Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: yes

Brief summary:
The primary objective of this trial is to investigate safety and tolerability of BI 705564 in healthy male subjects, following oral administration of multiple rising doses.

Secondary objectives are the exploration of the pharmacokinetics, including dose proportionality and investigation of linearity.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: SPT stands for skin prick test. arm 8: SPT stands for skin prick test.

Interventions: intervention 1: BI 705564 intervention 2: Placebo intervention 3: Midazolam
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Film-coated tablet intervention 3: Solution for injection

Protocol document:
Prot_002.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c18130121-05
EudraCT No.:
2017-003269-85
BI Trial No.:
1408-0002
BI Investigational
Product:
BI 705564
Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of 
multiple rising oral doses of BI 705564 (double-blind, randomised, 
placebo-controlled, parallel-group design) and evaluation of 
midazolam interaction (nested, open, fixed-sequence, intra-individual 
comparison) in healthy male subjects
Lay Title:
This study in healthy men tests how different doses of BI 705564 are 
taken up in the body and how well they are tolerated. The study also 
tests how BI 705564 affects the way the body breaks down 
midazolam.
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: 08 August 2018
Page 1 of 134
Proprietary confidential information
© 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 705564
Protocol date:
Trial number:
Revision date:
08 August 2018
18 September 2017
1408-0002
Title of trial:
Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple rising oral 
doses of BI 705564 (double-blind, randomised, placebo-controlled, parallel-group 
design) and evaluation of midazolam interaction (nested, open, fixed-sequence, intra-
individual comparison) in healthy male subjects
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
(1) To investigate safety, tolerability, pharmacokinetics and pharmacodynamics 
following multiple rising oral doses of BI 705564
(2) To investigate the effect of BI 705564 on the pharmacokinetics of midazolam 
given as oral microdose - in dose group (DG)s 2 to 5
Methodology:
(1) Double-blind, randomised (within dose group), placebo-controlled, parallel-group 
comparison
(2) Nested, open, fixed-sequence, intra-individual comparison - in DGs 2 to 5
No. of subjects: 
total entered:
60* (50 in DGs 1 to 5, and an additional 10 in DG 8)
each treatment:
10 per dose group; 8 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 number of subjects entered may 
exceed 50, but will not exceed 70 subjects entered.
Diagnosis:
(1) DGs 1 to 5: Not applicable
(2) DG 8,


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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:
08 August 2018
18 September 2017
1408-0002
Main criteria
for inclusion:
(1) DGs 1 to 5: Healthy male subjects, age of 18 to 50 years, body mass index (BMI) 
of 18.5 to 29.9 kg/m2
(2) DG 8, only
 
 
Test product (1):
BI 705564 film-coated tablet
Dose:
10 mg (DG 1), 20 mg (DG 2), 40 mg (DG 3), 60 mg (DG 5), 80 mg (DG 4)
 
 
Mode of admin.:
Oral with 240 mL of water after a standard continental breakfast
Test product (2)
(DGs 2 to 5):
Midazolam for injection used as oral solution
Dose:
75 µg q.d.
Mode of admin.:
Oral with 240 mL of water after a standard continental breakfast
Comparator product to 
test product (1):
Matching placebo
Dose:
Not applicable
Mode of admin.:
Oral with 240 mL of water after a standard continental breakfast
Duration of treatments: (1) DGs 1 to 5: BI 705564 or placebo: Day 1 (1 single dose) and Days 4 to 17 
(14 days q.d.)
(2) DGs 2 to 5: Midazolam: Day -1 and Day 17 (1 single dose, each)


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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:
08 August 2018
18 September 2017
1408-0002
Criteria for 
pharmacokinetics:
Secondary endpoints
(1) BI 705564
After the first dose:
AUCτ,1 and Cmax
After the last dose:
AUCτ,ss and Cmax,ss
(2) Midazolam (DGs 2 to 5)
After single doses:
AUC0-tz and Cmax
Criteria for 
pharmacodynamics:


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 705564
Protocol date:
Trial number:
Revision date:
08 August 2018
18 September 2017
1408-0002
Criteria for safety:
Primary endpoint
(1) BI 705564
Safety and tolerability of BI 705564 by the number [N (%)] of subjects with adverse 
reactions.


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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:
08 August 2018
18 September 2017
1408-0002
Statistical methods:
(1) BI 705564
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.
Linearity index will be estimated using a linear model providing a two-sided 95% CI.
Attainment of steady state will be analysed by a repeated measures linear model for 
trough concentrations (Cmin) of BI 705564 with dose as an additional covariate, if 
permissible.
(2) Midazolam (DGs 2 to 5)
Descriptive statistics will be calculated for all endpoints.
Relative bioavailability will be estimated by the ratios of the geometric means (test/
reference) for the secondary endpoints. Additionally, their two-sided 90% CIs will be 
provided. This method corresponds to the two one-sided t-tests procedure, each at the 
5% significance level. Since the main focus is on estimation and not testing, an 
acceptance range is not specified. The statistical model will be an ANOVA on the 
logarithmic scale including effects for ‘subjects’, and ‘treatment’. CIs will be 
calculated based on the residual error from ANOVA.


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FLOW CHART
(DGs 1 to 5)
Visit
Day
Planned time (relative to first 
BI 705564 administration)
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9 BI 705564
PK blood MDZ9
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs &
concomitant therapy5
1
-21 to -5
Screening (SCR)1
x
x
x
x
2
-4 to -2
-72:00
08:00
Ambulatory visit
x6
x
-1
-25:30
06:30
Admission to trial site and Allocation 
to treatment14: BI 705564 or placebo
x2,15
x2, 
16
x2
x2
x2
-24:30
07:30
Standard continental breakfast
-24:00
08:00
Midazolam administration 16
-23:45
08:15
x16
-23:30
08:30
x16
-23:00
09:00
x16
x16
x16
-22:30
09:30
x16
-22:00
10:00
240 mL fluid intake
x16
x16
x16
x16
-21:30
10:30
x16
-21:00
11:00
x16
-20:00
12:00
240 mL fluid intake, thereafter lunch3
x16
x16
x16
x16
-18:00
14:00
x16
-16:00
16:00
Snack (voluntary)3
x16
x16
x16
-14:00
18:00
Dinner3
1
-1:00
07:00
x2
x2
x2,8
x2
x2
-0:30
07:30
Standard continental breakfast
0:00
08:00
BI 705564 or placebo administration
0:30
08:30
x
1:00
09:00
x
x8
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
x8
x
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x8
x
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3
x
x8
x
x
10:00
18:00
Dinner3
12:00
20:00
x
x8
x
x 
2
24:00
08:00
Breakfast (voluntary),
discharge from trial site
x
x
x8
x
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x
x
4
70:30
06:30
Admission to trial site
x2,13
x2
x2,8
x2
x2
72:00
08:00
BI 705564 or placebo administration11
5
96:00
08:00
BI 705564 or placebo administration11
x2
x
x
6
120:00
08:00
BI 705564 or placebo administration11
x2
x8
x
x


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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 and 
alcohol breath test), demographics (including determination of body height and weight, smoking status and alcohol 
history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. 
2.
Time is approximate. The respective procedure is to be performed and completed within 3 h 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, body weight, vital signs, ECG, safety laboratory, recording of 
AEs and concomitant therapies.
5.
AEs/ infections/ bleeding events (as of Day 4) and concomitant therapies will be recorded throughout the trial but will 
be specifically asked for at the time points indicated in the Flow Chart above.
Visit
Day
Planned time (relative to first 
BI 705564 administration)
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9 BI 705564
PK blood MID9
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs &
concomitant therapy 5
2
7
144:00
08:00
BI 705564 or placebo administration11
x
x
8
168:00
08:00
BI 705564 or placebo administration11
x8
x
x
9
192:00
08:00
BI 705564 or placebo administration11
x2
x8
x
x
10
216:00
08:00
BI 705564 or placebo administration11
x
x8
x12
x
11
240:00
08:00
BI 705564 or placebo administration11
x2
x8
x12
x
12
264:00
08:00
BI 705564 or placebo administration11
x8
x12
x
13
288:00
08:00
BI 705564 or placebo administration11
x2
x8
x12
x
14
312:00
08:00
BI 705564 or placebo administration11
x8
x12
x
15
336:00
08:00
BI 705564 or placebo administration11
x2
x8
x12
x
16
360:00
08:00
BI 705564 or placebo administration11
x2
x8
x12
x
17
383:00
07:00
x2
x7,2
x2, 
16
x8,2
x12,
2
x2
383:30
07:30
Standard continental breakfast
384:00
08:00
Last BI 705564 or placebo
administration & Midazolam16
384:15
08:15
x16
384:30
08:30
x7
x16
385:00
09:00
x7
x16
x8
x
385:30
09:30
x7
x16
386:00
10:00
240 mL fluid intake
x
x7
x16
x8
x
x
386:30
10:30
x16
387:00
11:00
x7
x16
388:00
12:00
240 mL fluid intake, thereafter lunch3
x7
x16
x8
x
x
390:00
14:00
x7
x16
392:00
16:00
Snack (voluntary)3
x7
x16
x8
x
x
394:00
18:00
Dinner3
396:00
20:00
x7
x8
x
x
18
408:00
08:00
Breakfast (voluntary),
discharge from trial site
x
x7
x8
x12
x
418:00
18:00
Ambulatory visit
x7
x
19
432:00
08:00
Ambulatory visit
x7
x8
x
x
20
456:00
08:00
Ambulatory visit
x7
x
3
24 to 27
End of trial (EOT) examination4
x
x
x
x


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6.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to first administration of study drug. 
This safety laboratory can be omitted, if the screening examination is performed on Days -6 or -5.
7.
At these time points, additional blood samples for metabolite identification will be taken (refer to Section 5.5.2.2). 
A blank sample is to be taken prior to any medication intake (Day -1).
8.
The ECG recording has to be performed as triple at this time point. At baseline (Day 1 at -1:00) three pre-dose triplicate 
ECGs within 10 min are to be recorded.
9.
Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK data) 
including addition of samples and visits as long as the total blood volume taken does not exceed 500 mL per subject.
11. After a standard continental breakfast
12. Including oral body temperature
13. Including drug screening and alcohol breath test
14. Allocation to treatment may be performed at any time following enrolment but must be completed prior to (first) drug 
administration.
15. Only drug screening and alcohol breath test.
16. Only DGs 2 to 5


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(DG 8/ 28 Days)
Visit
Day
Planned time (relative to first 
BI 705564 administration)
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9 BI 705564
Skin Prick Test
CD69 & CD63 blood
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs &
concomitant therapy5
1
-21 to -4
Screening (SCR)1
x
x
x
x
x
2
-3 to -1
-72:00
08:00
Ambulatory visit
x6
x6
x
1
-1:30
06:30
Admission to trial site and Allocation 
to treatment14: BI 705564 or placebo
x2, 
15
x2
x2
x2,8
x2, 
12
x2
-0:30
07:30
Standard continental breakfast
0:00
08:00
BI 705564 or placebo administration
0:30
08:30
x
1:00
09:00
x
x8
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
x8
x
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x8
x
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3
x
x8
x
x
10:00
18:00
Dinner3
12:00
20:00
x
x8
x
x
2
23:00
07:00
x
x
x8
x
x
23:30
07:30
Standard continental breakfast
24:00
08:00
BI 705564 or placebo administration
discharge from trial site
x12
x
3
47:00
07:00
Ambulatory visit
x
x
47:30
07:30
Standard continental breakfast
48:00
08:00
BI 705564 or placebo 
administration17
x
x
4
71:00
07:00
Ambulatory visit
x
x
71:30
07:30
Standard continental breakfast
72:00
08:00
BI 705564 or placebo administration17
x
x
5
95:00
07:00
Ambulatory visit
x
x
95:30
07:30
Standard continental breakfast
96:00
08:00
BI 705564 or placebo administration17
x
x
6
119:00
07:00
Ambulatory visit
x
x
119:30
07:30
Standard continental breakfast
120:00
08:00
BI 705564 or placebo administration17
x
x
7
143:00
07:00
Ambulatory visit
x
x
143:30
07:30
Standard continental breakfast
144:00
08:00
BI 705564 or placebo administration17
x
x


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Visit
Day
Planned time (relative to first 
BI 705564 administration)
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9 BI 705564
Skin Prick Test
CD69 & CD63 blood
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs &
concomitant therapy 5
2
8
167:00
07:00
Ambulatory visit
x2
x2
x2
x2
x2, 8
x12, 
2
x2
167:30
07:30
Standard continental breakfast
168:00
08:00
BI 705564 or placebo administration17
x
x
9
191:00
07:00
Ambulatory visit
x
x
191:30
07:30
Standard continental breakfast
192:00
08:00
BI 705564 or placebo administration17
x
x
10
215:00
07:00
Ambulatory visit
x
x
215:30
07:30
Standard continental breakfast
216:00
08:00
BI 705564 or placebo administration17
x
x
11
239:00
07:00
Ambulatory visit
x
x
239:30
07:30
Standard continental breakfast
240:00
08:00
BI 705564 or placebo administration17
x
x
12
263:00
07:00
Ambulatory visit
x
x
263:30
07:30
Standard continental breakfast
264:00
08:00
BI 705564 or placebo administration17
x
x
13
287:00
07:00
Ambulatory visit
x
x
287:30
07:30
Standard continental breakfast
288:00
08:00
BI 705564 or placebo administration17
x
x
14
311:00
07:00
Ambulatory visit
x
x
311:30
07:30
Standard continental breakfast
312:00
08:00
BI 705564 or placebo administration17
x
x
15
335:00
07:00
Admission to trial site
x13, 
2
x2
x8, 2
x12,
2
x2,
335:30
07:30
Standard continental breakfast
336:00
08:00
BI 705564 or placebo administration
16
360:00
08:00
BI 705564 or placebo administration11
x8
x
x
17
384:00
08:00
BI 705564 or placebo administration11
x8
x
x
18
408:00
08:00
BI 705564 or placebo administration11
x8
x
x
19
432:00
08:00
BI 705564 or placebo administration11
x8
x
x
20
456:00
08:00
BI 705564 or placebo administration11
x8
x
x
21
480:00
08:00
BI 705564 or placebo administration11
x8
x
x
22
504:00
08:00
BI 705564 or placebo administration11
x2
x2
x8, 2
x12, 
2
x2
23
528:00
08:00
BI 705564 or placebo administration11
x8
x
x
24
552:00
08:00
BI 705564 or placebo administration11
x8
x
x
25
576:00
08:00
BI 705564 or placebo administration11
x8
x
x
26
600:00
08:00
BI 705564 or placebo administration11
x8
x
x
27
624:00
08:00
BI 705564 or placebo administration11
x8
x
x


