groups up to at least 48 h post dosing.
∀
Vital signs in the current and preceding dose groups up to at least 48 h post dosing.
∀
Clinical laboratory tests in the preceding dose groups and clinical laboratory tests of 
the first cohort of the current dose group up to at least Visit 2 Day 8.


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∀
Preliminary PK data for selected time points, as per Section 7.3.5. For escalation from 
Dose Group 1 to Dose Group 2, preliminary PK data are not required.
∀
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.
The investigator and/ or the sponsor should stop dose escalation in case the safety evaluation 
leads to concerns that would not allow higher dosing.
An overview of all relevant trial activities is provided in Flow Chart 1. For visit schedules 
and details of trial procedures at selected visits, see Sections 6.1 and 6.2, respectively.
Food effect part
This part will be performed as a randomised, open-label, two-way crossover trial part in 
healthy male subjects in order to compare the test treatment (T) to the reference treatment 
(R).
A 10 mg dose will be tested in a group of 12 subjects. For decision criteria see Section 
2.3.2.7.
The subjects will be randomly allocated to the two treatment sequences (T-R or R-T). The 
treatments will be one 10 mg tablet of BI 705564 in the fed state (T) and one 10 mg tablet of 
BI 705564 in the fasting state (R). For details, see Section 4.1.
There will be a washout period of at least 10 days between treatments.
An overview of all relevant trial activities is provided in Flow Chart 2. For visit schedule and 
details of trial procedures at selected visits, see Sections 6.1 and 6.2, respectively.
Single rising dose part under fed conditions
This part is designed single-blind, partially randomised, and placebo-controlled within 
parallel dose groups.
A total of 32 healthy male subjects is planned to participate in the single rising dose part
under fed conditions, resulting in 4 sequential groups comprising 8 subjects each. However, 
additional subjects may be entered to allow testing of additional doses on the basis of the 
experience gained during the conduct of the trial (e.g. preliminary PK data), provided that the 
planned and approved highest dose will not be exceeded. Thus, the actual number of subjects 
entered in the single rising dose part may exceed 32, but will not exceed 48 subjects entered. 
Such changes may be implemented via non-substantial CTP amendments.


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Within each dose group, 6 subjects will receive the active drug and 2 will receive placebo. 
Only one dose is tested within each dose group. Dose groups will be treated consecutively in 
ascending order of doses. Each dose group will consist of 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 1 hour later by the 
second subject (placebo) followed at least 1 hour later by the third subject (active) followed 
at least 10 minutes later by the fourth subject (active).
If BI 705564 treatment is safe and showed acceptable tolerability in the first cohort, subjects 
in the second cohort will be treated not earlier than 2 days later (at least 46 h between the 
1st subject of each cohort) in a single-blind, randomised manner. In the second cohort, a time 
interval of at least 10 minutes will be maintained between administrations of trial drug to the 
individual subjects.
A time interval of at least 10 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 
dose groups to be evaluated are outlined in Table 3.1: 2 below.
Table 3.1: 2
Dose groups in the single rising dose part under fed conditions
Dose Group
7
8
12*
13*
Dose (mg) q.d.
20
40
80
160
Formulation
Tab
Tab
Tab
Tab
Number of subjects
8
8
8
8
Subjects with placebo
2
2
2
2
Subjects with active drug
6
6
6
6
* For technical reasons related to drug packaging, numbers 9-11 cannot be attributed to dose groups in the SRD 
part under fed conditions.
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 (see Section 3.3.4.2).
A documented Safety Review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested at any time 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).
The minimum data set for review consists of the following data:
∀
AEs in the current and preceding dose groups up to at least 48 h post dosing,
including clinically relevant findings from ancillary safety testing, as listed below.


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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 ECG and continuous ECG monitoring in the current and 
preceding dose groups up to at least 48 h post dosing.
∀
Vital signs in the current and preceding dose groups up to at least 48 h post dosing.
∀
Clinical laboratory tests in the preceding dose groups and clinical laboratory tests of 
the first cohort of the current dose group up to at least Visit 2 Day 8. 
∀
Preliminary PK data for selected time points, as per Section 7.3.5. 
∀
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.
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.
An overview of all relevant trial activities is provided in Flow Chart 3. For visit schedules 
and details of trial procedures at selected visits, see Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim 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 Standard 
Operation Procedures (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
 
The trial will be conducted at the
 
, under the supervision of the 
Principal Investigator.


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Safety laboratory tests will be performed by the local laboratory of the trial site, at 
 
The analyses of BI 705564 concentrations in plasma and urine will be performed at 
 
. 
BI 705564 metabolism analyses will be performed at the
 
The analyses of BI 705564 
will be performed at 
.
The 
 assay and 
 will be performed at the
 
.
The digitally recorded 12-lead ECGs 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.
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(S)
Single rising dose parts under fasting and fed conditions
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 705564.
With the rising dose design, single-blind conditions regarding the subject’s treatment (active 
or placebo) are maintained within each dose group. However, the current dose level will be 
known to subjects and investigators. 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, tolerability, and pharmacodynamics effects. Each dose group 
consists of 8 subjects with 6 on active treatment, and 2 on placebo. The placebo control group 


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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.
Food effect part
For relative bioavailability trials, the crossover design is preferred due to its efficiency. Since 
each subject serves as his own control, the comparison between treatments is based on a 
comparison within subjects rather than between subjects. This trial design, therefore, removes 
inter-subject variability from the comparison between treatments [R94-1529].
Blinding is not possible because the treatments are distinguishable.
The open-label treatment is not expected to bias results.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 48 healthy male subjects will enter the single rising dose part under fasting
conditions, that 12 healthy male subjects will enter the food effect part of the study, and that 
32 healthy male subjects will enter the single rising dose part under fed conditions (i.e., 92 
volunteers in total).
The actual number of subjects entered into the trial may exceed the total of 92 (all three trial 
parts together), if additional, intermediate doses within the approved dose range will be tested 
in the single rising dose part under fasting conditions (see Section 3.1). Subjects will be 
recruited from the volunteers' pool of the trial site.
Subjects that were entered and treated in the single rising dose part under fasting conditions
may be entered again in the food effect part, provided the time interval between the drug 
administration in the single rising dose part and the first drug administration in the food effect
part is more than 60 days. Subjects that were entered and treated in the single rising dose part 
under fasting conditions are not allowed to be entered in the single rising dose part under fed 
conditions.
Only male subjects will be included into the study because hitherto no data on reproductive 
toxicology are available.
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:


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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 50 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)
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)
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


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19. Inability to comply with dietary regimen of the trial site
20. A marked baseline prolongation of QT/ QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for 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. Repeated absolute B cell (CD19+) counts below 40/μL at screening
25. Repeated platelet counts below 100 cells/nL at screening
26. Serum potassium below normal range at screening
27. A history or current clinical signs of acute pancreatitis
For study restrictions, see Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision.
2. The subject needs to take concomitant drugs that interfere with the investigational product 
or other trial medication.
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events (AEs), or diseases).
4. An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP 
>180/100 mmHg) or of clinically relevant changes in ECG requiring intervention as well 
as unexplained liver enzyme elevations at any time during the trial.
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.
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.


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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 CRF.
3.3.4.2
Discontinuation of the trial by the sponsor
BI 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. More specifically, the trial will be terminated, if more than 50% 
of subjects 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 that is considered 
to be unacceptable.
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 will be stopped as soon as at least 2 subjects at one dose level on active 
drug shows relevant individual QT prolongation, i.e. a QTc increase of greater than 60 ms 
from baseline in connection with absolute QT or QTc greater than 500 ms which has been 
confirmed by a repeat ECG recording.
6. Dose escalation will be stopped, if the Cmax or AUC0-24 of at least 2 subjects of one dose 
group increases above the following exposure thresholds or, if the estimated gMean
exposure of the next dose group is expected 
 
 Estimation will be done based on preliminary pharmacokinetics results of 
preceding dose groups (see Section 7.3.5).
3.3.5
Replacement of subjects
In case there are less than 4 subjects on active drug per dose level in the single rising dose
parts under fasting or fed conditions or less than 9 subjects per dose level in the food effect 
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, and will be 
assigned to the same treatment as the subject he replaces.


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4.
TREATMENTS
Global Amendment No 4 – major changes in Section 4:
With this amendment, 120 mg and 160 mg dose groups in the SRD part under fasting
conditions and the 40 mg dose group of the food effect part were deleted. An additional SRD 
part under fed conditions was added. See Section 3 and Appendix 11 for details.
4.1
TREATMENTS TO BE ADMINISTERED
The investigational product has been manufactured by Boehringer Ingelheim Pharma GmbH 
& Co. KG and Almac Clinical Services Limited in UK.
4.1.1
Identity of BI investigational product and comparator product
Single rising dose part under fasting conditions
Powder for oral solution
The characteristics of the test product are given below:
Substance:
BI 705564
Pharmaceutical formulation: Powder for oral solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Drug in bottle:
20 mg
Unit strength:
0.25 mg/mL (concentration in prepared solution)
Posology:
4 mL (1 mg)-0-0 (DG 1); 12 mL (3 mg)-0-0 (DG 2)
Route of administration:
p.o.
Duration of use:
Single dose
Component for reconstitution: The oral solution for dosing will be prepared as detailed in the 
reconstitution instruction given in Appendix 10.1 using a solvent containing hydroxypropyl-
beta-cyclodextrin (HP-ß-CD). The solvent will be supplied in separate 100 mL glass vials and 
will be used as placebo solution (see Appendix 10.1).
Tablets
The characteristics of the test product are given below:
10 mg Tablet
Substance:
BI 705564
Pharmaceutical formulation: Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:


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Posology:
Route of administration:
p.o.
Duration of use:
Single dose
The characteristics of the reference product (placebo) are given below:
Oral solution
Substance:
Matching placebo containing hydroxypropyl-beta-cyclodextrin
Pharmaceutical formulation: Oral solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
(4 mL)-0-0 (DG 1); (12 mL)-0-0 (DG 2)
Route of administration:
p.o.
Duration of use:
Single dose
Tablets
Substance:
Placebo matching in size and weight to 10 mg tablet
Pharmaceutical formulation: Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
1-0-0 (DG 3); 2-0-0 (DG 4); 4-0-0 (DG 5); 8-0-0 (DG 6)
Route of administration:
p.o.
Duration of use:
Single dose
Food effect part
The characteristics of the test products are given below:
Tablet (fed and fasting)
Substance:
BI 705564
Pharmaceutical formulation: Film-coated tablet