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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 and 
alcohol breath test), demographics (including determination of body height and weight, smoking status and alcohol 
history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. 
2.
Time is approximate. The respective procedure is to be performed and completed within 3 h 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, body weight, vital signs, ECG, safety laboratory, recording of 
AEs and concomitant therapies.
5.
AEs/ infections/ bleeding events and concomitant therapies will be recorded throughout the trial but will be specifically 
asked for at the time points indicated in the Flow Chart above.
6.
Safety laboratory and SPT to be taken and to be medically evaluated within 3 days prior to first administration of study 
drug. These tests can be omitted, if the screening examination is performed on Days -6 to -4.
8.
The ECG recording has to be performed as triple at this time point. At baseline (Day 1 at -1:30) three pre-dose triplicate 
ECGs within 10 min are to be recorded.
9.
Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK data) 
including addition of samples and visits as long as the total blood volume taken does not exceed 500 mL per subject.
Visit
Day
Planned time (relative to first 
BI 705564 administration)
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9 BI 705564
Skin prick test
CD 69 & CD 63 blood
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs &
concomitant therapy 5
2
28
646:30
06:30
x2
x2
x2
x2
x8,2
x12,
2
x2
647:30
07:30
Standard continental breakfast
648:00
08:00
Last BI 705564 or placebo
administration 
648:30
08:30
x
649:00
09:00
x
x8
x
649:30
09:30
x
650:00
10:00
240 mL fluid intake
x
x
x8
x
x
651:00
11:00
x
652:00
12:00
240 mL fluid intake, thereafter lunch3
x
x8
x
x
654:00
14:00
x
656:00
16:00
Snack (voluntary)3
x
x8
x
x
658:00
18:00
Dinner3
660:00
20:00
x
x8
x
x
29
671:00
07:00
x
x
x8
x12
x
671:30
07:30
Breakfast (voluntary)
672:00
08:00
Discharge from trial site
682:00
18:00
Ambulatory visit
x
x
30
695:00
07:00
Ambulatory visit
x
x8
x
x
31
719:00
07:00
Ambulatory visit
x
x
3
34 to 
37
End of trial (EOT) examination4
x
x
x
x


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11. After a standard continental breakfast
12. Including oral body temperature
13. Including drug screening and alcohol breath test
14. Allocation to treatment may be performed at any time following enrolment but must be completed prior to (first) drug 
administration.
15. Only drug screening and alcohol breath test.
17. Administration of study medication on Days 3 to 14 is acceptable within  ± 1 h of the planned time.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................7
TABLE OF CONTENTS ................................................................................ 14
ABBREVIATIONS.......................................................................................... 18
1.
INTRODUCTION.................................................................................... 22
1.1
MEDICAL BACKGROUND............................................................................22
1.2
DRUG PROFILES.............................................................................................24
1.2.1.7
Prediction of human pharmacokinetics and therapeutic dose..38
1.2.2
Midazolam (DGs 2 to 5)........................................................................39
1.2.3
Skin Prick Test (DG 8, only)................................................................39
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 43
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................43
2.2
TRIAL OBJECTIVES.......................................................................................44
2.3
BENEFIT - RISK ASSESSMENT ...................................................................45
2.3.1
Procedure-related risks ........................................................................45
2.3.2
Drug-related risks and safety measures..............................................46
2.3.2.1
Mode of action.........................................................................46
2.3.2.2
Nature of the target ..................................................................47
2.3.2.3
Relevance of animal species and models.................................47
2.3.2.4
Findings in nonclinical safety studies......................................47
2.3.2.5
Drug induced liver injury.........................................................48
2.3.2.6
Risk minimization (safety precautions and stopping rules).....48
2.4
OVERALL ASSESSMENT AND CONCLUSION.........................................50
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 52
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................52
3.1.1
Administrative structure of the trial...................................................56
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................57


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3.3
SELECTION OF TRIAL POPULATION ......................................................58
3.3.1
Main diagnosis for study entry............................................................59
3.3.2
Inclusion criteria...................................................................................59
3.3.3
Exclusion criteria ..................................................................................59
3.3.4
Removal of subjects from therapy or assessments.............................61
3.3.4.1
Removal of individual subjects................................................61
3.3.4.2
Discontinuation of the trial by the sponsor..............................62
3.3.5
Replacement of subjects .......................................................................63
4.
TREATMENTS........................................................................................ 64
4.1
TREATMENTS TO BE ADMINISTERED....................................................64
4.1.1
Identity of BI investigational product and comparator 
products .................................................................................................64
4.1.2
Method of assigning subjects to treatment groups ............................65
4.1.3
Selection of doses in the trial................................................................65
4.1.4
Drug assignment and administration of doses for each subject .......66
4.1.5
Blinding and procedures for unblinding ............................................68
4.1.5.1
Blinding....................................................................................68
4.1.5.2
Procedures for emergency unblinding .....................................70
4.1.6
Packaging, labelling, and re-supply ....................................................70
4.1.7
Storage conditions.................................................................................71
4.1.8
Drug accountability ..............................................................................71
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................71
4.2.1
Other treatments and emergency procedures....................................71
4.2.2
Restrictions............................................................................................72
4.2.2.1
Restrictions regarding concomitant treatment .........................72
4.2.2.2
Restrictions on diet and life style.............................................73
4.3
TREATMENT COMPLIANCE.......................................................................73
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 74
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................74
5.1.1
Endpoints of efficacy.............................................................................74
5.1.2
Assessment of efficacy...........................................................................74
5.2
SAFETY..............................................................................................................74
5.2.1
Endpoints of safety................................................................................74
5.2.2
Assessment of adverse events...............................................................74
5.2.2.1
Definitions of adverse events...................................................74
5.2.2.2
Adverse event collection and reporting ...................................77
5.2.3
Assessment of safety laboratory parameters......................................79
5.2.4
Electrocardiogram................................................................................85
5.2.4.1
12-lead resting ECG.................................................................85
5.2.5
Assessment of other safety parameters...............................................87
5.2.5.1
Vital signs ................................................................................87


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5.2.5.2
Medical examinations..............................................................87
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................88
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................88
5.5.1
Pharmacokinetic endpoints..................................................................88
5.5.1.1
Secondary endpoints................................................................88
5.5.2
Methods of sample collection...............................................................91
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................91
5.5.3
Analytical determinations ....................................................................94
5.5.3.1
Analytical determination of BI 705564 plasma concentration 94
5.5.3.3
Analytical determination of Midazolam plasma concentration 
(DGs 2 to 5).............................................................................94
6.
INVESTIGATIONAL PLAN.................................................................. 98
6.1
VISIT SCHEDULE............................................................................................98
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................99
6.2.1
Screening period....................................................................................99
6.2.2
Treatment period ..................................................................................99
6.2.3
End of trial period...............................................................................100
7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE....................................................................................... 101
7.1
STATISTICAL DESIGN – MODEL .............................................................101
7.1.1
Objectives.............................................................................................101
7.2
NULL AND ALTERNATIVE HYPOTHESES ............................................101
7.3
PLANNED ANALYSES..................................................................................102
7.3.1
Primary analyses.................................................................................102
7.3.2
Secondary analyses .............................................................................102
7.3.4
Safety analyses.....................................................................................106


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7.3.5
Preliminary PK analyses 
........................107
7.3.6
PK analyses..........................................................................................107
7.4
HANDLING OF MISSING DATA ................................................................109
7.4.1
Safety....................................................................................................109
7.4.2
Plasma/urine drug concentration - time profiles (DGs 1 to 5)........109
7.4.3
PK parameters ....................................................................................109
7.5
RANDOMISATION ........................................................................................109
7.6
DETERMINATION OF SAMPLE SIZE ......................................................109
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS .............................................................................................. 111
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ........................................................................................................111
8.2
DATA QUALITY ASSURANCE ...................................................................111
8.3
RECORDS........................................................................................................112
8.3.1
Source documents ...............................................................................112
8.3.2
Direct access to source data and documents.....................................112
8.3.3
Storage period of records...................................................................112
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ...............................112
8.5
STATEMENT OF CONFIDENTIALITY.....................................................113
8.6
COMPLETION OF TRIAL............................................................................113
9.
REFERENCES....................................................................................... 114
9.1
PUBLISHED REFERENCES.........................................................................114
9.2
UNPUBLISHED REFERENCES...................................................................119
10. APPENDICES ........................................................................................ 122
10.1
DILUTION INSTRUCTIONS FOR MIDAZOLAM (DG 2 TO 5).............122
10.1.1 Required equipment and dosing aids – overview.............................122
10.1.2 Dilution procedure..............................................................................123
10.1.3 In-use stability.....................................................................................124
10.1.4 Mode of application ............................................................................124
11. DESCRIPTION OF GLOBAL AMENDMENT(S)............................ 128


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ABBREVIATIONS
ACE
Angiotensin converting enzyme
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve of the analyte in plasma
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 h
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
AUCss
AUC at steady state
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BAT
Basophil activation test
BCR
B-cell receptor
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BTK
Bruton’s tyrosine kinase
CA
Competent authority
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady-state


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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
DDI
Drug-drug interaction
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
FE
Food effect
GCP
Good Clinical Practice
GI
Gastro-intestinal
GLP
Good laboratory practice
gMean
Geometric mean
hERG
Human ether-a-go-go related gene
HPC
Human Pharmacology Centre
HR
Heart rate
IB
Investigator’s brochure
IC50
Half maximal inhibitory concentration
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IPV
Important protocol violation
IRB
Institutional Review Board
ISF
Investigator site file
IV
Intravenous
LC-MS/MS
Liquid chromatography with tandem mass spectrometry


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MDZ
Midazolam
MedDRA
Medical Dictionary for Regulatory Activities
MIST
Metabolites in safety testing
MRD
Multiple-rising dose
NOA
Not analysed
NOAEL
No observed adverse effect level
NOEL
No observed effect level
NOR
No valid result
NOS
No sample available
PfOS
Powder for reconstitution of an oral solution
PK
Pharmacokinetic
PKS
Pharmacokinetic set
PO
Per os
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)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SLE
Systemic lupus erythematosus
SmPC
Summary of Product Characteristics
SOP
Standard Operation Procedure
SRD
Single-rising dose
ss
(at) steady state
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
Test product or treatment


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Tab
Tablet
TCPK
Trial clinical pharmacokineticist
TCPKa
Trial clinical pharmacokineticist analyst
TDMAP
Trial Data Management and Analysis Plan
TMF
Trial master file
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WOCBP
women of child-bearing potential
XLA
X-linked agammaglobulinemia


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Boehringer Ingelheim (BI) is developing BI 705564, an oral, small molecule inhibitor of
Bruton’s tyrosine kinase (BTK), a member of the Tec family of kinases, 


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1.2.1.7
Prediction of human pharmacokinetics and therapeutic dose
Information available for DGs 1 to 5
The metabolic clearance (CL) of BI 705564 in human is predicted to be 6.2 mL/min/kg, as
determined by scaling of metabolic stability data obtained from incubations with human
hepatocytes [n00250613-02]. The Vss in human is predicted to be 2.0 L/kg based on mean
body weight-normalized Vss values obtained from PK studies in rat, dog, and monkey. The
effective half-life value in human is predicted to be 3.7 h which was estimated based on the 
projected CL and Vss values. Human bioavailability is predicted to be 10% based on the dog
bioavailability data corrected by the difference in estimated hepatic first-pass extraction
between dog and human.


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 the therapeutic
dose of BI 705564 (free base) is predicted to be 12 mg q.d. with a corresponding Cmax,ss of
12 nM and an AUCss of 89 nM•h.
In study 1408-0001, a single dose of 20 mg under fasting conditions resulted in a mean Cmax
of about 13 nM which is in the range of the predicted therapeutic peak exposure. However, 
the mean predicted therapeutic systemic exposure of about 90 nM•h was not reached with a 
single dose of 80mg under fasting conditions (AUC0-24 of about72 nM•h). For details, refer to 
Section 1.2.1.5.
1.2.2
Midazolam (DGs 2 to 5)
Midazolam is a sensitive substrate of CYP3A4, used both in vitro and in vivo as a probe drug 
for CYP3A4 drug interactions. Absorption is rapid, with maximum concentrations reached 
around 15 to 30 min. Clearance is also rapid, with an elimination half-life of 1.5 to 2.5 h. The 
PK of midazolam has been found to be dose proportional over a range of at least 0.001 µg to
3 mg [R17-3022]. For further information, refer to the summary of product characteristics
[R17-3087].


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Considerations for DGs 1 to 5
This is the second trial with BI 705564 and the first with multiple dose administrations. The
objective of this trial is to investigate the safety, tolerability, pharmacokinetics and
pharmacodynamics of BI 705564 in male subjects. The chosen population of healthy 
volunteers using multiple rising oral doses is adequate to provide the basis for the phase 2
clinical development program of BI 705564
 This trial 
will provide pharmacokinetic information in healthy volunteers at steady state exposure.
A currently ongoing phase 1 trial, study 1408-0001 (amended) explored safety and 
tolerability in healthy male subjects after single doses. At the time of the original CTA 
submission of this protocol, the dose level of up to 80 mg was completed. Up to this dose 
level there were no dose-limiting AEs and no SAEs. Since in this single dose study the 
exposure was going to plateau from 40 mg onwards and the intake of food increased the 
exposure, the multiple dose study was performed under fed conditions.
Based on in vitro screening data, it cannot be excluded that BI 705564 might be an 
inactivator and/ or inducer of CYP3A4 (for details, refer to Section 1.2.1.4). To exclude a 
clinically relevant CYP 3A4 modulation with BI 705564 as perpetrator, an assessment of the 
effect of BI 705564 on the midazolam metabolism will be conducted in DGs 2 to 5, only. 
Therefore, these dose groups will receive a microdose of midazolam before start and at the 
end of treatment with BI 705564.
The safety- and PK data obtained in this study will contribute to define appropriate doses for 
further clinical studies with BI 705564.


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2.2
TRIAL OBJECTIVES
DGs 1 to 5
The primary objective of this trial is to investigate safety and tolerability of BI 705564 in 
healthy male subjects, following oral administration of multiple rising doses of 10 mg, 
20 mg, 40 mg, 60 mg, and 80 mg q.d. over 14 days.
Secondary objectives are the exploration of the pharmacokinetics, including dose 
proportionality and investigation of linearity.
In addition, the effect of BI 705564 on the pharmacokinetics of midazolam, given as an oral 
microdose, will be explored in dose groups 2 to 5.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
Additional considerations for DG 8


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2.3
BENEFIT - RISK ASSESSMENT
DGs 1 to 5
Participation in this trial is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of BI 705564 
which is expected to offer advantages compared with other BTK inhibitors in non-
oncological indications due to its high selectivity. Subjects in this trial are exposed to risks of 
study procedures and risks related to the exposure to the 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. The same risks apply to venipuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.