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Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
Route of administration:
p.o.
Duration of use:
Single dose
Single rising dose part under fed conditions
Tablets
The characteristics of the test product are given below:
10 mg Tablet
Substance:
BI 705564
Pharmaceutical formulation: Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
Posology:
Route of administration:
p.o.
Duration of use:
Single dose
100 mg Tablet
Substance:
BI 705564
Pharmaceutical formulation: Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
Route of administration:
p.o.
Duration of use:
Single dose
The characteristics of the reference product (placebo) are given below:
Tablets
Substance:
Placebo matching in size and weight to 10 mg tablet


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Pharmaceutical formulation: Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
2-0-0 (DG 7); 4-0-0 (DG 8); 8-0-0 (DG 12); 6-0-0 (DG 13)
Route of administration:
p.o.
Duration of use:
Single dose
Substance:
Placebo matching in size and weight to 100 mg tablet
Pharmaceutical formulation: Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
1-0-0 (DG 13)
Route of administration:
p.o.
Duration of use:
Single dose
4.1.2
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. Subjects willing to participate will be recruited to dose groups in the 
single rising dose- or food effect part according to their temporal availability. As soon as 
enough subjects have been allocated to 1 of the 12 dose cohorts (2 cohorts per dose group) in 
the single rising dose part under fasting conditions, the following subjects will be allocated to 
one of the other dose cohorts in the single rising dose part under fasting conditions. As soon 
as enough subjects have been allocated to 1 of the 8 dose cohorts (2 cohorts per dose group) 
in the single rising dose part under fed conditions, the following subjects will be allocated to 
one of the other dose cohorts in the single rising dose part under fed conditions. In the food 
effect part, there is only one dose group. Therefore, the allocation of subjects to dose cohorts 
or groups 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 dose groups are not expected.
The randomisation list with study subject numbers and allocated treatments will be provided 
to the trial site in advance. 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
Doses, selected for this trial, are intended to cover the sub-therapeutic as well as the 
estimated therapeutic and supra-therapeutic range and include a safety margin (see Section 
1.2 and 2.1).
4.1.4
Drug assignment and administration of doses for each subject
Single rising dose part under fasting conditions
Treatments to be evaluated are outlined in Table 4.1.4: 1. The number of units/ dose volume 
for placebo corresponds to the number of units/ dose volume of the respective dose group.
Table 4.1.4: 1
BI 705564 and placebo treatments, oral administration under fasting
conditions
Dose
group
Substance
Pharmaceu
tical form
Unit strength
Number of units / dose volume 
per administration
Total 
daily dose
1
BI 705564
Oral 
solution
0.25 mg/mL
4 mL
1 mg
2
BI 705564
Oral 
solution
0.25 mg/mL
12 mL
3 mg
3
BI 705564
Film-coated 
tablet
10 mg
1 tablet
10 mg
4
BI 705564
Film-coated 
tablet
10 mg
2 tablets
20 mg
5
BI 705564
Film-coated 
tablet
10 mg
4 tablets
40 mg
6
BI 705564
Film-coated 
tablet
10 mg
8 tablets
80 mg
1-2
Placebo*
Oral 
solution
--
Identical to active treatment
--
3-6
Placebo*
Film-coated 
tablet
--
Identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups
The oral solutions for dosing (active drug and placebo) will be prepared according to the 
instruction given in Appendix 10.1 under the responsibility of the investigator.
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. 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 hours before the scheduled dosing.


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Subjects will be kept under close medical surveillance until at least 24 hours following drug 
administration. During the first 4 hours after drug administration, they are not allowed to 
sleep and will be confined to bed with a bed inclination angle of at least 45 degrees unless 
lower or supine position is required for trial-related measurements (e.g., recording of 12-lead 
ECG) or medical reasons (e.g., adverse events). For restrictions with regard to diet, see
Section 4.2.2.2.
Food effect part
This part follows a two-way crossover design. All subjects will receive the two treatments in 
randomised order. The treatments to be evaluated are outlined in Table 4.1.4: 2.
Table 4.1.4: 2
Dosage and treatment schedule – food effect part
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
Tablet, fed 
(Test)
BI 705564
Film-coated 
tablet
10 mg
1 tablet q.d.
10 mg
Tablet, fasting
(Reference)
BI 705564
Film-coated 
tablet
10 mg
1 tablet q.d.
10 mg
The medication will be administered as a single oral dose together with about 240 mL of 
water to a subject in the sitting or standing position under supervision of the investigating 
physician or an authorised designee. 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 starting no later than 10 hours before scheduled 
dosing.
In the ‘fed’ treatment, a high-fat, high-calorie meal will be served 30 minutes before drug 
administration. The meal must be completely consumed prior to drug administration. The 
composition of the standard 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.


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Table 4.1.4: 3
Composition of the high-fat, high-calorie meal
Ingredients
kcal
2 chicken eggs (whole content)1 for scrambled eggs
192
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum2
984
1
Alternatively liquid egg (consisting of pasteurized whole chicken egg) with an amount 
corresponding to 2 chicken eggs may be used.
2
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 hours following drug 
administration. During the first 4 hours after drug administration, they are not allowed to lie 
down (i.e. no declination of the upper body of more than 45 degrees from upright posture)
except, if required for trial-related measurements (e.g., recording of 12-lead ECG) or for 
medical reasons (e.g., adverse events). For restrictions with regard to diet see Section 4.2.2.2.
The treatments will be separated by a wash-out phase of at least 10 days between drug 
administrations.


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Single rising dose part under fed conditions
Treatments to be evaluated are outlined in Table 4.1.4: 4. The number of units for placebo 
corresponds to the number of units of the respective dose group.
Table 4.1.4: 4
BI 705564 and placebo treatments, oral administration
Dose
group
Substance
Pharmaceu
tical form
Unit strength
Number of units
per administration
Total 
daily dose
7
BI 705564
Film-coated 
tablet
10 mg
2 tablets
20 mg
8
BI 705564
Film-coated 
tablet
10 mg
4 tablets
40 mg
12**
BI 705564
Film-coated 
tablet
10 mg
8 tablets
80 mg
13**
BI 705564
Film-coated 
tablet
10 mg and 100 mg
6 tablets of 10 mg and 1 tablet of 
100 mg
160 mg
7, 8, 12,
13
Placebo*
Film-coated 
tablet
--
Identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups.
** For technical reasons related to drug packaging, numbers 9-11 cannot be attributed to dose groups in the 
SRD part under fed conditions.
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. The so-called four-eye principle (two-
person rule) should be applied for administration of trial medication, if correct dosage cannot 
be ensured otherwise.
Subjects will be kept under close medical surveillance until at least 24 hours following drug 
administration. During the first 4 hours after drug administration, they are not allowed to 
sleep and will be confined to bed with a bed inclination angle of at least 45 degrees unless 
lower or supine position is required for trial-related measurements (e.g., recording of 12-lead 
ECG) or medical reasons (e.g., adverse events). For restrictions with regard to diet, see
Section 4.2.2.2.
Additional doses
Additional subjects may be entered to allow testing of additional doses on the basis of the 
experience gained during the conduct of the trial (e.g. preliminary PK data), provided that the 
planned and approved highest dose will not be exceeded (see Section 3.1). Such changes may 
be implemented via non-substantial CTP amendments.
Application of food
A high-fat, high-calorie meal will be served 30 minutes before drug administration. The meal 
must be completely consumed prior to drug administration. The composition of the standard 
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: 5.


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Table 4.1.4: 5
Composition of the high-fat, high-calorie meal
Ingredients
kcal
2 chicken eggs (whole content)1 for scrambled eggs
192
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum2
984
1
Alternatively liquid egg (consisting of pasteurized whole chicken egg) with an amount 
corresponding to 2 chicken eggs may be used.
2
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 hours following drug 
administration. During the first 4 hours after drug administration, they are not allowed to lie 
down (i.e. no declination of the upper body of more than 45 degrees from upright posture)
except, if required for trial-related measurements (e.g., recording of 12-lead ECG) or for 
medical reasons (e.g., adverse events). For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
The database of this trial will be handled open-label, because no bias with regard to data 
cleaning or safety measures is expected. This is considered acceptable because the potential 
for bias seems to be low and does not outweigh practical considerations.
Single rising dose parts under fasting and fed conditions
The treatments administered (active or placebo) will be single-blind (blinded to subjects 
only). However, the current dose level will be known to the subjects.
The bioanalyst or analytical laboratory and the trial pharmacokineticist may receive the 
randomisation codes of the single rising dose part prior to official unblinding to perform the 
preliminary PK analysis. He or she will treat the codes confidentially.
In addition, the drug metabolism scientist may receive the randomisation codes prior to 
official unblinding to perform metabolites in safety testing analysis (MIST). 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 the time 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.


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Food effect part
This part of the trial will be handled in an open fashion throughout (that is, during the 
conduct, including data cleaning and preparation of the analysis). This is considered 
acceptable because the potential for bias seems to be low and does not outweigh practical 
considerations.
4.1.5.2
Procedures for emergency unblinding
As this trial will be conducted single blinded (single rising dose parts under fasting and fed 
conditions) and open-label (food effect part), the treatment information will be known to the 
investigator. Therefore, no emergency envelopes will be provided.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the 
 
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 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 – only in single rising dose part
∀
Batch number
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 
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 


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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 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 
authorize symptomatic therapy. In those cases, subjects will be treated as necessary and, if 
required, kept under supervision at the trial site or transferred to a hospital until all medical 
evaluation results have returned to an acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.


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Paracetamol and acetylsalicylic acid should be avoided. Ibuprofen should preferably be used 
for treatment of pain such as headache or toothache.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Charts. No food is allowed for at least 4 hours after drug intake.
From 1 hour before drug intake until lunch, fluid intake is restricted to the milk served with 
breakfast (see Table 4.1.4: 3 and Table 4.1.4: 5), the water administered with the drug, and an 
additional 240 mL of water served at 2 hours and 4 hours post-dose (mandatory for all 
subjects).
From lunch until discharge from the study centre, liquid intake is restricted to additional 
3 litres.
Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products including St. John's wort (Hypericum perforatum) are not 
permitted starting 7 days before administration of trial medication until after the last PK 
sample of each study period is collected.
Alcoholic beverages are not permitted starting 48 hours before 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 hours before administration of trial medication until the 
end of the in-house period at the trial site.
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 should be avoided during the 
entire study.
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
Single rising dose parts under fasting and fed conditions
Primary endpoint to assess safety and tolerability of BI 705564 is the number [N (%)] of 
subjects with drug-related adverse events (adverse reactions).
Further criteria of interest:
∀
AEs (including clinically relevant findings from the physical examination)
∀
Safety laboratory tests
∀
12-lead ECG
∀
Continuous ECG monitoring
∀
Vital signs (blood pressure, pulse rate)
Food effect part
Safety and tolerability of the investigational drug will be assessed based on:
∀
Adverse events (including clinically relevant findings from the physical examination)
∀
Safety laboratory tests
∀
12-lead ECG
∀
Vital signs (blood pressure, pulse rate)
These parameters will be evaluated in a descriptive way only, and are therefore considered to 
be ‘further parameters of interest’. A confirmatory analysis is not planned (see Section 7.3).


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5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:
∀
Results in death,
∀
Is life-threatening, this 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 or prolongation of existing hospitalisation,
∀
Results in persistent or significant disability or incapacity,
∀
Is a congenital anomaly/birth defect, or
∀
Is to be 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.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
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. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.


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AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI 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 given above.
The latest list of ‘Always Serious AEs’ can be found in the RDC system, a remote 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.
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
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. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
The following are considered as AESIs in this trial:
∀
Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters:
o
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
o
Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF or RDC system. In case of clinical symptoms of hepatic injury (icterus, 
unexplained encephalopathy, unexplained coagulopathy, right upper quadrant 
abdominal pain, etc.) without lab results (ALT, AST, total bilirubin) available, the 
Investigator should make sure these parameters are analysed, if necessary in an 
unscheduled blood test. Should the results meet the criteria of hepatic injury alert, the 
procedures described in the DILI checklist should be followed.
With the exception of DILI, no AESIs have been defined for this trial.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Enough discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.


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Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
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).
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 study drug treatment continues or remains 
unchanged.


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5.2.2.2
Adverse event collection and reporting
AEs 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 Charts. 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 careful 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, and intensity of the event as 
well as 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 through the residual effect period (REP), 
until an individual subject’s end of trial:
o
All AEs (serious and non-serious) and all AESIs.
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.
∀
After the individual subject’s end of trial:
o
The investigator does not need to actively monitor the subject for AEs but 
should only report relevant SAEs and relevant AESIs of which 
 may 
become aware of.


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Single rising dose parts and food effect part
The REP for BI 705564, when measurable drug levels or PD effects are still likely to be 
present after the last administration, is not known for this first-in-human trial. Therefore, all 
AEs reported until the end of trial examination (last per protocol contact) will be considered 
on treatment; see Section 7.3.4. The follow-up period describes the period of time from the 
last administration of trial medication until the end of trial examination (last per protocol 
contact).
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours of 
awareness) 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 
CRF pages and the BI SAE form (if applicable). The investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as an (S)AE in the CRF and on the 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 trial inclusion they will be considered as 
baseline conditions.


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All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, 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 Charts after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designee
for retests or drug screening. In the single rising dose part under fed conditions, fasting is not 
applicable to the post-dose safety laboratory on Day 1.
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.
Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
SCR
A1
B2
C3
EOT
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet 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
x
x
x
x
Automatic WBC 
differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, 
monocytes, lymphocytes
x
x
x
x
x
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Polymorphnuclear neutrophils (segs), band 
neutrophils (stabs), eosinophils, basophils, 
monocytes, lymphocytes 
Lymphocyte 
differentiation (relative 
and absolute; except 
for ratio)
T cells (CD3+), T helper cells 
(CD3+CD4+), cytotoxic T cells 
(CD3+CD8+), B cells (CD19+), natural 
killer cells (CD16+CD56+CD3-), double-
positive T cells (CD3+CD4+CD8+), 
CD4:CD8 ratio
x
--
--
x4
x
Serum 
immunoglobulins
IgA
IgG
IgM
x
x
x
--
--
--
--
--
--
x
x
x
x
x
x
Coagulation
Activated partial thromboplastin time 
(aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
x
x
x
x
x
--
x
x
x
x
x
x
x
x
x
1
A: Days -3 to -1
2
B: post-dose on Day 1 (single rising dose parts)
3
C: Days 2, 3, 8 (single rising dose parts) and Day 2 (food effect part)
4
Not on Day 3 (single rising dose parts)


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Table 5.2.3: 1
Routine laboratory tests (cont’d)
Functional lab group
Test name 
SCR
A1
B2
C3
EOT
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Glutamate dehydrogenase (GLDH)
Creatine kinase (CK); CK-MB only if CK is 
elevated 
Lactate dehydrogenase (LDH)
Lipase
Amylase
x
x
x
x
x
x
x
x
x
x
x
--
x
--
--
x
x
x
x
x
x
x
--
x 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hormones
Thyroid stimulating hormone (TSH)
x
Substrates
Plasma glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
C-Reactive Protein (CRP) 
Uric acid
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
x
x
x
x
x
x
x
x
x
Electrolytes
Sodium
Potassium
Calcium
x
x
x
x
x
--
x
x
x
x
x
x
x
x
x
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
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
x
x
x
x
x
x
x
x
x
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for 
instance, the presence of sediment bacteria, 
casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
1
A: Days -3 to -1
2
B: post-dose on Day 1 (single rising dose parts)
3
C: Days 2, 3, 8 (single rising dose parts) and Day 2 (food effect part)
4
Not on Day 3 (single rising dose parts)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. It is planned to perform these tests during screening only. Drug screening will be 
performed at screening and prior to each treatment period.


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed prior to each treatment period, and may be 
repeated at any time during the study at the discretion of an investigator or designee. The 
results will not be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
with the exception of 
the drug screening tests. These tests will be performed at the trial site using e.g. AccuSign®
DOA 10, MAHSAN®-Kombi/DOA10, or M-10/14-PDT test.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
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 Charts.
In order to achieve a stable heart rate at rest and to assure high quality recordings at 
comparable resting phases, all ECGs will be recorded for a 10-second duration after the 
subjects have rested for at least 5 minutes in a supine position. The site personnel will be 
instructed to assure a relaxed and quiet environment so that all subjects are at complete rest 
during the recordings. ECG assessment will always precede all other study procedures of the 
same time point (except blood drawing from an intravenous cannula which is already in 
place) to avoid impact of sampling on the ECG quality.
All ECGs will be stored electronically on the 
 
 Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 


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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.
All locally printed ECGs will be evaluated by the investigator or a designee.
ECGs may be repeated for quality reasons (like alternating current artefacts, muscle 
movements, electrode dislocation). For time points with triple ECGs, all three single ECGs 
will be repeated. For the repeats due to quality reasons, only the repeated ECG recordings 
will be sent to the central ECG lab, whereas the initially recorded ECGs will be discarded.
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
These ECGs are assigned to the prior scheduled time point. Unscheduled ECGs will not be 
included into the statistical analysis of interval lengths.
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 ECG machines or their 
manual corrections by the investigators will be used. In doubtful cases, ECGs may be sent 
upfront for centralised evaluation (see below). In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening), if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment.
Single rising dose parts under fasting and fed conditions: Triple ECGs will be recorded (three 
single ECGs within 180 sec) at all time points in Visit 2. At Visits 1 and 4, single ECGs will 
be recorded.
Food effect part: It is planned that single ECGs will be recorded for all time points. However, 
the number of ECGs per time point may be increased to three ECGs based on preliminary 
ECG results obtained during the single rising dose part of the study.
Single rising dose parts only
In the single rising dose parts, a centralised evaluation (during study and/or post study) of all 
12-lead ECGs recorded at Visit 2 will be performed by an independent ECG laboratory. This 
analysis will include the determination of cardiac axis (automatically) as well as the intervals 
RR, PR, QRS and QT measured semi-automatically.
With the exception of the first triple ECG (used as baseline before the first drug 
administration), only the first of the three replicate ECGs at a single assessment time will be 
evaluated. The remaining second and third replicate ECGs will be stored for additional 
analyses if required, e.g. by authorities at a later time point.
For each QT interval, the RR interval preceding the QT will be measured to calculate the 
respective frequency corrected QTc intervals ‘QTcF’ according to Fridericia’s formula 
(QTcF = QT/ RR1/3) and ‘QTcB’ according to Bazett’s formula (QTcB = QT/ RR1/2). The 
QTcF correction will be used for evaluation and reporting. Abnormalities detected during 
centralised ECG evaluation will not necessarily qualify as AE. All 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 


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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 blinding arrangements see Section 4.1.5.
Assessed ECGs will comply with the ICH E14 guidance document and supplements [R05-
2311, R13-0801, R13-4095] as well as the FDA requirements for annotated digital ECGs 
[R09-4830].
5.2.4.2
Continuous ECG monitoring
Cardiac rhythm (including heart rate) will be monitored by means of continuous 3-lead ECG 
recording for at least 15 minutes before (for baseline assessment) and 4 hours following drug 
administration using patient monitors (e.g. Carescape B450, GE Healthcare, Freiburg, 
Germany). Abnormal findings will be recorded as AEs if judged clinically relevant by the 
Investigator but no other data will be transferred to the database.
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap Pro 100, GE Medical Systems, Freiburg, Germany) at the times indicated in the 
Flow Charts, after subjects have rested for at least 5 minutes in a supine position. All 
recordings should be made using the same type of blood pressure recording instrument on the 
same arm if possible.
5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 
laboratory tests, and a physical examination. At the end of trial examination, it will include 
review of vital signs, 12-lead ECG, laboratory tests, and a physical examination.
 