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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 nonclinical safety studies.
2.3.2.1
Mode of action
BTK is a well characterized target with known functions in the immune signaling pathways
of B-cells and myeloid cell lineages (refer to Section 1.1). Clinical experience with the 
marketed BTK inhibitor ibrutinib is available (refer to Sections 1.1). 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 can be controlled by 
the application of antibiotics and gammaglobulin substitution, [R17-0404].
Ibrutinib treatment in patients with hematologic malignancies is associated with adverse
events including hypertension, thrombocytopenia, and GI complaints (abdominal pain,
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.
Haemorrhagic events which also occurred with a thrombocyte count within the reference 
range were reported under the treatment of ibrutinib. The underlying mechanism is believed 
to be an inhibition of collagen induced platelet aggregation. Although similar findings are not 
expect for BI 705564, at this stage of clinical development, subjects will be closely monitored 
throughout the study for bleeding events which includes also the assessment of platelet 
function.


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BI 705564 binds irreversibly to the BTK binding site (refer to Section 1.2.1). Therefore, the
reversibility of physiological (on-target) effects may be more linked to the re-synthesis rate of 
the BTK protein than to the PK profile of the compound. The time between BTK inhibition 
and complete recovery of BTK protein in humans is estimated to be between 7 and 10 days, 
with a recovery of 50% after about 2 to 3 days [R16-0021]. Therefore 7 days seems to be the 
minimum time between dose groups and from last administration of study drug until the end 
of trial examination.
2.3.2.2
Nature of the target
The BTK protein is intra-cellularly expressed in myeloid and lymphoid cell lines,
predominantly in the immune system (bone marrow, appendix, lymph nodes, tonsils, and
spleen), and the lung. [R17-0406] Although on-target effects are unlikely to occur after a 
multiple doses 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, although unlikely, in bacterial 
infections. Main safety measures performed throughout the study will be: (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 7 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 (refer to 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 PD 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 largely similar 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, refer to the current version of the IB 
[c12104992-03].
2.3.2.4
Findings in nonclinical safety studies
Documents supporting the submission of this trial with BI 705564 were compiled according 
to Good Clinical Practice (GCP) principles. All pivotal, nonclinical safety studies in support 
of this clinical trial were conducted in compliance with Good Laboratory Practice (GLP). For 
further information, refer to the current version of the IB [c12104992-03].
Safety pharmacology
A decrease in heart rate was observed at 50 mg/kg/day (NOAEL) in the 4-week dog
toxicity study (refer to Section 1.2.1.3) which was not observed at the next lower dose


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level of 20 mg/kg/day (NOEL). Reduction of heart rate was also observed after a
single dose of 50 mg/kg in the GLP dog telemetry study in dogs but not at a dose of
20 mg/kg. Heart rate will be intensely monitored throughout the study (refer to Flow
Chart). For further information, refer to current version of IB [c12104992-03].

Toxicology
In the 4-week rat toxicity study (refer to Section 1.2.1.3), a decrease in potassium of 
9 to 16 %, as compared to baseline, was observed in all dose groups. Safety laboratory
monitoring will include this parameter during the conduct of the study (refer to Flow
Chart and Section 5.2.3).
In the same study, dose independent, only partially reversible effects on the pancreas
(i.e. mixed interstitial infiltrates, fibrosis, acinar atrophy, hemorrhage) were noted.
These findings could be qualified as rat specific (refer to Section 1.2.1.3) and should 
not be relevant for humans. Nonetheless, subjects with any medical history of 
pancreatitis at screening will be excluded from the study. In addition, this organ will 
be monitored for any inflammatory signs by the determination of amylase and lipase 
throughout the study. Also, its endocrine function will be monitored by plasma 
glucose measurements (refer to Flow Chart and Section 5.2.3).
In the 4-week dog toxicity study (refer to Section 1.2.1.3), a not recovered B-cell
depletion (down to 34-43%, as compared to baseline) was noted at the highest dose
level of 50 mg/kg/day (NOAEL). Therefore, CD19+ B-cell counts and white blood
counts will be monitored throughout the study. At the very dose level of this study, a 
decrease in heart rate of 11.6 bpm, estimated from the electrocardiograms was 
observed. Intensive ECG monitoring will be performed after dosing throughout the 
study (refer to Flow Chart).
2.3.2.5
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. Refer also to Section 5.2.2.1 - Adverse events of special interest (AESIs).
2.3.2.6
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:
DGs 1 to 5

Careful starting dose selection.

Escalation factors limited to 2 with increasing doses.

For safety reasons, each dose group of 10 subjects (8 on active drug, 2 on placebo) 
will be divided into 2 cohorts of 5 subjects each (4 on active drug, 1 on placebo). Both 


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cohorts will be dosed in a randomized fashion and each drug administration will be
separated by at least 10 min. For orally administered drugs, this is usually a sufficient 
time frame to observe acute effects.

For each dose group, the 2 cohorts will be separated by at least 70 h (between the first
subjects of each cohort) to account for any intolerability resulting from 3 repeated 
doses of BI 705564. A continuous safety evaluation, including results of safety 
laboratories, ECG readings, recordings of vital signs and adverse events will be 
performed before the individual subject and the subsequent cohort is dosed.

Interim measurements of BI 705564 plasma levels will be performed. Dose escalation 
will be stopped, if the gMean of Cmax or AUC of a dose group exceeds the exposure 
thresholds of 312 nM for Cmax or 975 nM•h for AUC, or, if the estimated gMean of 
above parameters for the next higher dose group is expected to exceed these values. 
Estimations will be done based on preliminary PK results of preceding dose groups 
(refer to Section 7.3.5). This should provide a safety margin to the NOAEL of >20
(refer to Table 1.2.1.3: 1).

If one dose level is safe and shows acceptable tolerability, and if no stopping criterion
is met (refer to Section 3.3.4.2), the next higher dose may be given, keeping a 
minimum dosing interval of 7 days between first subjects of consecutive dose groups
due to the irreversible BTK binding of BI 705564 and the time to complete recovery 
of the BTK protein (refer also to Section 2.3.2.1).

Should any of the single doses, i.e. 20 mg, 40 mg, 60 mg, and 80 mg, tested in the 
ongoing study under fed conditions (1408-0001 – amended) be not safe or exceed the 
predefined above gMean exposure levels, these doses would not be applied in this 
multiple dose setting.

Extensive standard safety laboratory measurements including serum electrolytes,
serum amylase and lipase, differential white blood counts, as well as CD19+ B-cell
and platelet count and bleeding time (modified Ivy method using a Surgicutt) to 
monitor platelet function will be performed before and after study drug administration 
(refer to Flow Chart and Section 5.2.3).

Subjects will be closely monitored for infections and bleeding events throughout the 
study.

Repeated triplet 12-lead ECGs are scheduled throughout the study.

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, refer to Section 3.1.

Subjects will be hospitalized throughout the study from Day-1 (treatment with 
microdose of midazolam in dose groups 2 to 5) to Day 2 (treatment with single dose 
of BI 705564) and from Day 4 to Day 18 (repeated doses of BI 705564 and a single 
midazolam microdose on Day 17 in dose groups 2 to 5) 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 close medical 


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observation and thoroughly monitored for both, expected and unexpected adverse 
events.
2.4
OVERALL ASSESSMENT AND CONCLUSION
DGs 1 to 5
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
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, GI complaints and haemorrhagic events 
which may be related to off-target effects. In contrast, BI 705564 is considered to be a more


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selective BTK inhibitor and may have a more favorable safety profile due to less pronounced 
off-target effects.
Based on numerous published studies [R17-3022, R17-3023], treatment risks with a 
microdose of midazolam (i.e. 1/100 of a pharmacologically active dose) are considered 
unlikely.
Considering preclinical and preliminary data obtained in the first in man study of BI 705564
(1408-0001), the well characterized target structure and its physiologic role in B-cell 
differentiation and function, and taking into account the safety measures described above, 
participation in this multiple dose regimen does not represent an undue risk to healthy 
subjects.
Inhibition of BTK in patients with LN, SLE and rheumatoid arthritis 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, pro-inflammatory 
pathways, BI 705564 may slow or halt disease progression. Considering the medical need 
 
 taking into account the potential 
safety advantage of a highly selective BTK inhibitor, the expected benefit is likely to 
outweigh the potential risks and justifies exposure of healthy volunteers.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
DGs 1 to 5
A total of 50 healthy male subjects is planned to participate in the trial, according to 
5 sequential groups, comprising 10 subjects each. Additional subjects may be entered to 
allow testing of additional doses on the basis of experience gained during the trial conduct 
(e.g. preliminary PK data), provided the planned and approved highest dose will not be 
exceeded. Thus, the actual number of subjects entered may exceed 50, but will not exceed 
70 subjects entered. Such changes may be implemented via non-substantial CTP 
amendments.
The trial design is depicted in Figure 3.1: 1.
Figure 3.1: 1
Trial design of DGs 1 to 5


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BI 705564
The dose groups to be evaluated are outlined in Table 3.1: 1.
Table 3.1: 1
Dose groups
Dose Group
1
2
3
5
4
Daily dose (mg)
10
20
40
60
80
fed
fed
fed
fed
fed
Number of subjects
10
10
10
10
10
Subjects receiving placebo
2
2
2
2
2
Subjects receiving active drug
8
8
8
8
8
*
Application of 28 consecutive days


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DGs 1 to 5
This segment is designed as a double-blind, randomised (within dose group), placebo-
controlled, parallel-group comparison.
Subjects will receive ascending doses of BI 705564 on Day 1 and then over 14 consecutive 
days from Day 4 to Day 17.
Within each dose group, 8 subjects will receive BI 705564 (active drug) and 2 will receive 
placebo. Only one dose is tested within each dose group. Each dose group will consist of 
2 cohorts (5 subjects each, 4 on active drug and 1 on placebo) which will be treated 
subsequently for safety reasons. The time interval between these cohorts will be at least 70 h.
A continuous safety evaluation, including results of safety laboratories, ECG readings, 
recordings of vital signs and adverse events will be performed before the individual subject 
and the subsequent cohort is dosed.
The groups will be investigated consecutively in ascending order of doses, maintaining a time 
interval of at least 7 days between the last drug administration in the previous dose group and 
the first drug administration of the subsequent dose group.
The decision to proceed to the next dose group will be based upon the safety, tolerability and 
PK data of the preceding groups. The next dose will only be given, if, in the opinion of the 
investigator, no safety concerns arose in the preceding group (i.e. no dose-limiting events 
occurred) and, if none of the pre-specified trial-specific stopping criteria were met. For more 
details, refer to 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 anytime for any reasonable cause by the 
Principal Investigator (or an authorised deputy) or the sponsor of the study, e.g. because of 
any unforeseen adverse events, etc. Dose escalation will only be permitted, if no safety 
concerns exist in the opinion of the Principal Investigator (or an authorised deputy) and the 
trial clinical monitor (or an authorised deputy).
The minimum data set for review consists of the following data:

AEs (incl. monitoring of bleeding events) in the current and preceding dose groups up 
to at least 48 h of the last dose applied, i.e Visit 2, Day 19, 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 EGG in the current and preceding dose groups up to at least 48 h 
after the last dose, i.e. Visit 2, Day 19.

Vital signs in the current and preceding dose groups up to at least 48 h after the last 
dose, i.e. Visit 2, Day 19.

Clinical laboratory tests (including bleeding time to monitor platelet function and 
CD19+ count) in the current and preceding dose groups up to at least Visit 2, Day 18.

Preliminary PK data for a selected time period, as per Section 7.3.5.


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
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 (incl. monitoring of 
bleeding events) 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 (after consultation with the sponsor) 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 the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
Midazolam (DGs 2 to 5)
This segment is designed as a nested, open, fixed-sequence, intra-individual comparison.
The potential interaction of BI 705564 with a CYP3A4 substrate will be assessed separately 
in DGs 2 to 5 and in the subjects receiving placebo. This will be conducted in parallel to the 
multiple dose assessments, using a microdose of midazolam in DGs 2 to 5 (a sensitive 
CYP3A4 substrate) administered at 2 different time points (Day -1 and Day 17).


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3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to

Manage the trial in accordance with applicable regulations and internal SOPs,

Direct the clinical trial team in the preparation, conduct, and reporting of the trial,

Ensure appropriate training and information of local clinical monitors (CML), 
Clinical Research Associates (CRAs), and participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany.
The trial will be conducted at 
under the supervision of the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
Bleeding time by modified Ivy method (Surgicutt) to monitor platelet function will be 
measured at 
. Closure time, 
measured by PFA-200 (DG 8, only) to further characterise and monitor platelet function will 
be performed at Gerinnungszentrum Mannheim, Mannheim, Germany. For detailed 
description, refer to working manual in the ISF.
B-cell CD19+ count will be performed 
 
The analyses BI 705564 concentrations in plasma and urine (DGs 1 to 5) will be performed  
.


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The analyses midazolam concentrations in plasma (DGs 2 to 5) will be performed at the 
Department of Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, 
Biberach, Germany.
The digitally recorded 12-lead ECGs will be sent to
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research 
organisation appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
DGs 1 to 5
For multiple-rising dose trials, the design described in Section 3.1 is viewed favourable under 
the provision not to expose subjects involved to undue risks since the main study objective is 
to investigate safety and tolerability of BI 705564.
With the rising dose design, double-blind conditions regarding the subject’s treatment (active 
drug 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 PD effects. Each dose group consists of 10 subjects 
with 8 on active treatment, and 2 on placebo. The placebo control group includes all subjects 
of all dose groups treated with placebo. 8 subjects per active treatment group are in general 
considered as sufficient for the exploratory evaluation of pharmacokinetics.


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After the first dose (single dose segment), a sufficient wash-out period will be included 
before the second dose (first dose of the multiple dose segment) is administered. This will 
allow for appropriate calculation of the PK parameters after a single dose administration and 
for comparison with PK parameters at steady state.
The evaluation of a potential CYP3A4 interaction with BI 705564 using a microdose of 
midazolam is considered to be acceptable. A microdose of midazolam is not expected to have 
any pharmacological effects. Therefore, subjects are not exposed to undue risks. Also, the 
evaluation of the investigational drug should not be influenced. This assessment will allow 
for better judgement regarding acceptable co-medications in a Proof of Clinical Concept 
study and later in the phase 3 development.
3.3
SELECTION OF TRIAL POPULATION
DGs 1 to 5
It is planned that 50 healthy male subjects will enter the study. The actual number of subjects 
entered may exceed the total of 50, if additional intermediate doses will be tested (refer to
Section 3.1).Subjects will be recruited from the volunteers' pool of the trial site.
Only male subjects will be included into the study because hitherto no conclusive data on 
reproductive toxicology are available. With respect to the embryo-fetal risk derived from the 
treatment of male subjects with BI 705564, where it is theoretically possible that relevant 
exposure to BI 705564 may be achieved in women of child-bearing potential (WOCBP) from 
exposure to seminal fluid, male contraception (condom or sexual abstinence) should be used 
in order to avoid exposure of an existing embryo/ fetus [R16-0373] (refer to Section 3.3.3, 
exclusion criterion 23).
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.