 
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic and 
biomarkers 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 biomarkers and measurements, outlined in 
Section 5.6, are of exploratory nature only.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded.
Exact time points of plasma sampling will be derived from the 
 
 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
5.5.1.1
Primary endpoints
Single rising dose parts under fasting and fed conditions
Not applicable
Food effect part
The following primary endpoints will be determined for BI 705564:
∀
AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)
∀
Cmax (maximum measured concentration of the analyte in plasma)


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5.5.1.2
Secondary endpoints
Single rising dose parts under fasting and fed conditions
The following secondary endpoints will be determined for BI 705564:
∀
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
∀
Cmax
Food effect part
The following secondary endpoints will be determined for BI 705564:
∀
AUC0-∞
 
 
 
 


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 705564 plasma concentrations, 2.7 mL of blood will be taken from 
an antecubital or forearm vein into a K3-EDTA (tripotassium ethylenediaminetetraacetic 
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Charts. 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 minutes at about 
2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and stored in 
polypropylene 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 minutes, with interim storage of blood samples and aliquots in ice water or on ice
or cryoblocks. 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 


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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.
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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5.5.2.3
Urine sampling for pharmacokinetic analysis (single rising dose parts under 
fasting and fed conditions)
A blank urine sample will be collected before administration of trial medication (within the 
3 hours before drug dosing) and two 0.5 mL aliquots will be retained to check for analytical 
interference by concomitant or rescue medication.
All urine voided during the sampling intervals indicated in the Flow Charts will be collected 
in 2 liters polyethylene (PE) containers and stored at room temperature. Subjects are told to 
empty their bladders at the end of each sampling interval.
 
The urine weight/volume for each collection interval will be documented (however, no 
correction for the specific gravity of urine is done, i.e. 1 liter is defined to be equal to 1 kg). 
Two 0.5 mL aliquots will be stored in polypropylene (PP) tubes for bioanalytical 
measurement. In case more than one collection container is used in an interval, the contents 
of all containers are to be mixed before aliquots are prepared. Mixing should be done by 
transferring the entire content of all collection containers into a single PE/PP or glass 
container, and stirring the mixed fractions for about 1 minute (manually or using a stir bar or 
other stirring device out of PE, PP, Teflon or glass).
At minimum, the sample tube labels should list at least the following information: BI trial 
number, subject number, visit, and planned collection time. Further information such as 
matrix and analyte may also be provided.
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at 
about -20°C or below at the trial site. The second aliquot will be transferred 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.
After completion of the trial the urine 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) 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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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 Flow 
Chart 1 and Flow Chart 3 for the single rising dose part under fasting and fed conditions, 
respectively, and Flow Chart 2 for the food effect part.
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 and biomarkers).
Starting from 72 h post administration a deviation from the scheduled time for PK and 
biomarker sampling of ±70 min is acceptable. The biomarker samples planned time Day 6 
(single rising dose parts) may be taken on day 5 (up to 26 h earlier).
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 15 minutes for the first 4 hours after trial drug administration and ± 30 minutes
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 Charts 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 and urine collection intervals,
see Flow Charts. 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 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, see Sections 5.2.3 to 5.2.5.
 


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6.2.2
Treatment periods
Single rising dose parts under fasting and fed conditions
Each subject will receive one dose of the respective trial medication (BI 705564 or placebo) 
at Visit 2.
Study participants will be admitted to the trial site in the morning of Day 1 and kept under 
close medical surveillance for at least 24 hours following drug administration. Subjects will 
then be allowed to leave the trial site after formal assessment and confirmation of their fitness 
by the investigator or 
 designee. On all other study days, the study will be performed in an 
ambulatory fashion.
For details on time points and procedures for collection of plasma and urine samples for PK 
analysis, see Flow Chart 1, Flow Chart 3 and Section 5.5.2.
Safety measurements performed during the treatment period are specified in Section 5.2,
Flow Chart 1 and Flow Chart 3. For details on time points for all other trial procedures, refer 
to Flow Chart 1 and Flow Chart 3. AEs and concomitant therapy will be assessed 
continuously from screening until the end of trial examination.
Food effect part
Each subject is expected to participate in two treatment periods. The treatment periods will be 
separated by at least 10 days between drug administrations.
On Day 1 of each treatment period study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 hours following drug administration.
Subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness. On all other study days, the study will be performed in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
see Flow Chart 2 and Section 5.5.2.
Safety measurements performed during the treatment period are specified in Section 5.2 and 
Flow Chart 2. For details on time points for all other trial procedures, see Flow Chart 2. 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 


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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
Single rising dose parts under fasting and fed conditions
The primary objective of these parts of the trial is to investigate the safety and tolerability of 
BI 705564 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) and
pharmacodynamics (PD) of BI 705564. Endpoints as specified in 5.5.1 (for PK) and 5.7.1
(for PD) 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.
 
Food effect part
The primary objective of this part of the trial is to investigate a possible food effect, 
comparing the tablet formulation under fasting (Reference R) to that under fed conditions 
(Test, T) following oral administration. The trial is designed to allow an intra-subject 
comparison and will be evaluated statistically by use of an appropriate linear model.
The secondary objective is the evaluation and comparison of several pharmacokinetic 
parameters between treatments. They will be assessed by descriptive statistics.
The assessment of safety and tolerability will be an additional objective of this trial, and will 
be evaluated by descriptive statistics.
7.1.2
Endpoints
Single rising dose parts under fasting and fed conditions
Safety and tolerability will be determined on the basis of the parameters specified in 
Section 5.2.1. PK and PD endpoints are specified in Sections 5.5.1 (for PK) and 5.7.1 (for 
PD).
Food effect part
Food effect is to be determined on the basis of the primary and secondary pharmacokinetic 
endpoints (AUC0-tz, Cmax and AUC0-∞, see Section 5.5.1).


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Safety and tolerability will be determined on the basis of the parameters specified in 
Section 5.2.1.
7.1.3
Model
Single rising dose parts under fasting and fed conditions
Endpoints will be analysed by descriptive statistics. Inferential statistics is not planned (as 
explained in Section 7.2).
Secondary endpoints, as defined in Section 5.5.1.1, will be subjected to analysis of dose 
proportionality by use of the power model.
Food effect part
The statistical model used for the analysis of primary and key secondary endpoints 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. The model is 
described by the following equation:
yijkm = # + ∃i + sim + %j + &k + eijkm,
where
yijkm = logarithm of response (endpoint, see Section 7.1.2) measured on subject m in 
sequence i receiving treatment k in period j,
# = the overall mean,
∃i = the ith sequence effect, i = 1, 2,
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.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Single rising dose parts under fasting and fed conditions
Safety and tolerability of 10 different dose groups of BI 705564 (6 in SRD part under fasting
conditions and 4 in SRD part under fed conditions) are to be determined on the basis of the 


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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.
Confidence intervals will be computed and will have to be interpreted in the perspective of 
the exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
Food effect part
The food effect of the BI 705564 tablet will be estimated by the ratios of the gMeans 
(test/reference) for the primary and secondary PK endpoints. Additionally, their two-sided 
90% confidence intervals (CIs) will be provided. This method corresponds to the two one-
sided t-tests procedure, each at the 5% significance level. Since the main focus is on 
estimation and not testing, an acceptance range was not specified, that is, no hypothesis will 
be tested.
7.3
PLANNED ANALYSES
All individual data will be listed.
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.
7.3.1
Primary analyses
Single rising dose parts under fasting and fed conditions
Analysis of safety and tolerability is described in Section 7.3.4.
Food effect part
The pharmacokinetic endpoints listed in Section 5.5.1 will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-472].
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses, if they are not flagged for exclusion due to a protocol 
violation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject's data will be documented in the CTR.
Relevant protocol violations may be


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∀
Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to.
∀
Incorrect dose of trial medication taken.
∀
Use of restricted medications.
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example
∀
The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (median tmax is to be determined excluding the subjects 
experiencing emesis).
∀
The subject experiences emesis at any time during the labelled dosing interval.
∀
A pre-dose concentration is >5% of the Cmax value of that subject.
∀
Missing samples/concentration data at important phases of PK disposition curve.
The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS) who 
provide at least one primary or secondary PK parameter that was not excluded according to 
the description above. Thus, a subject will be included in the PKS, even if he contributes only 
one PK parameter value for one period to the statistical assessment. Point estimates of 
bioavailability, the ratios of the gMeans (test/ reference) for the primary and secondary
endpoints (see Sections 5.5.1.1 and 5.5.1.2), and their two-sided 90% confidence intervals 
(CIs) will be provided.
To this end, the PK endpoints will be log transformed (natural logarithm) prior to fitting the 
ANOVA model (see 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.
7.3.2
Secondary analyses
Single rising dose parts under fasting and fed conditions
The secondary parameters (see Section 5.5.1) will be calculated according to the BI Standard 
Operating Procedure (SOP) ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-472]. Analyses will be performed for 
BI 705564.
Plasma and urine concentration data and parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses, if they are not flagged for exclusion due to a 
protocol violation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.


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For more information on relevant protocol violations and the definition of the PKS, see
Section 7.3.1. Excluded subjects will be listed with their individual plasma concentrations. 
Individual pharmacokinetic parameters, however, will not be included in descriptive statistics 
for plasma concentrations, pharmacokinetic parameters or other statistical assessment.
Assessment of dose proportionality
Dose proportionality will be assessed using the secondary pharmacokinetic endpoints as 
specified in Section 5.5.1.2. Two separate analyses will be performed, one for the doses 
under fasting conditions, and one for the doses under fed conditions.
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.
ij
i
ij
ε
)
X
exp(
)
exp(Y
∋
(
(∋
)
∗
+
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.
Together with
)
exp(+
)
+∋
and
)
exp(
ε
ij
ij
,
)
∋
, taking natural logarithms converts this model 
to a linear form as follows:
ij
i
ij
ε
X
β
α
Y
−
(
−
)
where
ij
Y
logarithm of the pharmacokinetic endpoint for subject j at dose level i; j 
= 1, 2, …, N;
+ 
intercept parameter;
β
slope parameter;
i
X
logarithm of dose i;
ij
ε
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.
 