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3.3.1
Main diagnosis for study entry
In DGs 1 to 5, the study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. (a) DGs 1 to 5: Healthy male subjects according to the assessment of the investigator, 
based on a complete medical history, 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


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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 seizure 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 (DGs 1 to 5, only). Allergy to the trial 
medication or its excipients (all DGs)
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 the administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or 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 subject with WOCBP partner who is 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. Subjects who, in the investigator's judgement, are perceived as having an increased risk of 
bleeding, e.g. history of haemorrhagic disorders, clinical relevant petechial bleeding, 
occult blood in faeces, haematuria in repeated urine tests, trauma or surgery within the 


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last month, planned surgery during trial participation, history of arteriovenous 
malformation or aneurysm, history of gastroduodenal ulcer disease or gastrointestinal 
haemorrhage, history of intracranial, intraocular, spinal, retroperitoneal, or atraumatic 
intraarticular bleeding, use of drugs that may interfere with haemostasis during trial 
conduct (e.g. acetylic salicylic acid or other non-steroidal anti-inflammatory drugs)
25. Repeated platelet counts below 100 cells/nL at screening
26. Bleeding times (to monitor platelet function) above reference range at screening
27. Repeated absolute B-cell (CD19+) counts below 40/μL at screening
28. Serum potassium below normal range at screening
29. A history or current clinical signs of acute pancreatitis
For further restrictions, refer to Section 4.2.2 and Table 4.2.2.1: 1.
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/ further treatment, 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 (for DGs 1 to 5) 
 
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.


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5. The subject shows an elevation of AST and/ or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/ or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
6. The subject shows repeatedly an absolute B-cell (CD19+) count below 40/µL or a platelet 
count below 100 cells/nL.
7. The subject shows at Day 15 or Day 21 a prolonged bleeding time of above 1440 s, i.e. 
3 x ULN (DG 8, only).
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
A subject can also be removed from the trial, if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (e.g., by non-adherence to dietary rules, or non-
attendance at study assessments).
If a subject is removed, 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 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. If the discontinuation occurs before the end of the 
residual effect period (REP) which is defined as 7 days (refer to Section 5.2.2.2), the 
discontinued subject should, if possible, be questioned for AEs and concomitant therapies at 
or after the end of the REP in order to ascertain collection of AEs and concomitant therapies 
throughout the REP, if not contrary to any consent withdrawal of the subject. These 
discontinuations will be discussed in the CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings 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.
2. The expected enrolment goals overall or at a particular trial site are not met.
3. Violation of GCP or the CTP or the contract with BI by a trial site or investigator, 
disturbing the appropriate conduct of the trial.
4. The sponsor decides to discontinue the further development of the investigational 
product.


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DGs 1 to 5
5. Dose escalation will be stopped as soon as at least 2 subjects at one dose level on active 
drug showed relevant individual QT prolongation, i.e. a QTc increase of greater 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 gMean of Cmax or AUC of a dose group exceeds 
the exposure thresholds of 312 nM for Cmax or 975 nM•h for AUC, or, if the estimated 
gMean of above parameters for the next higher dose group is expected to exceed these 
values. Estimations will be done based on preliminary PK results of preceding dose 
groups (refer to Section 7.3.5).
7. Dose escalation will be stopped, should any of the single doses in study 1408-0001, i.e. 
20 mg, 40 mg, 80 mg and 160 mg, tested in the ongoing study under fed conditions be not 
safe or exceed the predefined above gMean exposure levels (refer to Section 2.3.2.6).
The investigator/ the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide, if and how many subjects will 
be replaced. 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
4.1
TREATMENTS TO BE ADMINISTERED
The investigational product has been manufactured
 
4.1.1
Identity of BI investigational product and comparator products
The characteristics of test (BI 705564)-, reference (placebo)- and probe (Midazolam) product 
are given below:
Table 4.1.1: 1
Test product
Substance
BI 705564
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
10 mg
Posology:
1-0-0 (DG 1); 2-0-0 (DG 2); 4-0-0 (DG 3); 8-0-0 (DG 4); 6-0-0 (DG 5), 
Route of administration:
Per os
Duration of use:
DGs 1 to 5: Day 1 (1 single dose) and Days 4 to 17 (14 days q.d.)
Table 4.1.1: 2
Test product
Substance
BI 705564
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
100 mg
Posology:
Not used
Route of administration:
Per os
Duration of use:
Table 4.1.1: 3
Reference product
Substance
Placebo matching in size and weight to 10 mg film-coated tablet
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
1-0-0 (DG 1); 2-0-0 (DG 2); 4-0-0 (DG 3); 8-0-0 (DG 4), 6-0-0 (DG 5),
 
Route of administration:
Per os
Duration of use:
DGs 1 to 5: Day 1 (1 single dose) and Days 4 to 17 (14 days q.d.)


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Table 4.1.1: 4
Reference product
Substance
Placebo matching in size and weight to 100 mg film-coated tablet
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
Not used
Route of administration:
Per os
Duration of use:
Table 4.1.1: 5
Probe product (DGs 2 to 5)
Substance
Midazolam (Midazolam-ratiopharm®)
Pharmaceutical formulation: 
Solution for injection
Source: 
Ratiopharm GmbH, Germany
Unit strength: 
5 mg/ 5 mL diluted to 50 μg/mL•1.5 mL (75 μg)
Posology 
q.d.
Route of administration: 
Per os
Duration of use:
Day -1 and Day 17 (1 single dose, each)
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. The subjects willing to participate will be recruited to dose groups 
according to their temporal availability. As soon as enough subjects have been allocated to 
1 of the 12 cohorts (2 cohorts per dose group), the following subjects will be allocated to one 
of the other dose cohorts. Therefore, the allocation of subjects to dose cohorts is not 
influenced by trial personnel, but only by the subjects’ temporal availability. As the study 
includes healthy subjects from a homogenous population, relevant imbalances between the 
dose groups are not expected.
The list of subject and medication numbers 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 the method 'first come first served'. Once a subject number has been 
assigned, it cannot be reassigned to any other subject.
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. For details, 
refer to Section 1.2 and 2.1.


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BI 705564
DGs 1 to 5
The dose range for this trial was selected on the basis of the data obtained in the then ongoing 
first-in-human single rising dose trial 1408-0001. At that time, dose levels up to 80 mg under 
fasting conditions were well tolerated.
Although a single dose of 20 mg under fasting conditions resulted in a mean Cmax of about 
13 nM (in the range of the predicted therapeutic peak exposure), the mean predicted 
therapeutic systemic exposure of about 90 nM•h was not reached with a single dose of 80 mg 
under fasting conditions (AUC0-24 of about72 nM•h). The reason for testing further doses 
under fed conditions (high-fat, high-calorie breakfast) was the observation in the FE part with 
10 mg that peak exposure (Cmax) increased by about 90% and systemic exposure (AUC0-24) 
by about 60% under food (for details, refer to Section 1.2.1.5).
Due to a short half-life of BI 705564 (refer to Section 1.2.1.5), no major accumulation is 
expected.
Midazolam (DG 2 to 5)
The dose of midazolam used for the DDI evaluation was chosen to be 75 μg which is within 
the definition of a microdose, i.e. a 1/100th of the therapeutic dose (in case of midazolam 
7.5 mg) or 100 μg whichever is smaller. Since midazolam PK is dose proportional ranging 
from the microdose to the therapeutic dose, the microdose should still be able to accurately 
predict CYP3A4 DDI liability, while remaining below a pharmacologically active 
concentration.
A solution for injection was chosen for administration as an oral solution, as a solution for 
injection is meant to be diluted and, thus, there is data available regarding the stability and 
compatibility of a diluted solution. Furthermore, the solution for injection contains 
midazolam in isotonic saline solution, while the oral solution has added excipients, making it 
less than ideal for such a dilution. Finally, the IV solution has been successfully diluted and
administered orally as a microdose in previous clinical studies without any reports of AEs
[R17-3022, R17-3023].
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of units for 
placebo corresponds to the number of units of the respective dose level.


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Table 4.1.4: 1
BI 705564 and placebo treatments, oral administration
Dose
group
Substance
Pharmaceutical 
form
Unit strength
Number of units
per administration
Total 
daily dose
1
BI 705564
film-coated tablet
10 mg
1 tablets (10 mg) q.d. for 15 days
10 mg
2
BI 705564
film-coated tablet
10 mg
2 tablets (10 mg) q.d. for 15 days
20 mg
3
BI 705564
film-coated tablet
10 mg
4 tablets (10 mg) q.d. for 15 days
40 mg
4
BI 705564
film-coated tablet
10 mg
8 tablets (10 mg) q.d. for 15 days
80 mg
5
BI 705564
film-coated tablet
10 mg
6 tablets (10 mg) q.d. for 15 days 
60 mg
8
BI 705564
film-coated tablet
10 mg
4 tablets (10 mg) q.d. for 28 days
40 mg
1-5
Placebo*
film-coated tablet
--
Identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups 
DGs 1 to 5
The trial will be divided into two segments (a single dose and a multiple dose segment). 
During the single dose segment (Days 1 to 3), subjects will receive one single dose of 
BI 705564 (or placebo) on Day 1. The multiple dose segment will start on Day 4 and subjects 
will receive doses once daily for 14 days (Days 4 to 17). The doses applied will range from 
10 to 80 mg of BI 705564 (or placebo).
Table 4.1.4: 2
Midazolam, oral administration (DGs 2 to 5)
Dose
group
Substance
Pharmaceutical 
form
Unit strength
Number of units
per administration
Total 
daily dose
2-5
Midazolam
Solution for 
injection
--
1 (Day -1) and 1(Day 17)
75 µg
The oral solutions for dosing midazolam will be prepared according to the instruction given 
in Appendix 10.1 by pharmacists or qualified pharmacy staff members or qualified medical 
study personnel at the trial site under the responsibility of the investigator.
The trial medication will be administered to the subjects, while in a sitting/ 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. To ensure a dosing 
interval of 24 h, the administration of trial medication should take place at the same time 
every day.
In each treatment, a standard continental breakfast will be served 30 min before drug 
administration. The meal must be completely consumed prior to drug administration. The 
composition of the standard continental breakfast is detailed in Table 4.1.4: 3.


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Table 4.1.4: 3
Composition of the standard continental breakfast
Ingredients
kcal
1 bread roll
164
15 g butter
113
1 slice of Gouda cheese (approximately 40g)
146
1 slice of meat (approximately 20g)
33
1 cup of decaffeinated coffee or tea (without sugar)
2
Sum1
458
1
The total caloric content was supplied approximately as following: 88 kcal as protein, 133 kcal
as carbohydrate, and 237 kcal as fat.
Subjects will be hospitalized and kept under close medical surveillance throughout the study 
from Day-1 (microdose of midazolam in DGs 2 to 5) to Day 2 (single dose segment with BI 
705564) and from Day 4 to Day 18 (multiple dose segment with BI 705564; single dose of 
microdose of midazolam in DGs 2 to 5). During the first 2 h 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 for medical examination), or to sleep. For restrictions with regard 
to diet, refer to Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.


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Midazolam (DGs 2 to 5)
This segment 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.
BI 705564
This segment of the trial is designed double-blind with regard to subjects and investigators 
(as well as the research staff at the trial site) in order to eliminate observer or performance 
bias. This means avoiding systematic differences in assessments regarding the subject’s 
treatment (active drug or placebo). According to the rising dose design, the current dose level 
will be known to subjects and investigators.
At the trial site, access to the randomisation schedule is restricted to unblinded pharmacists
and pharmacy staff members. Access to the codes will be controlled and documented by a 
signed confidentiality statement, which will be stored in the TMF. Persons directly involved 
in the clinical conduct of the trial will not have access to the treatment allocation prior to 
database lock.
Regarding the sponsor, the database of this trial will be handled open-label, meaning that the 
trial functions of the sponsor are unblinded (including clinical monitor, data manager, 
statistician, bioanalyst, pharmacokineticist, pharmacometrician, drug metabolism scientist as 
well as dedicated CRO personnel). The objective of the trial is not expected to be affected.
The trial site will only be unblinded after locking of the database.
In addition, the trial bioanalyst/ TCPK/ TCPKa will request the randomisation codes prior to 
official unblinding to perform the interim/ preliminary PK analysis. He or she will confirm in 
writing that the codes will be treated confidentially.
Within the central ECG lab, the staff involved with interval measurements and morphological 
analyses will be blinded with respect to the treatment and also with regard to the recording 
date and time as well as planned 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.
If an interim safety analysis of ECG data is required, a part of the staff of the ECG laboratory 
may be unblinded. This part of the staff is strictly separated from that part of the staff which 
is involved with interval measurements and assessments of single ECGs (blinded).


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4.1.5.2
Procedures for emergency unblinding
BI 705564
For the blinded segment of this trial, the investigator will be supplied with a set of sealed 
envelopes containing the medication codes for each subject according to the randomisation 
scheme. The envelopes will be kept unopened at the trial site until the end of data collection. 
An envelope may only be opened in emergency situations when the identity of the trial drug 
must be known to the investigator in order to provide appropriate medical treatment or to 
assure safety of trial participants. If the envelope for a subject is opened, the sponsor must be 
informed immediately. The reason for opening the code break must be documented on the 
envelope or appropriate CRF page along with the date and the initials of the person who 
broke the code. At the close-out visit all envelopes are collected.
Midazolam (DGs 2 to 5)
As this part of the trial will be conducted in an open fashion, the treatment information will 
be known. Therefore, no emergency envelopes will be provided.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. Smaller boxes/ 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 (or for midazolam a placeholder for subject number),

Batch number.
Ampules will be labelled with the reduced requirements.
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.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator/ pharmacist/ investigational drug storage manager 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,

Availability of a signed and dated clinical trial contract between the sponsor and the 
head of the trial site,

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/ pharmacist/ investigational drug storage manager 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/ pharmacist will maintain records that document adequately that 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/ pharmacist 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
DGs 2 to 5
Midazolam will be administered (in dose groups 2 to 5) as a 75 µg dose on Days -1 and 17 to 
assess the potential influence of BI 705564 on CYP3A4 modulation. For dilution and 
administration instructions, refer to Appendix 10.1.


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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
DGs 1 to 5
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.
Paracetamol and acetylsalicylic acid should be avoided. Ibuprofen should preferably be used
for treatment of pain such as headache or toothache.