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Graphical displays: To support the analyses of dose proportionality, graphical representations 
of the data might be created. These might include (but are not limited to) individual time-
courses of trough plasma concentrations and the gMean plasma concentration time profiles.
Food effect part
The secondary parameters (see Section 5.5.1) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ [001-MCS-36-472] and will statistically be assessed using the same 
methods as described for the primary endpoints.
 
 
 
 
 
 
 
 
 
 
 
7.3.4
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (i.e., all 
subjects who received at least one dose of study drug), will be included in the safety analysis. 
Safety analyses will be descriptive in nature and will be based on BI standards. No hypothesis 
testing is planned.


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The analyses will be done by ‘treatment at onset’.
Treatments will be compared in a descriptive way.
In the single rising dose parts, 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 and 
regardless of whether they participated in the single rising dose part under fed or under 
fasting conditions; the active treatment groups will be compared to the placebo group in a 
descriptive way. To explore potential differences between placebo subjects under fasting and 
under fed conditions, these two subgroups will be compared descriptively.
In all (single rising dose – fasting and fed - and food effect) parts, tabulations of 
frequencies/proportions will be used for the evaluation of categorical (qualitative) data, and 
tabulations of descriptive statistics will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
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. These assignments including the corresponding time 
intervals will be defined in detail in the TSAP. Please note that AEs occurring after the last 
per protocol contact but entered before database lock will be reported to drug safety only and 
will not be captured in the trial database.
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.
For the single rising dose parts (under fasting and fed conditions) of the study, 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 triple
ECG measurements prior to drug administration. The derivation of the quantitative and 
qualitative ECG endpoints and their analyses will be described in the TSAP.


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7.3.5
Interim analyses
Single rising dose parts under fasting and fed conditions
Preliminary safety analysis
No formal interim safety analysis is planned. However, if safety reasons require a preliminary
safety analysis of ECG data, a part of the staff of the ECG laboratory may be unblinded. This
part of the staff is strictly separated from the other part of the staff, which is involved with
interval measurements and assessments of single ECGs (they keep blinded).
Preliminary PK analyses
A preliminary analysis of PK parameters (Cmax and AUC0-24 of BI 705564) provided as 
individual values and gMeans at least of the first cohort per dose level, will be performed for 
each dose group before proceeding to the next higher level. 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 are available.
In contrast to the final PK 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 results will be distributed to the investigator and the trial team.
Depending on the results of available preliminary PK analyses, the tolerability and safety of
the compound, and changes of dosing schedule (e.g. additional intermediate doses),
additional PK preliminary analysis may be performed based on the request of the Trial 
Clinical Monitor, the investigator, or Trial Clinical Pharmacokineticist. No formal 
preliminary PK/PD report will be written.
No inferential statistical interim 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.
Food effect part
Preliminary PK analyses
A preliminary analysis of PK parameters (Cmax and AUC0-24 of BI 705564), provided as 
individual values and gMeans, will be performed before proceeding to the next higher level. 
Data from at least 6 subjects are needed to be available before proceeding to the next higher 
level.
In contrast to the final PK 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.


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The preliminary results will be distributed to the investigator and the trial team.
No formal preliminary PK/PD report will be written.
Note: Due to global amendment No 4, only one dose level (10 mg) is given in the food effect 
part. Therefore, proceeding to the next higher level in the food effect part is not applicable.
7.3.6
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 705564 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 (see Section 7.3.1) will be reported with their 
individual plasma (single rising dose parts under fasting and fed conditions, and food effect
part) and urine (single rising dose parts, only) concentrations and individual pharmacokinetic 
parameters; however, they will not be included in descriptive statistics for plasma (single 
rising dose parts under fasting and fed conditions and food effect part) and urine (single 
rising dose parts, only) concentrations or 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, 
(i.e., to the same number of decimal places provided in the bioanalytical report).
If a pre-dose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidance. The individual pharmacokinetic parameters of such a subject will be calculated and 
listed separately. If a pre-dose concentration is above BLQ, but less than or equal to 5% of 
the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
 
 
 
 


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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/urine 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 pre-dose values).
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
[001-MCS-36-472].
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.5
RANDOMISATION
Single rising dose parts under fasting and fed conditions
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 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.
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 (see
Section 3.3.5).


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Food effect part
Subjects will be randomised to one of the two treatment sequences in a 1:1 ratio. The block 
size will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, 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 (see 
Section 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
Single rising dose part under fasting conditions
It is planned to include a total of 48 subjects in this part of the trial. 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].
Single rising dose part under fed conditions
It is planned to include a total of 32 subjects in this part of the trial. 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].
Food effect
It is planned to enter a total of 12 subjects in this part of the trial. The planned sample size is 
not based on a power calculation but is judged to be adequate to attain reliable results and to 
fulfil the objectives and requirements of this exploratory trial.
With a sample size of 12 subjects, the following precision of the ratio of gMeans (test/
reference) can be expected. Precision is defined as the ratio of upper to lower confidence 
interval limit. Note that the precision is independent of the actual ratio of gMeans.
For this trial, no information on intra-subject variability is available from previous trials. 
Therefore, Table 7.6: 1 provides an overview on the achievable precision for estimating the 
ratio of gMeans (test/ reference) for three different gCV. For illustrative purposes, the
expected 90% confidence intervals with 95% coverage probability are displayed for different
values of gMeans ratios T/R in the two-period two-sequence crossover design.


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Table 7.6: 1
Precision that can be expected with 95% tolerance probability and 
illustrative two-sided 90% confidence intervals around the ratios of 
gMeans (T/R) for different gCVs in a 2x2 crossover trial in one dose 
group (N=12).
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
20
1.22
80
65.61
97.54
20
1.22
100
82.01
121.93
20
1.22
125
102.52
152.41
20
1.22
150
123.02
182.89
20
1.22
200
164.03
243.86
25
1.28
80
62.52
102.36
25
1.28
100
78.15
127.95
25
1.28
125
97.69
159.94
25
1.28
150
117.23
191.93
25
1.28
200
156.31
255.91
30
1.34
80
59.63
107.33
30
1.34
100
74.54
134.16
30
1.34
125
93.17
167.71
30
1.34
150
111.80
201.25
30
1.34
200
149.07
268.33
*Ratio of gMeans (test/reference) for a PK endpoint is defined by exp(#T)/exp(#R).
The calculation was performed as described by Julious [R11-5230] using R Version 3.2.2.


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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 personal trial-related data will be used by BI 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 medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by BI, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.


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The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, see
Section 4.1.8.
 
 
 
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
Data directly entered into 
(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 
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 (whichever 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 regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
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
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ICH E14: the clinical evaluation of QT/QTc interval prolongation and 
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R17-0403
Ibrutinib (Imbruvica) (Pharmacyclics): pharmacology/toxicology NDA 
review and evaluation, application number: 205552Orig1s000. 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205552Orig1s0
00PharmR.pdf (access date: 3 February 2017) ; Center for Drug 
Evaluation and Research.; 2013.


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R17-0404
Smith CE, Berglof A. X-linked agammaglobulinemia (synonyms: Bruton's
agammaglobulinemia, XLA).
https://www.ncbi.nlm.nih.gov/books/NBK1453/?report=printable (access 
date: 1 February 2017) ; In: Pagon RA, Adam MP, Ardinger HH, Wallace 
SE, Amemiya A, Bean LJH, et al, editors. GeneReviews [Online]. Seattle: 
University of Washington; 2016.
R17-0406
The human protein atlas: BTK.
http://www.proteinatlas.org/ENSG00000010671-BTK/tissue (access date: 
3 February 2017); 2017.
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.
 
 
 
 
 
 
 
 
 
 
 


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10.
APPENDICES
10.1
RECONSTITUTION INSTRUCTION(S)
10.1.1
Drug Supplies Overview
a) BI 705564 Powder for Oral Solution 20 mg (target solution concentration BI 705564: 
0.25 mg/mL), provided in 100 mL amber glass bottles with plastic screw cap.
b) Solvent for Oral Solution 80 mL (HP-ß-Cyclodextrin 100 mg/mL) provided in 
100 mL glass vials with flip-tear seal.
c) Empty appropriately labeled amber glass bottle, 100 mL with plastic screw-cap.
10.1.2
Required Equipment and Dosing aids - Overview
a) Mechanical (orbital) shaker for bottles (e.g. Bühler Typ KL2).
b) Dosing dispensers/syringes and bottle adapters.
For the withdrawal of respective volume aliquots from the final Oral Solution to be 
administered, amber BAXA/BAXTER ExactaMed Syringes should be used in a size 
as close as possible to the required dose volume. For this purpose, a range of syringe 
sizes from 1 mL up to 60 mL should be stocked at the trial site.
In order to ease the withdrawal of the oral solution from the glass bottles with the 
amber BAXA/BAXTER ExactaMed syringes, BAXA/BAXTER bottle adapters and 
dispenser tip caps should be used and stocked in the trial site, preferably 
BAXA/BAXTER Press-In Bottle Adaptors (PIBATM) or BAXA/BAXTER Adapta
Cap Bottle Adapters (E-28 mm)
Possible BAXA Med Oral amber dispensers:
∀
BAXA/BAXTER ExactaMed amber oral dispenser 1 mL
∀
BAXA/BAXTER ExactaMed amber oral dispenser 3 mL
∀
BAXA/BAXTER ExactaMed amber oral dispenser 5 mL
∀
BAXA/BAXTER ExactaMed amber oral dispenser 10 mL
∀
BAXA/BAXTER ExactaMed amber oral dispenser 20 mL
∀
BAXA/BAXTER ExactaMed amber oral dispenser 35 mL
∀
BAXA/BAXTER ExactaMed amber oral dispenser 60 mL
Only CE certified syringes are to be used!