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4.2.2.2
Restrictions on diet and life style
DGs 1 to 5
While admitted to the trial site, subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 4 h after the first and last drug 
intake (Days -1, 1 and 17). On the remaining days (Days 4 to 16), food is not allowed for at 
least 2 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water served on Days -1, 1 and 17 at 2 h and 4 h 
post-dose (mandatory for all subjects).
During the days of urine collection, total fluid intake should be at least 1 litre and should not 
exceed 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 the first administration of trial medication until after the last 
PK sample is collected.
Alcoholic beverages are not permitted starting 48 h before administration of trial medication 
until after the last PK sample is collected.
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 10 h before administration of first 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 urinary excretion (not applicable for DG 8) 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, refer to 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
A continuous safety evaluation, including results of safety laboratories, ECG readings, 
recordings of vital signs and adverse events will be performed before the individual subject 
and the subsequent cohort is dosed.
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 705564 is the number [N (%)] of 
subjects with adverse reactions.
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.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death,


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
Is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death, if more severe,

Requires inpatient hospitalisation,

Requires prolongation of existing hospitalisation,

Results in persistent or significant disability or incapacity, or

Is a congenital anomaly/birth defect, or

Is deemed serious for any other reason, if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.2.2, subsections ‘AE collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters
1.
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
2.
aminotransferase (ALT, and/ or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 


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


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
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.
5.2.2.2
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/ concomitant diagnoses), and relevant changes from 
baseline are noted subsequently.
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary.
As a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
In DGs 1 to 5, as of Day 4, subjects will be questioned and examined for bleeding events at 
the time points indicated in the Flow Chart.
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  until an individual subject’s end of trial:
1.
All AEs (serious and non-serious) and all AESIs
2.
The only exception to this rule are AEs (serious and non-serious) and AESIs in 
phase 1 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: 
1.
The investigator does not need to actively monitor the subject for AEs but should 
only report related SAEs and related AESIs of which the investigator may 
become aware of by any means of communication, e.g. phone call. Those AEs 
should, however, not be reported in the CRF.


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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 at this early stage of development and
therefore conservatively defined as 7 days (for details, refer to Section 2.3.2.1). Therefore, all 
AEs reported until the end of trial examination (last per protocol contact) will be considered 
on treatment. 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 h) 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 following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions.

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered 
asbaseline conditions and should be collected in the CRF only.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no further 
information can be obtained.


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5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designee
for retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10.
Manual differential white blood cell count or urine sediment examinations will only be 
performed, if there is a clinically relevant abnormality in the automatic blood cell count or in 
the urinalysis, respectively.
The bleeding time will be measured by a modified Ivy method using a Surgicutt (Adult)
[R17-3223].


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Table 5.2.3: 1
Routine laboratory tests - DGs 1 to 5
Functional lab group
Test name 
SCR, EOT
D-4 to -2
D1(pre-), 2 & 4(pre)
D10(pre)
17(pre-)
D17(2h post-)
D18
Haematology
Haematocrit
x
x
x
x
x
x
x
Haemoglobin
x
x
x
x
x
x
x
Red blood cell count (RBC)
x
x
x
x
x
x
x
Reticulocyte count
x
White blood cell count (WBC)
x
x
x
x
x
x
x
Platelet count
x
x
x
x
x
x
x
Automatic WBC differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, 
monocytes, lymphocytes
x
x
x
x
x
x
x
Manual differential WBC (if 
automatic
differential WBC is abnormal
and clinically relevant in the 
opinion of the investigator)
Polymorphnuclear neutrophils (segs), 
band neutrophils (stabs), eosinophils, 
basophils, monocytes, lymphocytes
Lymphocyte differentiation 
(relative and absolute)
Lymphocyte panel, including B-cell 
(CD19+) count 
x
x
x
x
x
x
Serum immunoglobulins
IgA, IgG, IgM
x
Coagulation
Activated partial thromboplastin time 
(aPTT)
x
x
x
x
x
x
x
Prothrombin time (Quick’s test and INR)
x
x
x
x
x
x
x
Fibrinogen
x
x
x
x
x
x
x
Platelet function
Bleeding time* with the modified Ivy 
method using a Surgicutt
x
x
x
Enzymes
Aspartate transaminase (AST/GOT)
x
x
x
x
x
x
Alanine transaminase (ALT/GPT)
x
x
x
x
x
x
Alkaline phosphatase (AP)
x
Gamma-glutamyl transferase (GGT)
x
x
x
x
x
x
Glutamate dehydrogenase (GLDH)
x
Creatine kinase (CK), CK-MB, only if 
CK is elevated
x
Lactate dehydrogenase (LDH)
x
x
x
x
x
x
Lipase
x
x
x
x
x
x
Amylase
x
x
x
x
x
x
Hormones
Thyroid stimulating hormone (TSH)
x
Substrates
Plasma glucose
x
x
x
x
x
Creatinine
x
x
x
x
x
x
Total bilirubin
x
x
x
x
x
x
Direct bilirubin
x
x
x
x
x
x
Total protein
x
C-Reactive Protein (CRP)
x
x
x
x
x
x
Uric acid
x
Total cholesterol
x
Triglycerides
x
*
Measured up to 30 min


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Table 5.2.3: 1
Routine laboratory tests - DGs 1 to 5 (cont’d)
Functional lab group
Test name
SCR, EOT
D-4 to -2
D1(pre-), 2 & 4(pre)
D10(pre)
17(pre-)
D17(2h post-)
D18
Electrolytes
Sodium
x
x
x
x
x
x
Potassium
x
x
x
x
x
x
Calcium
x
Urinalysis (Stix)
Urine nitrite
x
x
x
x
x
Urine protein
x
x
x
x
x
Urine glucose
x
x
x
x
x
Urine ketone
x
x
x
x
x
Urobilinogen
x
x
x
x
x
Urine bilirubin
x
x
x
x
x
Urine erythrocytes
x
x
x
x
x
Urine leukocytes
x
x
x
x
x
Urine pH
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)
x
Faecal occult blood
Haemoccult Test (Firma Beckman 
Coulter)
x
x
x
D
Day
pre-
pre-dose
post- post-dose


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The tests listed in Table 5.2.3: 3 and 5.2.3: 4 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 admission to study site.


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Table 5.2.3: 3
Exclusionary laboratory tests - DGs 1 to 5
Functional lab group
Test name
SCR
D-1 & 4(all pre-)
Drug screening (urine)
Amphetamine/MDA
x
x
Barbiturates
x
x
Benzodiazepine
x
x
Cannabis
x
x
Cocaine
x
x
Methadone
x
x
Methamphetamines/MDMA/XTC
x
x
Opiates
x
x
Phencyclidine
x
x
Tricyclic antidepressants
x
x
Alcohol test (breath)
x
x
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
x
Hepatitis B core antibody (qualitative)
x
Hepatitis C antibodies (qualitative)
x
HIV-1 and HIV-2 antibody (qualitative), HIV-1 p24-antigen
x
D
Day
pre-
pre-dose


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To encourage compliance with alcoholic restrictions, a breath alcohol test 
 
will be performed at screening and at admission to trial site, 
and may be repeated at any time during the study at the discretion of an investigator or his/ 
her 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 urinalysis stix, drug screening and Haemoccult test which will be performed 
at the trial site using Combur9 Test, AccuSign® DOA 10 Test and Haemoccult Test 
 
 respectively.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph 
 
at the time points given in the Flow Chart. Electrode placement will be performed 
according to the method of Wilson, Goldberger and Einthoven, modified by Mason and Likar 
(hips and shoulders instead of ankles and wrists). Precise electrode placement will be marked 
with an indelible mark on the skin to allow reproducible placement throughout the study.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment so that all subjects are at 
complete rest. All ECGs will be recorded for a 10-second duration after subjects have rested 
for at least 5 min in a supine position. ECG recording will always precede all other study 
procedures scheduled for the same time point (except for blood drawing from an intravenous 
cannula that is already in place) to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 s applies as well. The repeat ECGs are assigned to the respective scheduled 
time point. 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 in the sponsor’s database.
Unscheduled ECGs will not be included into the statistical analysis of interval lengths.


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Data transfer
ECGs, taken at time points specified in the Flow Chart, will be transferred electronically to 
the central ECG lab
for evaluation.
In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded.
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (refer to TMF).
Evaluation
1.
Central ECG lab
Central ECG lab evaluation (of Visit 2 ECGs only) will be performed for the first of 
three replicate ECGs per time point given in the Flow Chart. 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 baseline, where 3 triplicate ECGs are recorded, only the first triplicate ECG (i.e. 3 
single ECGs) will be evaluated.
RR and QT intervals will be determined semi-automatically, whereas PR, QRS 
intervals and QRS-axis are measured automatically by a validated GE 12-SL-
algorithm or equivalent.
Heart rate (HR) and the QT interval corrected for HR (QTc e.g. QTcF and QTcB) will 
be determined by the sponsor (refer also to TSAP for details).
All semi-automatic interval measurements in one subject will be performed on the 
same lead. The intervals will be measured from four cardiac cycles (beats) in lead II. 
If lead II shows a flat T wave or is not measurable for any reason, lead V5 will be 
used, or if that lead is not measurable, then lead I will be used. The lead actually used 
will be reported in the CTR.
For automatic interval measurements no lead will be provided.
For blinding arrangements, refer to Section 4.1.5.1. No more than two blinded readers 
will evaluate all ECGs of the study. ECGs from a particular subject should be 
evaluated by a single reader. For quality assurance and control of measurements, all 
ECGs of a subject will be subsequently reviewed by the ECG technician supervisor or 
his/ her designee to assess the overall variance of the measured intervals and, to detect 
accidental switching of leads and/ or false subject assignments of the ECGs. After 
quality control, the fiducial point markings will be reviewed by the cardiologist 
assigned to the study.
Evaluation of ECGs will comply with the ICH E14 guidance document and 
supplements [R07-4722, R16-0366] as well as the FDA requirements for annotated 
digital ECGs [R09-4830].


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2.
Trial site
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (refer also to Section 3.3) of a subject and for the 
assessment of cardiac safety during the study, the QT and QTcB values generated by 
the computerised ECG system or their manual corrections by the investigators will be 
used. In doubtful cases, ECGs may be sent upfront (i.e. prior to the regular data 
transfer) for cardiologic assessment by the central lab. In this case, these centrally 
measured results would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening), if judged 
clinically relevant by the investigator. Any ECG abnormalities will be monitored carefully 
and, if necessary, the subject will be removed from the trial and will receive the appropriate 
medical treatment. 
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap, GE Medical Systems, Freiburg, Germany) at the times indicated in the Flow 
Chart, after subjects have rested for at least 5 min in a supine position. All recordings should 
be made using the same type of blood pressure recording instrument on the same arm, if 
possible.
Oral body temperature will be measured at times, indicated in the Flow Chart, using a 
standard device.
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, oral body 
temperature), 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, body weight 
and a physical examination.
As part of questioning for AEs, at time points indicated in the Flow Chart, starting with 
Day 4, subjects will be examined for infections and bleeding events which include, e.g. 
inspection of skin and visible mucosal surfaces (petechial bleeding or bruising), faecal test 
for occult blood and haematuria.


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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 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 PK parameters and 
measurements outlined in Section 5.5 are generally used assessments of drug exposure. The 
biomarkers and PD parameters 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 PK sampling will be recorded in the CRFs.
Actual sampling times will be used for determination of PK parameters.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK data) including addition of samples and 
visits as long as the total blood volume taken per subject does not exceed 500 mL. Such 
changes would be implemented via non-substantial CTP amendments.
5.5.1
Pharmacokinetic endpoints
The following PK parameters will be determined if feasible:
5.5.1.1
Secondary endpoints
BI 705564
After the first dose:

AUCτ,1 (area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ after administration of the first dose)

Cmax (maximum measured concentration of the analyte in plasma)
After the last dose:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)


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Midazolam (DGs 2 to 5)
After the first and last doses:

Cmax and AUC0-tz


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
BI 705564
For quantification of BI 705564 plasma concentrations, 2.7 mL of blood will be taken from 
an antecubital or forearm vein into an K3-EDTA (tripotassium ethylenediaminetetraacetic 
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venipuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 
2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and stored in 
polypropylene 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 120 min, with interim storage of blood samples and aliquots in ice water, 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 
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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Midazolam (DGs 2 to 5)
For quantification of midazolam plasma concentrations, 4 mL of blood will be taken from an
antecubital or forearm vein into a K3-EDTA-anticoagulant blood drawing tube at the times
indicated in the Flow Chart. Blood will be withdrawn by means of either an indwelling
venous catheter or by venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 
2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and stored in 
polypropylene tubes. The first aliquot should contain at least 1.0 mL plasma the second 
aliquot should contain the remaining plasma. The process from blood collection until transfer 
of plasma aliquots into the freezer should be completed within 120 min, with interim storage 
in ice water, 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 the analytical laboratory, plasma samples will be stored at about 
-20°C or below until analysis.
At a minimum, 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 after the final study
report has been signed.


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5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 705564 plasma concentration
BI 705564 concentrations in plasma will be determined by a validated LC-MS/ MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis. 
 
.
As described in Section 4.1.5, the bioanalyst will be unblinded during sample analysis.
5.5.3.3
Analytical determination of Midazolam plasma concentration (DGs 2 to 5)
Midazolam concentrations in plasma will be determined by a validated LC-MS/ MS assay. 
All details of the analytical methods will be available prior to the start of sample analysis.
The analyses will be performed at the Department of Drug Metabolism and 
Pharmacokinetics, BI Pharma GmbH & Co. KG, Biberach, Germany.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day -1(in DGs 1 to5) and Day 1 (in DG 8) 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 ± 30 min is acceptable.
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 15 min for the first 4 h after trial drug administration and ± 30 min thereafter. 
If scheduled at the same time point in the Flow Chart, ECG should be the first and meal the 
last activity. Furthermore, if several measurements, including venepuncture, are scheduled at
the same time, venepuncture should be the last of activities due to its inconvenience to the 
subject and possible influence on physiological parameters with the exception of screening 
and EOT visit.
For planned individual plasma concentration sampling times and urine collection intervals,
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times must be recorded and will be used for the determination
of PK parameters.
If a subject misses an appointment, it will be rescheduled, if possible. The relevance of 
measurements outside permitted time windows will be assessed no later than at the Blinded 
Report Planning Meeting.
DGs 1 to5
BI 705564 will be administered on Day 1 and on Day 4 through to Day 17 at 0h (planned 
time).
Midazolam will be administered on Day -1 and on Day 17 at 0h.
The tolerance for drug administration on Days -1, 1 and 17 will be ± 1 min. On all other 
treatment days it will be ± 10 min.


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
6.2.2
Treatment period
Trial medication will be taken orally by each subject under direct supervision of the 
investigator or his/ her designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
For details on time points and procedures for sample collection refer to Flow Chart and 
Section 5.5.2.
Safety measurements performed during the treatment period are specified in Section 5.2 and 
in the Flow Chart. For details on time points for all other trial procedures, refer to the Flow 
Chart. AEs and concomitant therapy will be assessed continuously from screening until the 
end of trial examination.
DGs 1 to5
Each subject will receive a single dose of BI 705564 or placebo on Day 1 and from Day 4 to 
Day 17 (14 days).
A single midazolam microdose will be administered on Day -1 and on Day 17 (DGs 2 to 5).
Study participants will be admitted to the trial site the morning of Day -1, at which point the 
first midazolam microdose will be administered. They will be kept under close medical 
surveillance for at least 24 h following the first BI 705564 administration on Day 1. Subjects 
will then be allowed to leave the trial site the morning of Day 2, after formal assessment and 
confirmation of their fitness by the investigator or 
 designee. On Day 2 in the evening and 
Day 3 in the morning, the study will be performed in an ambulatory fashion.
In the morning of Day 4, participants will be admitted to the trial site again and kept under
close medical surveillance for at least 24 h following the last drug administration on Day 17.
After this 14 day hospitalization period, subjects will then be allowed to leave the trial site 
after formal assessment and confirmation of their fitness by the investigator or 
designee. 
On Days 18 to 20, the study will be performed in an ambulatory fashion.


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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, refer to Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
BI 705564
DGs 1 to 5
The primary objective of this trial is to investigate the safety and tolerability of BI 705564. 
This will be achieved 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 are not planned (as 
explained in Section 7.2).
The secondary objective is the exploration of the pharmacokinetics  and pharmacodynamics 
(PD) of BI 705564. Endpoints, as specified in Sections 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.
Trough concentration values will be analysed regarding attainment of steady state as a pre-
requisite for calculation of steady state parameters. Additionally, the linearity index will be 
estimated, if feasible. PD markers and their percentage change from pre-dose will be 
summarized.
Midazolam (DGs 2 to 5)
The relative bioavailability of midazolam in the presence and absence of BI 705564 will be 
evaluated separately within dose levels 2 to 5 and separately for all subjects receiving 
placebo. For details, refer to Section 7.3.3.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of 6 different DGs (DG 3 
will be exposed to 40 mg) of 
BI 705564 are to be determined on the basis of the investigated parameters in comparison to 
placebo. It is not planned to test any statistical hypotheses with regard to these variables in a 
confirmatory sense. Instead, they will be described in their entirety and evaluated by 
descriptive statistical methods.


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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.
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 Blinded Report Planning 
Meeting and provided in the TSAP.
7.3.1
Primary analyses
Analysis of safety and tolerability is described in Section 7.3.4.
7.3.2
Secondary analyses
The secondary parameters (refer to 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 parent drug.
Plasma 
concentration data and parameters of a subject will be included in the
statistical 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 Blinded 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:

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),

Missing samples/ concentration data at important phases of PK disposition curve.


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The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS) who 
provide at least one PK parameter that was not excluded according to the description above.
Assessment of dose proportionality
Dose proportionality will be assessed using the PK endpoints as specified in Section 5.5.1.1.
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 PK endpoint for subject j at dose level i; where i = 1, 2, 
…, 5, j = 1, 2, …, 8,

intercept parameter,
β
slope parameter,
iX
logarithm of dose i,
ijε
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 PK 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.
Linearity index
Linearity with respect to multiple administration will be explored using the linearity index 
(LI) that will be computed as follows:



0
,
AUC
AUC
LI
ss



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In order to construct a confidence interval for LI, a statistical model using AUCτ,ss and AUC 
0-∞will be set up: A linear model on the logarithmic scale including effects for 'subject' and 
'AUC type' can be applied, where 'subject' is a random effect and 'AUC type' a fixed effect.
 =  + 
 + s + e , where

logarithm of the response (AUC after first dose, AUC after last dose) for subject j
and AUC type i; where i = 1 (after first dose) or 2 (after last dose) and j=1, 2,…, 8,

the overall mean,


the AUC type I,
s
the effect associated with subject j (random effect),
e
random error associated with subject j at AUC type i (assumed to be independent 
and identically normally distributed).
A pairwise comparison of both areas via the log transformed difference
log(
,
) = log(,) - log()
will then be performed including calculation of a 2-sided 95% CI. The back transformed
point estimate then represents the estimate of LI. Perfect linearity with respect to multiple 
administrations holds true, if this index equals unity.
Generally, this model will be applied to each dose level separately. If there is evidence that 
the areas are comparable across dose levels, they can be analysed simultaneously. The 
corresponding model will then include the log transformed dose as (additional) covariate.
Attainment of steady state
Attainment of steady state will be explored by using the trough concentrations of BI 705564
between Days 4 and 18 and the concentrations taken directly at the end of the first and the 
last dosing interval for each dose level. Pairwise comparisons of concentrations are 
performed using 2-sided 95% CIs based on the t-distribution. The calculation is based on a 
repeated measures linear model on the logarithmic scale.
 =  + 
 + s + e , where

logarithm of the concentrations for subject j at time i, i = 1, 2, … and
j=1, 2,…, 8,

the overall mean,


the effect associated with time point i (repeated effect),
s
(random) effect of subject j, j=1, 2, ..., 8,
e
random error associated with subject j at time i (assumed to be independent
and identically normally distributed).


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Dose can be included as an additional covariate, if there is evidence that the trough 
concentration profiles are comparable across dose levels.
The model will be used to explore the time to steady state by comparing concentrations 
pairwise from different time points: log-transformed differences between all subsequent time 
points (log(Cpre,i/Cpre,j) = log(Cpre,i) - log(Cpre,j), where j>i) will be compared and adjusted 
means (Least Squares Means) as well as 2-sided 95% CIs will be calculated. Thereafter, these 
quantities will be back-transformed by exponentiation to give the corresponding (adjusted) 
ratio and CI.
Comparisons which reveal CIs (for the adjusted ratio) not including 100% will be inspected 
to determine, if the differences between time points are resulting from not yet attaining 
steady-state.
For further details, refer to the TSAP (such as selection of covariance structure and 
comparison of time points).
Graphical displays
To support the analyses of dose proportionality, linearity and attainment of steady state, 
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 (geometric) mean 
plasma concentration time profiles.


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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.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. As the treatment duration in DG 8 is different from the treatment duration 
in DGs 1 to 5, all safety outputs for the placebo group will be displayed both, together and 
separately for DGs 1 to 5 and DG 8. The active treatment groups will be compared to the 
placebo group in a descriptive way. Tabulations of frequencies/ proportions will be used for 
the evaluation of categorical (qualitative) data, and tabulations of descriptive statistics will be 
used to analyse continuous (quantitative) data.
The analyses will be done by ‘randomised treatment’.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (refer to 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).
AEs 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 (refer to Section 5.2.2.1) and other significant 
AEs (according to ICH E3) will be listed separately.


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Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.
A centralised evaluation of all 12-lead ECGs recordings (refer to Section 5.2.4) will be the 
basis for the ECG variables QT, HR, QTcF, QTcB, PR, QRS, RR, and further derived ECG 
parameters. The baseline value of an ECG variable is defined as the mean of the triplicate
ECG measurements prior to drug administration. The derivation of the quantitative and 
qualitative ECG parameters and their analyses will be described in the TSAP.
7.3.5
Preliminary PK analyses
A preliminary analysis of PK parameters (AUC0-24 and Cmax of BI 705564), provided as 
individual values and geometric means of the first cohort per dose level, will be performed 
for

Dose levels 1, 2, 3 and 5 (n) before proceeding to the subsequent dose level 2, 3, 5 
and 4
(Note: Data from the first cohorts of the above mentioned dose levels will be sufficient as 
long as the data from at least 2 subjects on active treatment were available).
In contrast to the final PK/ PD calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows or not. Therefore, minor deviations of preliminary and final results may occur. 
The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without subject identification. The preliminary 
results will be distributed to the Investigator and the trial team.
Depending on the results of available preliminary PK/ PD analyses, the tolerability and safety 
of the compound, and changes of dosing schedule (e.g. additional intermediate doses),
additional PK/ PD 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 his/her deputy) is allowed to postpone further dose progression until a 
preliminary analysis of the data already obtained has been performed.
7.3.6
PK analyses
The PK 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).


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Subjects who are not included in the PKS (refer to Section 7.3.1) will be reported with their 
individual plasma/ urine concentrations and individual PK parameters. However, they will 
not be included in descriptive statistics for plasma/ urine concentrations, PK parameters or 
other statistical assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of PK parameters. Concentrations used in the PK calculations 
will be in the same format as provided in the bioanalytical report (that is, to the same number 
of decimal places provided in the bioanalytical report).


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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 (DGs 1 to 5)
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), or BLQ (below the lower limit of quantification) will be displayed as 
such and not replaced by zero at any time point (this rule also applies to the lag phase,
including pre-dose values).
7.4.3
PK 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 will 
be set to zero. All other BLQ 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
Subjects will be randomised within each dose group in a 4:1 ratio which reflects the ratio of 
subjects receiving active drug to placebo.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system which involves 
a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
also to Section 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
BI 705564
It is planned to include a total of 50 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 10 subjects per dose group (8 on active treatment, and 


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2 on placebo) is commonly used in multiple-rising dose studies of the present type and is in 
general considered as sufficient for the exploratory evaluation of multiple dose safety and 
pharmacokinetics.
Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose will not be exceeded. Thus, the actual number of subjects entered 
may exceed 50, but will not exceed 70 subjects entered.
Midazolam (DGs 2 to 5)
It is planned to enter a total of 50 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.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the investigator or the trial site and 
the sponsor. As a general rule, no trial results should be published prior to finalisation of the 
CTR.
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 Boehringer 
Ingelheim in accordance with the local data protection law. The level of disclosure must also 
be explained to the subject.
The subject must be informed that his medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/ IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/ inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/ IECs, or by regulatory authorities. The quality assurance 


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auditor will have access to all medical records, the investigator’s trial-related files and
correspondence, and the informed consent documentation of this clinical trial.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. Refer to Section 4.1.5.2 for 
rules about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/ IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/ on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.


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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.
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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472
Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c12104992-03
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Rheumatoid Arthritis, 09 Jul 2018.
n00244934-01
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Systemic Lupus Erythematosus. 25 February 2016.
n00247877-01
 Prediction of BI 738797 Pharmacokinetics and 
Therapeutic dose in Human. 20 Jan 2016.
n00248910-01
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19 September 2016.
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 Inhibition of Cytokine Production (IL-6) from B cells. 
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n00248913-01
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Therapeutic Dose in Human. 16 Aug 2016.
n00250625-01
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Toxicity and Toxicokinetics Study in the Rat. (BI study no. 16R076). 
Draft dated 13 January 2017.
n00250668-01
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Toxicity and Toxicokinetics Study in the Dog Followed by a Four-Week 
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n00252848-01
 A Pharmacological Assessment of the Effect of BI 705564 
BS on the Respiratory System of Wistar Han Rats (BI study no. 16R057) 
13 October 2016.
n00252850-01
 A Pharmacological Assessment of the Effects of 
BI 705564 BS on the Central Nervous System of Wistar Han Rats. 
(BI study no. 16R058). 13 October 2016.
n00252895-01
 BI 705564: In Vivo Mammalian Erythrocyte Micronucleus 
Assay in Rats. (BI study no. 16R065) 20 January 2017.
n00252978-01
 Species comparison of in vitro protein binding of [14C]BI 
705564 to rat, dog and human plasma proteins and to the isolated 
proteins HSA and hAGP. 13 Oct 2016.
n00253071-01
 Validation of an LC/MS/MS Bioanalytical Method for the 
Analysis of BI 705564 in Dog Plasma. 11 Nov 2016.
n00253072-01
 A Pharmacological Assessment of the Effects of 
BI 705564 BS on the Cardiovascular System of the Beagle Dog Using 
Telemetry. (BI study no. 16R059) 13 January 2017.
n00253073-01
 Validation of an LC-MS/MS Bioanalytical Method for the 
Analysis of BI 705564 in Rat Plasma. 11 Nov 2016.
n00253091-01
 BI 705564 (30201129) Invitrogen Combined. 
14 October 2016.
n00253092-01
 BI 705564 EuroFins 
 Profiler .14 October 2016.
n00253250-01
 BI 705564: In Vitro Mammalian Cell Micronucleus Assay in 
Human Peripheral Blood Lymphocytes (HPBL) Cells (BI study no. 
16R064) 19 December 2016.


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n00253255-01
 BI 705564: Bacterial Reverse Mutation Assay. (BI study 
no. 16R063). 15 December 2016.
n00253256-01
 BI 705564: Effect on hERG inactivating Tail Currents 
recorded from Stably Transfected HEK 293 cells. (BI study no. 
16R068). 20 January 2017.
n00253287-01
 Influence of BI 705564 (0.2, 0.6 and 2 mg/kg PO) on 
hemodynamic and electrocardiographic parameters in conscious dogs. 
(BI study no. GP2015/0211/PH5). 09 December 2016.
n00253487-01
 BI 705564: In vitro inhibition studies on 
cytochrome P450 dependent metabolic reactions. 08 Nov 2016.
n00253544-01
 Quantitative whole-body autoradiography in male pigmented 
rats after single oral administration of [14C]BI 705564. 
18 November 2016.
n00255825-01
 Assessment of inactivation of the major 
cytochrome P450 isoforms by BI 705564. 26 Jun 2017.
n00257025-01
 Evaluation of induction potential of cytochrome 
P450 isoforms by BI 705564 in cultured human hepatocytes. 
11 Jul 2017.
n00257435-01
Excretion of radioactivity in urine, faeces and bile after oral and 
intravenous administration of [14C]BI 705564 to rats. 02 Aug 2017.
n00259630-01
[14C]BI 705564: Metabolite profiling and identification in Wistar Han 
rats. Report in progress.
n00260845-01
[14C]BI 705564: Metabolite profiling and identification in human 
hepatocytes. Report in progress.


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10.
APPENDICES
10.1
DILUTION INSTRUCTIONS FOR MIDAZOLAM (DG 2 TO 5)
10.1.1
Required equipment and dosing aids – overview
Dosing and diluting syringes:
1.
Henke Sass Wolf 2-part disposable HSW NORM-JECT® Syringes 3 mL
2.
Henke Sass Wolf 2-part disposable HSW NORM-JECT® Syringes 24 mL
3.
Needle tip
Only CE certified syringes WITHOUT rubber stoppers are to be used!


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10.1.2
Dilution procedure
Solution for use with up to 13 subjects
Step 1: 
Open the commercial isotonic saline solution (0.9% NaCl).
Step 2: 
Attach a needle tip to the 3 mL syringe and withdraw a bit more than 1 mL of 
the midazolam solution [concentration: 1 mg/mL] from the originator 
ampoule using a 3 mL syringe.
Step 3:
Remove any air bubbles in syringe (turn upside down and gently push out air 
by depressing the plunger); ensure that exactly 1 mL midazolam solution 
remains in the 3 ml syringe.
Step 4:
Remove and dispose of needle tip; transfer the full 1 mL of midazolam 
solution into an appropriate glass container (with cap) by completely 
depressing the plunger on the 3 mL syringe.
Step 5: 
Attach a needle tip to the 24 mL syringe and withdraw a bit more than 19 mL 
isotonic saline solution into the 24 mL syringe; remove air bubbles (see 
Step 3) and ensure exactly 19 mL isotonic saline solution remains in the 24 ml 
syringe.
Step 6:
Remove and dispose of needle tip; transfer the full 19 mL of isotonic saline 
solution into the same glass container with the midazolam solution by 
completely depressing the plunger on the 24 mL syringe.
Step 7:
Following addition of the midazolam and saline solutions into the glass 
container, ensure the glass container is closed using the corresponding cap. 
The content of the glass container should be mixed thoroughly by swirling 
gently for approximately 1 min.
Step 8:
Extract a little more than 1.5 mL of the dilution solution using a new 3 ml 
syringe; remove bubbles (see Step 3) and ensure that exactly 1.5 mL of the 
diluted midazolam solution (final concentration: 50 µg/mL) remains in the 
3 mL syringe; the solution is now ready for oral administration. 
The final midazolam microdose Oral Solution concentration is 50 ug/mL, for 
administration of 1.5 mL (75 ug), which can be administered per os directly from the 
syringe.