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
13 APR 2017
EudraCT number
2017-000324-98
BI Trial number
1408-0001
BI Investigational Product(s)
BI 705564
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising oral doses of 
BI 705564 (single-blind, partially randomised, 
placebo-controlled parallel group design) and 
food effect on a tablet formulation of BI 705564 
(open-label, randomised, single-dose, two-period, 
two-sequence crossover design) in healthy male 
subjects
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
-
Flow Chart
-
5.5.2.3
-
5.6.2
-
6.1
Description of change
-
Addition of explanatory footnote to “Day -3 
to -1” safety laboratory in food effect part 
[Change in Flow Chart (2)].
-
Correction of time window of “Day 6” 
biomarker blood withdrawal [Changes in 
Flow Chart (1) and in Section 6.1].
-
Algorithm to stop further biomarker sampling 
in a dose group beyond 48 h was changed 
from “dose group” to “cohort” [Changes in 


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footnote 14 of Flow Chart (1) and Section 
5.6.2]
-
Tween is added to urine containers for urine 
sampling for pharmacokinetic analyses 
[Change in Section 5.5.2.3).
Rationale for change
-
Explanatory footnote to “Day -3 to -1” safety 
laboratory in food effect part was added to 
align procedures with those of the single 
rising dose part.
-
Time window of “Day 6” biomarker blood 
withdrawal was corrected for logistical 
reasons.
-
Change from dose group to cohort (in the 
algorithm to stop further biomarker sampling) 
due to logistical reasons.
-
Tween is added to prevent adsorption of drug 
to the wall of the urine collection containers.


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Number of global amendment
2
Date of CTP revision
03 MAY 2017
EudraCT number
2017-000324-98
BI Trial number
1408-0001
BI Investigational Product(s)
BI 705564
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising oral doses of 
BI 705564 (single-blind, partially randomised, 
placebo-controlled parallel group design) and 
food effect on a tablet formulation of BI 705564 
(open-label, randomised, single-dose, two-period, 
two-sequence crossover design) in healthy male 
subjects
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
5.5.2.3
Description of change
10 mL instead of 40 mL of 10% Tween 20 
solution will be added to each 2 liter collection 
container prior to the start of urine sampling
Rationale for change
Change needed due to analytical issues during the 
course of method validation at 


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Number of global amendment
3
Date of CTP revision
08 AUG 2017
EudraCT number
2017-000324-98
BI Trial number
1408-0001
BI Investigational Product(s)
BI 705564
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising oral doses of 
BI 705564 (single-blind, partially randomised, 
placebo-controlled parallel group design) and 
food effect on a tablet formulation of BI 705564 
(open-label, randomised, single-dose, two-period, 
two-sequence crossover design) in healthy male 
subjects
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
-
Clinical Trial Protocol (CTP) Synopsis
-
Flow Chart (Single Rising Dose [SRD] Part)
-
Section 2.1.4
-
Section 2.1.5
-
Section 3.1
Description of change
-
Statements that food effect part will be 
performed after the single rising dose part 
were deleted (in CTP Synopsis, Section 2.1.4, 
Section 2.1.5, and Section 3.1)
 
Rationale for change
-
For logistical reasons, the lower dose group of 
the food effect part (10 mg) will be pulled 
forward, without having terminated the SRD 
part. This is possible, as the necessary safety 
window, defined in Section 2.1.4 of this CTP, 


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has been explored in the SRD part of this 
study.
 
 
 
 
 
 
 


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Number of global amendment
4
Date of CTP revision
11 SEP 2017
EudraCT number
2017-000324-98
BI Trial number
1408-0001
BI Investigational Product(s)
BI 705564
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising oral doses of 
BI 705564 (single-blind, partially randomised, 
placebo-controlled parallel group design) and 
food effect on a tablet formulation of BI 705564 
(open-label, randomised, single-dose, two-period, 
two-sequence crossover design) in healthy male 
subjects
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
-
Synopsis
-
Flow Chart
-
Table of contents
-
Sections 1.2.1, 1.2.2, 1.2.3.2, 1.2.3.6, 1.2.4.1, 
and 1.2.5
-
Sections 2.1, 2.1.2, 2.1.3, 2.1.4, 2.1.5, 2.2, 
2.3.2.1, 2.3.2.5, and 2.3.2.7
-
Sections 3, 3.1, 3.2, 3.3, 3.3.4.2, and 3.3.5
-
Sections 4, 4.1.1, 4.1.2, 4.1.4, 4.1.5.1, 4.1.5.2, 
and 4.2.2.2
-
Sections 5.2.1, 5.2.2.2, 5.2.3, 5.2.4.1, 5.5.1.1, 
5.5.1.2, 5.5.1.3, 5.5.2.2, 5.5.2.3, 5.5.2.4, 5.6.1, 
and 5.6.2
-
Sections 6.1 and 6.2.2
-
Sections 7.1.1, 7.1.2, 7.1.3, 7.2, 7.3.1, 7.3.2, 
7.3.3, 7.3.4, 7.3.5, 7.3.6, 7.3.7, 7.5, and 7.6


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-
Section 9
Description of change
-
Single rising dose part under fed conditions
added, with single doses of 20 mg, 40 mg, 
80 mg, and 160 mg BI 705564 or placebo, 
given following a high-fat, high-calorie 
breakfast. Design and study procedures in the 
single rising dose part under fed conditions 
are identical to the pre-existing single rising 
dose part under fasting conditions with the 
following exceptions:
o
Addition of high-fat, high-calorie 
breakfast prior to administration of 
BI 705564
o
Modification of sampling for blood for 
 
o
No stability samples will be taken
o
No samples for metabolite 
identification will be taken.
o
Safety laboratory at time point +4 h is 
not at fasting conditions (due to the 
breakfast taken before administration 
of BI 705564)
-
Up to 2 additional dose groups may be 
investigated in the single rising dose part 
under fed conditions.
-
No additional dose groups may be 
investigated in the single rising dose part 
under fasting conditions.
-
Number of subjects changed: Total entered 
number increased from 88 to 92; number in 
single rising dose part under fasting condition 
reduced from 64 to 48; number in food effect 
part reduced from 24 to 12; number of 
subjects in single rising dose part under fed 
conditions added as 32 subjects. Additional 
subjects can be included in single rising dose
part under fed conditions (up to 16 additional 
subjects) in order to test up to 2 additional 
doses, provided the planned and approved 
highest dose will not be exceeded, i.e. the 
total number of subjects in the trial (all three 
parts together) may be higher than 92 but not 
higher than 108 subjects.


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-
Test product BI 705564 as 100 mg tablet and 
corresponding placebo tablet are not 
applicable to the amended single rising dose 
part under fasting conditions.
-
In the single rising dose part under fasting
conditions, doses 120 mg and 160 mg are not 
given (dose groups 7 and 8 in the single rising 
dose part under fasting conditions are 
deleted).
-
In the food effect part, only one dose (10 mg) 
is tested. The dose of 40 mg is not tested in 
the food effect part. 
-
Flow Chart 3 added.
-
Minor editorial changes.
-
Update of IB reference to version 2.
-
Deletion of statement that doses will be 
increased with decreasing escalation factors.
-
Change of wording of primary objective in 
order to include both the single rising dose 
part under fasting and the part under fed 
conditions.
-
Change of risk minimization wording to 
explain that in the single rising dose part 
under fed conditions, escalation factors of 2 
are chosen.
-
Addition of Section 7.3.3 to explain statistical 
comparison of PK data from single rising dose 
part fed and single rising dose part fasting.
-
Determination of sample size for single rising 
dose part under fasting conditions and for 
food effect part corrected to reflect the 
changes in subject numbers in the trial parts; 
determination of sample size for single rising 
dose part under fed conditions added.
-
 
-
Drug test “M-10/14-PDT test” added.
Rationale for change
 
 
 
 


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-
Doses of 120 mg and 160 mg in the single 
rising dose part under fasting conditions are 
not justified, as no further increase of 
systemic plasma exposure parameters of 
BI 705564 is expected.
-
Additional dose groups are not applicable to 
the single rising dose part under fasting
conditions, as this was not done in this part, 
and the single rising dose part under fasting
conditions is completed.
-
The 40 mg food effect part is neither covered 
by available safety data from the single rising 
dose part under fasting conditions, nor is it 
required, due to addition of a single rising 
dose part under fed conditions.
 
 
 
 
-
New drug test added, because name of drug 
test has been changed (however, test remains 
identical; only change of name).


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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c22177016-01
BI Trial No.:
1408.1
Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of
single rising oral doses of BI 705564 (single-blind, partially
randomised, placebo-controlled parallel group design) and food 
effect on a tablet formulation of BI 705564 (open-label, 
randomised, single-dose, two-period, two-sequence crossover
design) in healthy male subjects
Including Protocol Amendment 1, 2, 3 and 4 [c13141675-05]
Investigational
Product:
BI 705564
Responsible trial 
statisticians:
Phone: 
Fax: 
Phone: 
Fax: 
Date of statistical 
analysis plan:
16 MAR 2018 SIGNED 
Version:
Final
Page 1 of 37
Proprietary confidential information
! 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


Boehringer Ingelheim
TSAP for BI Trial No: 1408.1
Page 2 of 37
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
...............................................................................10
...............................................................................11
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................16
......................................................................................................17
6.5
POOLING OF CENTRES .................................................................................17
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................17
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................18
7.
PLANNED ANALYSIS......................................................................................22
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........23
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................24
7.3
TREATMENT COMPLIANCE........................................................................24
7.4
PRIMARY ENDPOINTS...................................................................................24
7.5
SECONDARY ENDPOINTS.............................................................................26
7.5.1
Key secondary endpoints....................................................................................26
7.5.2
Secondary endpoints...........................................................................................26
................................................................................28
7.7
EXTENT OF EXPOSURE.................................................................................28
7.8
SAFETY ANALYSIS..........................................................................................28
7.8.1
Adverse events.....................................................................................................28
7.8.2
Laboratory data ..................................................................................................30
7.8.3
Vital signs.............................................................................................................30
7.8.4
ECG......................................................................................................................30
7.8.5
Others...................................................................................................................32
8.
REFERENCES....................................................................................................33
........................34
........................34


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...35
...36
10.
HISTORY TABLE..............................................................................................37