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10.1.3
In-use stability
The chemical in-use stability of the dilution solution is 24 h after its preparation, incl. storage
at room temperature (15-25°C) in Henke Sass Wolf 2-part disposable HSW NORM-JECT®
syringes until administration.
10.1.4
Mode of application
Microdoses of Midazolam will be administered orally as specified in the Clinical Trial 
Protocol (refer to Flow Chart for dosing schedule). 1.5 ml of diluted midazolam solution 
(concentration 50 µg/mL) will be administered from a syringe, as described above.
Please note that it is the responsibility of the TCM to assure that appropriate supplies are used 
for administration of a dose and dosing is limited to the allowed dosing range for a specific 
dose formulation as stated in this Dilution Instruction.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
02 November 2017
EudraCT number
2017-003269-85
BI Trial number
1408-0002
BI Investigational Product(s)
BI 705564
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising oral doses 
of BI 705564 (double-blind, randomised, placebo-
controlled, parallel-group design) and evaluation 
of midazolam interaction (nested, open, fixed-
sequence, intra-individual comparison) 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
Section 2.3.2.6 , Section 3.1 and Section 5.2
Description of change
The following statement was added:’ A 
continuous safety evaluation, including results of 
safety laboratories, ECG readings, recordings of 
vital signs and adverse events will be performed 
before the individual subject and the subsequent 
cohort is dosed.’
Rationale for change
Specification of methods for continuous safety 
evaluation before dosing individual subjects and 
subsequent cohorts due to request of BfArM


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Number of global amendment
1
Section to be changed
Throughout the document
Description of change
Minor orthographical and stylistic mistakes were 
corrected
Rationale for change
N/A


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Number of global amendment
2
Date of CTP revision
27 November 2017
EudraCT number
2017-003269-85
BI Trial number
1408-0002
BI Investigational Product(s)
BI 705564
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising oral doses 
of BI 705564 (double-blind, randomised, placebo-
controlled, parallel-group design) and evaluation 
of midazolam interaction (nested, open, fixed-
sequence, intra-individual comparison) 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, footnote 16
Sections 2.1, 2.2, 2.3.2.6
Sections 3.1, Figure 3.1: 1
Sections 4.1.1 (Table 4.1.1: 5), 4.1.4, Table 4.1.4: 
2, 4.1.5.1, 4.2.1
Sections 5.5.1.1, 5.5.1.2, 5.5.2.1
Sections 6.1, 6.2.2
Sections 7.1.1, 7.3.3
Description of change
Microdoses of midazolam only be applied in dose 
groups 2 to 5
Rationale for change
Logistical issues
Section to be changed
Flow Chart
Description of change
Allocation to treatment BI 705564 or placebo will 
be performed at Day-1, as already described in 


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Number of global amendment
2
footnote 14
Rationale for change
Correction of inconsistency
Section to be changed
Throughout the document
Description of change
Minor orthographical and stylistic mistakes were 
corrected
Rationale for change
N/A


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Number of global amendment
3
Date of CTP revision
04 April 2018
EudraCT number
2017-003269-85
BI Trial number
1408-0002
BI Investigational Product(s)
BI 705564
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising oral doses 
of BI 705564 (double-blind, randomised, placebo-
controlled, parallel-group design) and evaluation 
of midazolam interaction (nested, open, fixed-
sequence, intra-individual comparison) 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
An intermediate dose level of 60 mg will be 
inserted according chapter 3.1 of this CTP. The 
randomised trial medication of DG 5 (160 mg) 
will be used for this dose level (only the 10 mg 
tablets will be administered). Therefore the inter-
mediate dose level will be named DG 5, subject 
numbers will be 501-510. If DG 5 is safe and well 
tolerated it may be followed by the original plan-
ned DG 4 (80 mg). The originally planned dose 
level of 160 mg BI 705564 will not be performed. 
Section to be changed
Synopsis, 2.2., 2.3.2.6, 3.1, 4.1.1, 4.1.4, and 7.3.5
Description of change
Insertion of intermediate dose level of 60 mg
Rationale for change
In the light of bleeding time prolongation in all 
subjects on active treatment (expected side effect 
– see 2.3.2.1) and observed cases of haematuria  
[1 subject with macrohaematuria (accompanying 
urinary tract infection), 2 subjects with micro-
haematuria (positive sediment in 1 case)] it was 
decided to reduce the escalation step.


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Number of global amendment
4
Date of CTP revision
08 August 2018
EudraCT number
2017-003269-85
BI Trial number
1408-0002
BI Investigational Product(s)
BI 705564
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising oral doses 
of BI 705564 (double-blind, randomised, placebo-
controlled, parallel-group design) and evaluation 
of midazolam interaction (nested, open, fixed-
sequence, intra-individual comparison) 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
New information regarding the additional dose 
group (DG) 8 is found in most sections of the 
document.
Description of change
(1) Extension of treatment duration with 40 mg of 
BI 705564 from 15 to 28 days to further 
characterize the substance with respect to 
bleeding time.
(2) Additional stopping rule for individual 
subject: Further application of study medication 
will be stopped, should the subject show at Day 
15 or Day 21 a prolonged bleeding time of above 
1440 s (3 x ULN).
(3) In addition to bleeding time, the closure time 
will be measured with the Innovance® PFA-200, 
using the Dade® PFA Collagen/EPI and the 
Dade® PFA Collagen/ADP test cartridges to 
further monitor and characterize platelet function.


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Number of global amendment
4
(6) No application of midazolam as micro-dose, 
since the influence of midazolam on BI 705564 
was already characterized in previous DGs.
(7) No measurement of urine PK and plasma 
metabolites, since these parameters were already 
sufficiently characterized in previous DGs.
(8) Correction of inconsistencies regarding the 
unblinding of the study.
(9) Stylistic adjustments and correction of 
typographic errors.
Rationale for change
Refer to ‘description of change’, above


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c18130121
5.0
clinical-trial-protocol-revision-04
Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple rising oral
doses of BI 705564 (double-blind, randomised, placebo-controlled, parallel-group
design) and evaluation of midazolam interaction (nested, open, fixed-sequence,
intra-individual comparison) in healthy male subjects
Author-Trial Clinical Monitor
08 Aug 2018 16:36 CEST
Approval-Team Member Medicine
08 Aug 2018 16:57 CEST
Author-Trial Clinical
Pharmacokineticist
08 Aug 2018 16:59 CEST
Author-Trial Statistician
09 Aug 2018 09:08 CEST
Approval-Therapeutic Area 
10 Aug 2018 04:25 CEST
Verification-Paper Signature
Completion
10 Aug 2018 08:43 CEST


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 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c18130121
5.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c25683256-01
BI Trial No.:
1408-0002
Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of
multiple rising oral doses of BI 705564 (double-blind, randomised,
placebo-controlled, parallel-group design) and evaluation of
midazolam interaction (nested, open, fixed-sequence, intra-
individual comparison) in healthy male subjects
Including Protocol Amendment 1, 2, 3 and 4 [c18130121-05]
Investigational
Product:
BI 705564
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
14 MAR 2019 SIGNED 
Version:
Final
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINTS...................................................................................10
5.2
SECONDARY ENDPOINTS.............................................................................10
5.2.1
Key secondary endpoints....................................................................................10
5.2.2
Secondary endpoints...........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................14
6.1
TREATMENTS...................................................................................................14
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................17
6.3
SUBJECT SETS ANALYSED...........................................................................19
6.5
POOLING OF CENTRES .................................................................................21
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................21
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................22
7.
PLANNED ANALYSIS......................................................................................26
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........28
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................28
7.3
TREATMENT COMPLIANCE........................................................................28
7.4
PRIMARY ENDPOINTS...................................................................................29
7.5
SECONDARY ENDPOINTS.............................................................................29
7.5.1
Key secondary endpoints....................................................................................29
7.5.2
Secondary endpoints...........................................................................................29
7.7
EXTENT OF EXPOSURE.................................................................................36
7.8
SAFETY ANALYSIS..........................................................................................36
7.8.1
Adverse events.....................................................................................................36
7.8.2
Laboratory data ..................................................................................................38
7.8.3
Vital signs.............................................................................................................38
7.8.4
ECG......................................................................................................................38
7.8.5
Others...................................................................................................................40
8.
REFERENCES....................................................................................................41


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10.
HISTORY TABLE..............................................................................................46


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR .........................................................15
Table 6.2: 1
Important protocol deviations ..........................................................................18
Table 6.3: 1
Subject sets analysed........................................................................................20
Table 7.5.2: 1 Available pre-dose concentrations for steady state assessment .......................32
Table 10: 1
History table .....................................................................................................46


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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
AUCτ,1
Area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ after administration of the first dose
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ
BI
Boehringer Ingelheim
BTK
Bruton’s tyrosine kinase
BWU
Bioavailability/Bioequivalence, Within-Subject Design, uncontrolled
CARE
Clinical Analysis and Reporting Environment
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ
Cpre,t
Pre-dose concentration of the analyte in plasma immediately
before administration of the next dose at time point t, trough level
Cτ
Plasma concentration at the end of the dosing interval
Cτ,ss
Plasma concentration at the end of steady state
CRF
Case Report Form
CS
Compound symmetry
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic Coefficient of Variation


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Term
Definition / description
DB
Dose Proportionality, Between-Subject Design
DBLM
Database Lock Meeting
DG
Dose group
ECG
Electrocardiogram
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
HR
Heart rate
ICH
International Conference On Harmonisation
iPD
Important Protocol Deviation
LI
Linearity Index
LLT
Lower Level Term
Max
Maximum
MedDRA
Medical Dictionary For Regulatory Activities
Mida
Midazolam
Min
Minimum
MMRM
Mixed model with repeated measurements
N
Number of non-missing observations
O*C
Oracle Clinical
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
PK parameter analysis set
PT
Preferred Term
REML
Restricted maximum likelihood
QD
Quaque die, once daily
RAGe
Report Appendix Generator system
REP
Residual Effect Period


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Term
Definition / description
RPM
Report Planning Meeting
SAS®
Statistical Analysis System
SD
Standard Deviation
SOC
System Organ Class
TMCP
Translational Medicine and Clinical Pharmacology
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 or higher, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated Clinical Analysis and 
Reporting Environment (CARE), including SAS® (current Version 9.4, by SAS Institute Inc., 
Cary, NC, USA), and a number of SASTM-based tools (e.g., macros for the analyses of 
Adverse Event (AE) data or laboratory data; Report Appendix Generator system (RAGe) for 
compilation/formatting of the Clinical Trial Report (CTR) appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP. The following change compared to the protocol will be made:
The definition of study phases for the analyses of adverse events is contradictory in the CTP.
As the residual effect period (REP) is not known at this early stage of development, the on 
treatment phase for each subject will be defined as time of first administration of BI / Placebo 
until 0:00h on the day after the subject’s trial termination date. Therefore, no REP and no 
follow-up period will be considered.
According to the Reference Document 3 of the Boehringer Ingelheim (BI) Statistical Position 
Paper on Statistical Methods for PK (13), the 90% confidence intervals (CI) should be 
considered for all described PK analyses. Therefore, the 90% CI will be used instead of the 
95% CI.
The ANOVA model for investigation of relative bioavailability will include effects 
accounting for the following sources of variation: ‘subjects’ and ‘time point’ and not 
‘subject’ and ‘treatment’.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 5.2.1 of the CTP:
Primary endpoint to assess safety and tolerability of BI 705564 is the number [N (%)] of 
subjects with adverse reactions.
Please note, that adverse reactions are defined and analysed as drug-related AEs.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 5.5.1.1 of the CTP: 
BI 705564
After the first dose:

AUCτ,1 (area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ after administration of the first dose)

Cmax (maximum measured concentration of the analyte in plasma)
After the last dose:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ)
Midazolam (DGs 2 to 5)
After the first and last doses:

Cmax and 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)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
DGs 1 to 5
It is planned that in total 50 healthy male subjects participate in this study. There were to be 5 
sequential dose groups comprising 10 subjects per group. Within each dose group, 8 subjects 
will receive the active drug and 2 will receive placebo.
Subjects will receive ascending doses of BI 705564 on Day 1 and then over 14 consecutive 
days from Day 4 to Day17: 10 mg (DG 1), 20 mg (DG 2), 40 mg (DG 3), 60 mg (DG 5) and 
80 mg (DG 4).


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Table 6.1: 1
Labels for treatments for use in the CTR 
Dose 
group
Treatment
Short label
1-5
P/Q*
Placebo tablet on Day 1 and Days 4 to 17
(+ Midazolam, solution, 75μg, po, qd)
Placebo 
1-5
P/Q/R
Placebo tablet 
(+ Midazolam, solution, 75μg, po, qd)
Placebo total
1
A
BI 705564, 10 mg tablet, qd on Day 1 and 
Days 4 to 17
BI 10mg 
2
B
BI 705564, 2*10mg tablet, qd on Day 1 
and Days 4 to 17 + 
Midazolam, solution, 75μg, po, qd on Day 
-1 and Day 17
BI 20mg 
3
C
BI 705564, 4*10mg tablet, qd on Day 1 
and Days 4 to 17 + 
Midazolam, solution, 75μg, po, qd on Day 
-1 and Day 17
BI 40mg 
5
E
BI 705564, 6*10mg tablet, qd on Day 1 
and Days 4 to 17 + 
Midazolam, solution, 75μg, po, qd on Day 
-1 and Day 17
BI 60mg 
4
D
BI 705564, 8*10mg tablet, qd on Day 1 
and Days 4 to 17 + 
Midazolam, solution, 75μg, po, qd on Day 
-1 and Day 17
BI 80mg
*: The ‘Placebo’ group in the safety evaluation will consist of all placebo treated subjects of 
DGs 1-5, regardless of the dose group in which they were treated.


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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 (BI or Placebo))

On treatment
o
BI/Placebo treatment (separately for each treatment, ranging from the time of 
first administration of BI / Placebo until 0:00h on the day after the subject’s 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).
Two types of AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT) of the CTR 
displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening will not be included in this analysis. 
The following totals will be provided in addition:

a total over all on treatment phases included in this analysis ("Total on treatment") 
(Section 15.3 only)
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of 
the CTR displays:

Screening 

On treatment (labelled with the name of the study treatment (short label))
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:

a total over all study phases ("Total")
Tables of vital signs, ECG and laboratory values will present results by the above mentioned 
on treatment phase.
For detailed information on the handling of the treatments in the O*C views, refer to 
Technical TSAP ADS (analysis data set) plan and Analysis Data Reviewer´s guide. 


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6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (RPM). At this meeting, all 
manual deviations identified at the sites by the CRAs and deviations too complex to program 
will be reviewed by the trial team to decide which are considered important. For definition of 
important protocol deviations (iPD), and for the process of identification of these, refer to the 
Boehringer Ingelheim (BI) SOP "Identify and Manage Important Protocol Deviations (iPD)" 
(2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM minutes via an accompanying Excel spreadsheet (3). The following Table 6.2: 1
contains the categories which are considered to be iPDs in this trial. If the data show other 
iPDs, this table will be supplemented accordingly by the time of the RPM/DBLM at the 
latest.
The iPDs will be summarised and listed.


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


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6.3
SUBJECT SETS ANALYSED

Treated set (TS):
This subject set includes all subjects who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.
This is the full analysis set population in the sense of ICH-E9 (1). It is used for 
demographics, baseline characteristics, and safety analyses, as well as for the description 
of biomarkers and the PD endpoints 
Section 7.3.2 of the CTP: Plasma 
 concentration data and parameters of a subject
will be included in the statistical 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 Blinded 
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:

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),

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 of DGs 1-5
receiving BI 705564 who provide at least one secondary PK parameter that was not 
excluded according to the description above.
It is used for assessment of dose proportionality, for the estimation of the linearity index
and for the analysis of the attainment of steady state.


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
PKS-Midazolam (PKS-Mida):
The PKS-Midazolam (PKS-Mida) includes all subjects from the TS receiving 
BI 705564 / Placebo and Midazolam (DGs 2-5) who provide at least one secondary PK 
parameter for Midazolam that was not excluded according to the description above.
It is used for investigation of relative bioavailability.
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
PKS-Mida
ECGPCS
Primary and further safety endpoints 
(incl. ECG) 
X
Secondary PK endpoints (BI 705564)
X
Secondary PK endpoints (Midazolam)
X
Demographic/baseline endpoints
X
Important protocol deviations
X
Disposition
X


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6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.4.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (5).
For placebo subjects the missing plasma concentration values will be replaced by 0 for the 
exposure response analysis. For subjects on active drug, missing plasma concentration values 
with ‘BLQ’ in the comment field will be replaced by ½ LLOQ.


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before first administration of 
BI 705564 or Placebo (Day 1, -1:00).
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.
Study measurements and assessments scheduled to occur ‘before’ trial medication
administration on Day -1 (in DGs 1 to 5) and Day 1 (in DG 8) 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 
 sampling of ± 30 min is acceptable.
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests
will be ± 15 minutes for the first 4 h after trial drug administration and ± 30 minutes
thereafter.
[…]
DGs 1 to5
BI 705564 will be administered on Day 1 and on Day 4 through to Day 17 at 0h (planned
time).
Midazolam will be administered on Day -1 and on Day 17 at 0h.
The tolerance for drug administration on Days -1, 1 and 17 will be ± 1 min. On all other
treatment days it will be ± 10 min.


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7.
PLANNED ANALYSIS
Section 7.3.4 of the CTP: As the treatment duration in DG 8 is different from the treatment 
duration in DGs 1 to 5, all safety outputs for the placebo group will be displayed both, 
together and separately for DGs 1 to 5 and DG 8.
The placebo group of DGs 1 to 5 will consist of all placebo treated subjects in DGs 1 to 5, 
regardless of the dose group in which they were treated.
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Sections 7.5.2 and 7.6) 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 the 
department of Translational Medicine and Clinical Pharmacology (TMCP) at BI and will be 
presented in Section 15.6 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.
The individual values of all subjects will be listed, sorted by treatment group, subject number, 
and visit. 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation


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


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Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (7).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised by treatment group and in total. 
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the latest version of the coding system of the 
Medical Dictionary for Drug Regulatory Activities (MedDRA). Medications will be coded 
using the latest version of the World Health Organization Drug Dictionary (WHO-DD). The 
coding version number will be displayed as a footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre under supervision of the investigating physician or a designee. The 
measured plasma concentrations and urinary excretion (not applicable for DG 8) 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 (refer to Section 6.2) and described in the CTR.


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7.4
PRIMARY ENDPOINTS
Refer to Section 7.8 for a description of the analysis of safety and tolerability of BI 705564.
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 of BI 705564 (DGs 1 to 5)
Dose proportionality of the PK endpoints AUCτ,1 and Cmax in plasma after the first dose of 
BI 705564 and AUCτ,ss and Cmax,ss in plasma after the last dose of BI 705564 will be explored 
using the power model that describes the functional relationship between dose and PK 
endpoints based on the PKS. The basic model consists of a regression model applied to log-
transformed data (log-transformation refers to using the natural logarithm). The corresponding 
ANCOVA (Analysis of Covariance) model includes the logarithm of the dose as a covariate.
The model is described by the following equation:
Yij = α + β*Xi + εij
where
Yij
logarithm of the PK endpoint for subject j at dose level i; 
j = 1, 2, …, 8, i = 1,…, 5,
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 90% CI for the slope will be 
computed. Perfect dose proportionality would correspond to a slope of 1. The assumption of 
a linear relationship between the log-transformed PK 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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This analysis will be accomplished by using the XPKISTAT macro (design DB), based on 
the PKS.
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).
Linearity index (DGs 1 to 5)
Analysis of the linearity index (LI) will be based on the PKS.
Section 7.3.2 of the CTP: Linearity with respect to multiple administration will be explored 
using the linearity index (LI) that will be computed as follows:
AUC
AUC
ss
LI



0
,

In order to construct a confidence interval for LI, a statistical model using AUCτ,ss and 
AUC0-∞will be set up: A linear model on the logarithmic scale including effects for ‘subject’ 
and ‘AUC type’ can be applied, where ‘subject’ is a random effect and ‘AUC type’ a fixed 
effect.
Yij = μ + τi + sj + eij, where
Yij
logarithm of the response (AUC after first dose, AUC after last dose) for subject j and 
AUC type i; where i=1 (after first dose (day 1)) or 2 (after last dose (day 17 (DGs 1-
5))) and j=1,2,…,8
μ
the overall mean
τi
the AUC type i (fixed effect)
sj
the effect associated with subject j (random effect)
eij
random error associated with subject j at AUC type i (assumed to be independent and 
identically normally distributed)
The covariance matrix is chosen to be an unstructured matrix to allow for different variances 
for the two AUC types. In case the model does not converge (due to the unstructured
covariance matrix), a compound symmetry structure can be chosen instead.


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A pairwise comparison of both areas via the log transformed difference
)
log(
)
log(
)
log(
0
,
0
,






AUC
AUC
ss
ss
AUC
AUC


will then be performed including calculation of a 2-sided 90% CI. The back transformed 
point estimate then represents the estimate of LI. Perfect linearity with respect to multiple 
administrations holds true if this index equals unity.
Generally, this model will be applied to each dose level separately. If there is evidence that 
the areas are comparable across dose levels, they can be analysed simultaneously. The 
corresponding model will then include the log transformed dose as (additional) covariate.
The following SAS code will be used to fit the model: 
PROC MIXED DATA=indata; 
CLASS AUCtype subject; 
MODEL logkp = AUCtype / DDFM=KR; 
REPEATED AUCtype / subject=subject TYPE=UN; 
LSMEANS AUCtype / PDIFF CL ALPHA=0.1;
RUN;
Attainment of steady state (DGs 1 to 5)
Attainment of steady state will be explored by using the trough concentrations of BI 705564
between Days 4 and 18 and the concentrations taken directly at the end of the first and the 
last dosing interval for each dose level based on the PKS. 
The following Table 7.5.2: 1 summarises the available pre-dose concentrations available for 
steady state assessment:


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Table 7.5.2: 1 Available pre-dose concentrations for steady state assessment
Day
2
4
5
6
9
11
13
15
16
Planned 
time [h]
24
70:30
96
120
192
240
288
336
360
PK 
Parameter
Cτ / 
C24
Cpre,2
Cpre,3
Cpre,4
Cpre,7
Cpre,9
Cpre,11
Cpre,13
Cpre,14
Day
17
18
Planned 
time [h]
383
408
PK 
Parameter
Cpre,15
Cτ,ss / 
C24,ss
Individual time-courses of trough plasma concentrations and the (geometric) mean plasma 
concentration time profile will be plotted by dose group. 
The attainment of steady state will be explored separately for each dose level by using a 
repeated measures linear model on the logarithmic scale including ‘time’ as a repeated effect 
and 'subject' as random effect,. 
Section 7.3.2 of the CTP: The calculation is based on a repeated measures linear model on 
the logarithmic scale.
Yij = μ + i + sj + eij, where
Yij
logarithm of the concentrations for subject j at time i, i=1, 2, …  and 
j=1, 2,…, 8

the overall mean,
i
the effect associated with time point i (repeated effect),
sj
(random) effect of subject j, j=1, 2,…, 8
eij
random error associated with subject j at time i (assumed to be independent 
and identically normally distributed).
Dose can be included as an additional covariate, if there is evidence that the trough 
concentration profiles are comparable across dose levels.


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The model will be used to explore the time to steady state by pairwise comparing 
concentrations pairwise from different time points: log-transformed differences between all 
subsequent time points (log(Cpre,i/Cpre,j) = log(Cpre,i) - log(Cpre,j), where j>i) will be compared 
and adjusted means (Least Squares Means) as well as 2-sided 90% CIs will be calculated. 
Thereafter, these quantities will be back-transformed by exponentiation to give the 
corresponding (adjusted) ratio and CI.
Comparisons which reveal CIs (for the adjusted ratio) not including 100% will be inspected 
to determine, if the differences between time points are resulting from not yet attaining 
steady-state.
As default, the structure of the covariance matrix will be unstructured (type=UN or UNR). In 
case an unstructured covariance matrix does not work, the following covariance structures 
will be chosen, in the pre-defined order: Toeplitz or AR1. A Compound Symmetry (CS)
structure should not be considered, as this structure already postulates a steady-state. For the 
approximation of the degrees of freedom the Kenward and Roger method is recommended.
The following SAS code will be used to fit the model: 
PROC MIXED DATA=indata; 
CLASS subject time;
MODEL logkp = time / DDFM=KR; 
REPEATED time / TYPE=UN SUBJECT=subject; 
LSMEANS time / DIFF CL ALPHA=0.1; 
RUN;
If there is evidence that the trough concentration profiles are comparable across dose levels,
they may additionally be analysed simultaneously (e.g. if dose proportionality is given).
Please refer to BI Statistical Position Paper - Statistical Methods for PK (14).
Investigation of relative bioavailability (Midazolam in DGs 2 to 5)
Relative bioavailability is to be determined on the basis of the secondary PK parameters 
(Cmax and AUC0-tz after the first and last dose) of Midazolam based on the PKS-Mida. Those 
parameters will be log-transformed (natural logarithm) prior to fitting the model.
Section 7.3.3 of the CTP:
The statistical model used for the analysis of secondary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. This model will include effects 
accounting for the following sources of variation: ‘subjects’ and ‘time point’. The effect 
‘subjects’ will be considered as random, whereas the other effects will be considered as fixed. 
The model is described by the following equation:
Yij = µ+ τi + sj + eij, where


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Yij = 
logarithm of the endpoint for subject j (j=1, 2, …, 8) at Day -1 (first dose of 
midazolam, i=1) or at Day 17 (last dose of midazolam, i=2),
µ
the overall mean,
τi
the effect associated with time point i (Day -1 or Day 17)
sj
(random) effect of subject j, j=1, 2, …, 8, and
eij
random error associated with the subject j at time i (assumed to be 
independent and identically normally distributed).
The effect of BI 705564 on midazolam will be estimated by the ratios of geometric means 
(with the last dose of midazolam as the test and the first dose of midazolam as the reference) 
and their two-sided 90% confidence intervals (CIs) for Cmax and AUC0-tz. CIs will be 
calculated based on the residual error from ANOVA. These quantities will then be back 
transformed to the original scale to provide the point estimate and 90% CIs for each 
secondary endpoint.
This model will be evaluated separately for each dose group and, separately, for the placebo 
group.
The analysis will be accomplished by using the XPKISTAT macro, based on PKS-Mida
(design BWU).
As a sensitivity analysis, a joint model for all doses will be investigated, including ‘dose’ as 
an additional factor. The corresponding ANCOVA model will include the logarithm of the 
dose as a covariate by using the XPKISTAT macro, including CLASSFIX=dose.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
If not stated otherwise, the safety results will be sorted by treatment group.
The safety data for treated subjects who failed to complete the study (dropouts or
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials” [001-MCG-156] (9).
The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs). 
For analysis multiple AE occurrence data on the Case Report Form (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 (AESI))


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
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
two occurrences is given if the second occurrence started within one hour after end of 
the first occurrence)
For further details on summarization of AE data, please refer to [001-MCG-156] (9).
Section 5.2.2.1 of the CTP: The following are considered as Adverse Events of Special 
Interest (AESIs):

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters
1.
an elevation of Aspartate Aminotransferase (AST) and/ or Alanine 
Aminotransferase (ALT) ≥3-fold Upper Limit of Normal (ULN) combined with 
an elevation of total bilirubin ≥2-fold ULN measured in the same blood sample, 
and/or
2.
aminotransferase (ALT, and/ or AST) elevations ≥10 fold ULN
The analysis of adverse events will be based on the concept of treatment emergent AEs. 
Section 5.2.2.2 of the CTP: The Residual Effect Period (REP) for BI 705564, when 
measurable drug levels or PD effects are still likely to be present after the last 
administration, is not known at this early stage of development […] Therefore, all AEs 
reported until the end of trial examination (last per protocol contact) will be considered on 
treatment […].
For more details see the TSAP ADS plan.
According to ICH E3 (10), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at the RPM/DBLM at latest.
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 
drug-related AEs, for subjects with drug related serious adverse events and for subjects with 
AESIs.
The SOC and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.


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For disclosure of adverse events on EudraCT additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on 
BI standards [001-MCG-157] (11).
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possible 
clinically significant will be highlighted in the data listings.
It is the investigator's responsibility to decide whether a lab value is clinically significant 
abnormal or not (at the RPM/DBLM at the latest).
Bleeding times as well as, fold changes (value/baseline) and percent changes from baseline 
will be listed and descriptive statistics over time will be performed.
Individual time courses of bleeding times will be provided. The distribution of bleeding 
times, as well as the respective fold changes (value/baseline) and percent changes from 
baseline will be presented by treatment at each time point using boxplots.
For dose groups 1 to 3 (up to 40mg) bleeding time was only measured for 10 min. Therefore 
bleeding times over 600 sec may not be captured.
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate).
Descriptive statistics over time will be performed for oral body temperature. 
Body weight at screening and post examination will be listed only.
7.8.4
ECG
12-lead ECG
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, 
 


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


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


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