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR (SRD part under fasting and fed 
conditions)........................................................................................................12
Table 6.1: 2
Labels for treatments for use in the CTR (FE part)..........................................13
Table 6.2: 1
Important protocol violations...........................................................................15
Table 6.3: 1
Subject sets analysed........................................................................................17
Table 6.7: 1
Time schedule of 12-lead ECG recordings (SRD part)....................................20
Table 10: 1
History table .....................................................................................................37


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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-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BB
Bioavailability/Bioequivalence, inter-individual comparison
BI
Boehringer Ingelheim
BWC
Bioavailability/Bioequivalence, Within-Subject Design, Time-Controlled
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic Coefficient of Variation
DB
Dose Proportionality, Between-Subject Design
DBLM
Database Lock Meeting
ECG
Electrocardiogram
ECGPCS
ECG Pharmacokinetic Concentration Set
FE
Food Effect
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
ICH
International Conference On Harmonisation
LLT
Lower Level Term
Max
Maximum


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Term
Definition / description
MedDRA
Medical Dictionary For Regulatory Activities
Min
Minimum
O*C
Oracle Clinical
PK
Pharmacokinetic(s)
PKS
PK parameter analysis set
PT
Preferred Term
PV
Protocol Violation
R
Reference Treatment
RAGe
Report Appendix Generator system
REP
Residual Effect Period
RPM
Report Planning Meeting
SAS®
Statistical Analysis System
SD
Standard Deviation
SOC
System Organ Class
SRD
Single rising dose
T
Test treatment
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
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 trial database within the Oracle ClinicalTM (O*C) system.
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 5.2.1 of the CTP:
Single rising dose parts under fasting and fed conditions
Primary endpoint to assess safety and tolerability of BI 705564 is the number [N (%)] of
subjects with drug-related adverse events (adverse reactions).
Section 5.5.1.1 of the CTP:
Food effect part
The following primary endpoints will be determined for BI 705564:
∀
AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)
∀
Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY 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 5.5.1.2 of the CTP: 
Single rising dose parts under fasting and fed conditions
The following secondary endpoints will be determined for BI 705564:
∀
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity)
∀
Cmax
Food effect part
The following secondary endpoints will be determined for BI 705564:
∀
AUC0-∞


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Safety:
Further criteria of interest:
∀
AEs (including clinically relevant findings from the physical examination)
∀
Safety laboratory tests
∀
12-lead ECG
∀
Continuous ECG monitoring (SRD parts under fasting and fed conditions only)
∀
Vital signs (blood pressure, pulse rate) 
For detailed information (formula) please refer to Section 7.8.
 
 
 
 
 
 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
It is planned that in total 92 volunteers participate in this study.
48 healthy male subjects will enter the SRD part under fasting conditions (8 per dose group, 6 
on active and 2 on placebo), 12 healthy males will enter the FE part (one dose group, all on 
active) and 32 healthy males will enter the SRD part under fed conditions (8 per dose group, 
6 on active and 2 on placebo) of the study.
It is possible that the same subject participate in the SRD part as well as in the FE part. If this 
is the case, the information from the prior participation will be used for total baseline 
characteristics. Subjects participating in both parts will be identified in the RPM/DBLM.
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 under fasting and fed 
conditions)
Treatment
Short label
P/Q
Placebo PfOS / tablet, qd, fasted
Placebo fast
V
Placebo, tablet, qd, fed
Placebo fed
P/Q/V*
Placebo PfOS / tablet fasted or fed
Placebo total
A
BI 705564, 0.25 mg/mL solution, 1 mg, po, qd
BI 1mg fast
B
BI 705564, 0.25 mg/mL solution, 3 mg, po, qd
BI 3mg fast
C
BI 705564, 10 mg tablet, fasted qd
BI 10mg fast
D
BI 705564, 2*10 mg tablet, fasted qd
BI 20mg fast
E
BI 705564, 4*10 mg tablet, fasted qd
BI 40mg fast
F
BI 705564, 8*10 mg tablet, fasted qd
BI 80mg fast
G
BI 705564, 2* 10 mg tablet, fed qd
BI 20mg fed
H
BI 705564, 4* 10 mg tablet, fed qd
BI 40mg fed
L
BI 705564, 8* 10 mg tablet, fed qd
BI 80mg fed
M
BI 705564, 6*10mg + 100mg tablets, fed qd
BI 160mg fed
*: The placebo total group in the safety evaluation will consist of all placebo treated subjects,
regardless of the dose group in which they were treated and regardless of whether they 
participated in the single rising dose part under fed or under fasting conditions.


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Table 6.1: 2
Labels for treatments for use in the CTR (FE part) 
Treatment
Short label
R 
BI 705564, 10 mg tablet, fasted qd
BI 10mg fast
S 
BI 705564, 10 mg tablet, fed qd
BI 10mg fed
The following separate study phases will be defined for the analyses of AEs:
∀
Screening (ranging from 0:00 h on day of informed consent until first administration 
time of study drug)
∀
On treatment
(SRD parts under fasting and fed conditions: separately for each treatment, ranging 
from administration time of study drug until 0:00 h on the day after  trial termination 
date;
FE part: separately for each treatment, ranging from administration time of study drug 
until administration time of next study drug dose or 0:00 h on the day after  trial 
termination date)
Please note that all AEs reported between start of trial drug administration and the last per-
protocol contact will be considered on treatment (i.e. no follow-up period is considered in this 
trial).
Displays of AEs will be presented separately for the treatments described in Table 6.1: 1 and 
Table 6.1: 2 above, including “Placebo total”.
Two types of AE displays will be provided in the report:
A) Section 15.3 (separately for combined SRD parts and FE part) and Appendix 16.1.13.1.8 
(for ClinicalTrials.gov (separately for combined SRD parts and FE part) and EudraCT 
(all parts combined)) 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 on treatment phases included in this analysis ("Total on treatment")
(Section 15.3 only)
∀
SRD parts: a total over all BI-treated phases under fasting conditions (“BI fast total”)
∀
SRD parts: a total over all BI treated phases under fed conditions (“BI fed total”)
∀
SRD parts: a total over all BI-treated phases (“BI total”)
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of 
the CTR displays:
∀
Screening 


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∀
On treatment (labelled with the name of the study treatment (short label))
In Section 16.1.13.1.8 AE tables (separately for combined SRD parts and FE part), the 
following totals will be provided in addition:
∀
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, including “Placebo total”.
For detailed information on the handling of the treatments in the O*C views refer to 
Technical TSAP ADS (analysis data set) plan. 
6.2
IMPORTANT PROTOCOL VIOLATIONS
Data discrepancies and deviations from the CTP will be identified for all randomised 
subjects.
Listings of protocol deviations and of unresolved discrepancies will be provided to be 
discussed at the combined report planning and database lock meeting (RPM/DBLM), e.g. 
deviations in drug administration, in blood sampling etc. At this meeting, it will be decided 
whether the discrepant data can be used as they are or whether the data have to be corrected
in the clinical database.
Each protocol deviation must be assessed to determine whether it is an important protocol 
violation. A protocol violation (PV) is important if it affects the rights or safety of the study 
subjects or if it can potentially influence the primary outcome measure(s) for the respective 
subjects in a way that is neither negligible nor in accordance with the study objectives. This 
last category of important PV forms the basis for the decision of whether a subject does or 
does not belong to an analysis set. PVs that do not influence the subject's rights and safety or 
the evaluability of the subjects for the main study objectives are called non-important PVs.
These are only considered when checking the trial quality in general.
If any important PVs are identified, they are to be summarized into categories and will be 
captured in the RPM/DBLM minutes via an accompanying Excel spreadsheet [001-MCS-50-
413_RD-02] (2). The following table contains the categories which are considered to be 
important protocol violations in this trial. If the data show other important PVs, this table will 
be supplemented accordingly by the time of the RPM/DBLM.


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Table 6.2: 1
Important protocol violations
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 primary or secondary data
F
Incorrect timing1
F1
Certain violations of time schedule used to measure primary or secondary data
G
Other trial specific important violations
G1
Incorrect intake of meal before administration of treatment
G2
PVs affecting safety and rights
1 Time deviations will only be flagged as important PV, when leading to exclusion of the entire subject from an analysis set
Source: ‘Protocol Violation Handling Definitions’ [001-MCS-50-413_RD-01] (3)


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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 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 7.3.1 of the CTP: Plasma concentration data and parameters of a subject will be 
included in the statistical pharmacokinetic (PK) analyses, if they are not flagged for 
exclusion due to a protocol violation relevant to the evaluation of PK (to be decided no later 
than in the Report Planning Meeting) or due to PK non-evaluability (as revealed during data 
analysis, based on the criteria specified below). Exclusion of a subject's data will be 
documented in the CTR.
Relevant protocol violations may be
∀
Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to.
∀
Incorrect dose of trial medication taken.
∀
Use of restricted medications.
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if
for example
∀
The subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (median tmax is to be determined excluding the subjects 
experiencing emesis).
∀
The subject experiences emesis at any time during the labelled dosing interval.
∀
A pre-dose concentration is >5% of the Cmax value of that subject.
∀
Missing samples/concentration data at important phases of PK disposition curve.
∀
PK parameter analysis set (PKS):
The PK parameter analysis set (PKS) includes all subjects from the TS receiving 
BI 705564 who provide at least one primary or secondary PK parameter (AUC or Cmax) 
that was not excluded according to the description above.
Thus, a subject will be included in the PKS, even if he contributes only one PK 
parameter value for one period to the statistical assessment (FE part).


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It is used for assessment of dose proportionality (SRD parts under fasting and fed 
conditions) and for assessment of the food effect (FE part and each dose level that was 
tested under both fasting and fed conditions).
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.
 
 
 
Table 6.3: 1
Subject sets analysed
Analysis set
Class of endpoint
TS
PKS
ECGPCS
Primary and further safety endpoints (incl. ECG) 
X
ECG endpoints and plasma concentrations used in 
exposure-response analysis
X
Primary and Secondary PK endpoints 
X
Demographic/baseline endpoints
X
Important PVs/Disposition
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.


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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 per single ECG will be computed with the reduced (1, 2 or 3) number of cardiac cycles.
If replicate ECG recordings (out of generally three) 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. In case of a missing qualitative ECG finding 
at baseline, a finding observed on treatment will be categorized as “new onset”.
For placebo subjects the missing plasma concentration values will be replaced by 0 for the 
exposure response analysis.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For laboratory parameters, the baseline value is defined as the last measurement before first 
trial drug administration in the first treatment period. 
For vital signs and PK parameters, the baseline value is defined as the last measurement 
before trial drug administration in each treatment period.
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 CTP Flow Chart 1 and CTP Flow Chart 3 for the single rising dose part under 
fasting and fed conditions, respectively, and CTP Flow Chart 2 for the food effect part.
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 and biomarkers).


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Starting from 72 h post administration a deviation from the scheduled time for PK and
biomarker sampling of ±70 min is acceptable. The biomarker samples planned time Day 6
(single rising dose parts) may be taken on day 5 (up to 26 h earlier).
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests
will be ± 15 minutes for the first 4 hours after trial drug administration and ± 30 minutes
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.
For the SRD parts under fasting and fed conditions, 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:


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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
-02:00
Baseline
triplicate ECG
00:30
On treatment
first of three replicate 
ECG
01:00
first of three replicate 
ECG
01:30
first of three replicate 
ECG
02:00
first of three replicate 
ECG
03:00
first of three replicate 
ECG
04:00
first of three replicate 
ECG
06:00
first of three replicate 
ECG
08:00
first of three replicate 
ECG
12:00
first of three replicate 
ECG
2
24:00
first of three replicate 
ECG
3
48:00
first of three replicate 
ECG
4
72:00
first of three replicate 
ECG
4
11 to 15
End of trial 
examination
NA
Triple ECGs will be recorded (three single ECGs within 180 sec) at all time points in Visit 2. 
At Visits 1 and 4, single ECGs will be recorded.
Section 5.2.4.1 of the CTP: With the exception of the first triple ECG (used as baseline 
before the first drug administration), only the first of the three replicate ECGs at a single 
assessment time will be evaluated.
The baseline value of an ECG variable is defined as the mean of the 3 triplicate ECG 
measurements prior to drug administration.
For the exposure response analyses, pairs of ECG measurements and corresponding plasma 
concentrations will be built using the same time points, e.g. HR change from baseline and 


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plasma sample taken at planned time 0:30 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 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 time deviation between ECG recording and PK blood sampling 
can be bigger.
For the FE part, no centralised evaluation of all 12-lead ECG recordings is planned.


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7.
PLANNED ANALYSIS
The combined SRD parts and FE part will be evaluated separately.
In the combined SRD parts, the placebo group under fasting (labelled “Placebo fast”) and the 
placebo group under fed conditions (labelled “Placebo fed”) will be compared, as well as the 
combined placebo group (labelled “Placebo total”) to all active treatment groups.
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 Sections 7.4 and 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 BI and 
will be presented in Section 15.6 of the CTR.
Descriptive data analysis of PD endpoints will be performed by department Translational 
Medicine and Clin. Pharmacology at BI and will be presented in Section 15.7 of the CTR.
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.
In the combined SRD parts, the individual values of all subjects will be listed, sorted by 
treatment group, subject number, and visit. 
In the FE part, the individual values of all subjects will be listed, sorted by treatment 
sequence, subject number, visit and actual treatment (if appropriate).
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations as well as for all PK parameters, the following descriptive 
statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation


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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/sequence. 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 analysis data set (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.
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 (combined SRD parts). 
The data of the FE part will be summarised by treatment sequence and in total.


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For public disclosure, both trial parts will be combined. In case that a subject participate in 
both trial parts, the information from the prior participation will be used for total baseline 
characteristics.
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
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 (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
Safety evaluation – combined SRD parts under fasting and fed conditions
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 705564.
Investigation of relative bioavailability (food effect evaluation) – FE part
Relative bioavailability is to be determined on the basis of the primary and secondary PK 
parameters (AUC0-tz, Cmax and AUC 0-∞). Those parameters will be ln-transformed (natural 
logarithm) prior to fitting the model.
Primary analysis
Section 7.1.3 of the CTP: The statistical model used for the analysis of primary (AUC0-tz
and Cmax) and […] secondary (AUC 0-∞) endpoints 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 


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effect ‘subjects within sequences’ will be considered as random, whereas the other effects 
will be considered as fixed. The model is described by the following equation:
yijkm = μ+ ζi + sim + πj + τk + eijkm, where
yijkm = logarithm of response (AUC0-tz, Cmax, AUC 0-∞) measured on subject m in 
sequence i receiving treatment k in period j,
μ
the overall mean,
ζi
the ith sequence effect, i = 1, 2
sim 
the effect associated with the mth subject in the ith sequence, m =1, 2, ..., ni
πj
the jth period effect, j = 1, 2
τk
the kth treatment effect, k = 1, 2
eijkm
the random error associated with the mthsubject in sequence i who received 
treatment k in period j.
The difference between the expected means for test treatments (tablets under fed conditions,
T) and reference treatment (tablets under fasting conditions, R) ln(T)-ln(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.
The analysis will be accomplished by using the XPKISTAT macro, based on PKS (design 
BWC).
 
 
 


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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 parts under fasting and fed conditions
Section 7.3.2 of the CTP: Two separate analyses will be performed, one for the doses under 
fasting conditions, and one for the doses under fed conditions.
Dose proportionality of the PK endpoints AUC 0-∞and Cmax in plasma of BI 705564 will be
explored using the power model that describes the functional relationship between dose and 
PK endpoints. The basic model consists of a regression model applied to ln-transformed data. 
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 pharmacokinetic endpoint for subject j at dose level i; 
j = 1, 2, …, N, 
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 7.3.2 of the CTP:  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 ln-transformed pharmacokinetic endpoint and the ln-
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. 
This analysis will be accomplished by using the XPKISTAT macro (design DB), based on 
the PKS.


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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).
A joint analysis (fasting and fed conditions) of dose proportionality will not be performed.
Investigation of relative bioavailability (food effect evaluation) – FE part
Refer to TSAP Section 7.4 for a description of the analysis of food effect for the secondary 
endpoint AUC0-∞.
 
 
 
 
 
 


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Safety
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 705564.
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 (combined SRD 
parts) or by actual treatment (FE part).
In the combined SRD parts, the placebo group under fasting (labelled “Placebo fast”) and the 
placebo group under fed conditions (labelled “Placebo fed”) will be analysed separately and 
compared, as well as the combined placebo group (labelled “Placebo total”) to all active 
treatment groups.
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.


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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). 
For analysis multiple AE occurrence data on the CRF 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)
∀
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 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 AESI in this trial:
∀
Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters:
o
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
o
Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. 
Section 5.2.2.2 of the CTP: The REP for BI 705564, when measurable drug levels or PD 
effects are still likely to be present after the last administration, is not known for this first-in-
human trial. Therefore, all AEs reported until the end of trial examination (last per protocol 
contact) will be considered on treatment […].
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 a Medical Quality Review
Meeting.
An overall summary of AEs (including AESIs) will be presented.
The frequency of subjects with AEs will be summarized by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with other 
significant AEs according to ICH E3 (10), for subjects with serious AEs, for subjects with 


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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 system organ class). 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 clinically 
relevant will be highlighted in the data listings.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator’s comments on the CRF or at the RPM/DBLM at the latest. It is the 
investigator's responsibility to decide whether a lab value is clinically significant abnormal or 
not. Standard or project-specific rules for flagging clinically significant values will not be 
applied in this study.
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate).
7.8.4
ECG
Continuous safety ECG monitoring (by investigator) – (SRD parts only)
Clinically relevant abnormal findings will be reported as adverse events.
No separate listing or analysis of continuous ECG monitoring will be prepared.


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12-lead ECG (SRD parts + FE part)
Abnormal findings 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 in the SRD parts:
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 
concentration is evaluated using an exposure response model.
This model will be evaluated separately for doses under fasting conditions and doses under 
fed conditions.
For the following analyses, all time points with available ECG endpoints and time-matched 
plasma concentrations of all dose groups 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.
As a first step, it is investigated if there is a potential delayed or accelerated (e.g. metabolites) 
effect of the drug on QTcF. A general visual impression is provided by overlaying time 
profiles of plasma concentrations and QTcF changes from baseline (#QTcF). All figures will 


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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 tables of the CTR).
The relationship between BI 705564 plasma concentrations and QTcF changes from baseline 
will be investigated in an exploratory manner using a random coefficient model approach to 
estimate the difference in means between BI 705564 and placebo in QTcF change from 
baseline and its 90% confidence interval at the geometric mean of the Cmax for each dose. 
Additionally, the estimated slope with its 90% confidence interval will be provided. The used 
random coefficient model is based on Garnett et al. 2016 (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, the BI 705564 plasma concentration against the response will be plotted as 
well as the (fixed effect) regression line, its 90% confidence interval and the geometric mean 
of Cmax for each dose. For each subject and each time point, subtract the mean value of all 
individual observed ΔQTc values from the placebo group for this time point from the 
individual observed ΔQTc value for this subject and time point. This results in estimates for 
“individual ΔΔQTc” values. These estimates will only be used for plotting purposes.
To check model assumptions, the conditional residuals will be plotted and presented in the 
statistical Appendix. In case of non-linearity or if there is evidence for a delayed effect, 
further models will be explored that better characterise the PK/ECG relationship 
(log(concentration), effect compartment, non-linear model 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 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 9.3 using all time 
points. A scatterplot of QTcF vs RR including the estimated 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 this plot.
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-50-413_RD-02: “Important Manual Protocol Violations Spreadsheet”, current 
version, IDEA for CON.
3.
001-MCS-50-413_RD-01: “Protocol Violation Handling Definitions”, current version, 
IDEA for CON.
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, Needleman K, Liu J, Brundage R, Wang Y; Operational characteristics of 
linear concentration-QT models for assessing QTc interval in the thorough QT and phase 
I clinical studies. Clin Pharmacol Ther 100 (2), 170 - 178 (2016)


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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
16-MAR-18
None
This is the final TSAP without any 
modification