Clinical trial NCT04194645
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2020-01-09; Completion date: 2021-03-25
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objectives of this trial are to investigate safety, tolerability and pharmacokinetics (PK) of BI 474121 in healthy male subjects following oral administration of single rising doses.

Detailed description:

Arms: arm 1: This arm comprises all placebo treated participants of the single rising dose (SRD) part treated with an oral solution (placebo treated participants of the two lowest dose group (DG)s). Participants receiving placebo were equally distributed across dose groups. A single dose of BI 474121 matching placebo powder for oral solution was administered after an overnight fast together with 240 milliliter (mL) of water to participants who were in a standing position. arm 2: This arm comprises all placebo treated participants of the SRD part treated with a tablet (placebo treated participants of the five upper DGs). Participants receiving placebo were equally distributed across dose groups. A single dose of BI 474121 matching placebo tablet was administered after an overnight fast together with 240 mL of water to subjects who were in a standing position. arm 3: A single dose of 0.25 mg BI 474121 was solved in 0.5 mL of water and was administered after an overnight fast together with 240 mL of water to participants who were in a standing position. arm 4: A single dose of 1 mg BI 474121 was solved in 2mL of water and was administered after an overnight fast together with 240 mL of water to participants who were in a standing position. arm 5: A single dose of 2.5 mg BI 474121 was administered as 1 uncoated 2.5 mg tablet after an overnight fast together with 240 mL of water to participants who were in a standing position. arm 6: A single dose of 5.0 mg BI 474121 was administered as 2 uncoated 2.5 mg tablets after an overnight fast together with 240 mL of water to participants who were in a standing position. arm 7: A single dose of 10.0 mg BI 474121 was administered as 1 uncoated 10.0 mg tablet after an overnight fast together with 240 mL of water to participants who were in a standing position. arm 8: A single dose of 20.0 mg BI 474121 was administered as 2 uncoated 10.0 mg tablets after an overnight fast together with 240 mL of water to participants who were in a standing position. arm 9: A single dose of 40.0 mg BI 474121 was administered as 4 uncoated 10.0 mg tablets after an overnight fast together with 240 mL of water to participants who were in a standing position. arm 10: Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (Reference (R)), in period 2 as 1 uncoated tablet with 240 mL of water after an overnight fast (Test 2 (T2)) and in period 3 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (Test 1 (T1)). Between periods was a wash-out period of at least 7 days. arm 11: Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (R), in period 2 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1) and in period 3 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2). Between periods was a wash-out period of at least 7 days. arm 12: Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2), in period 2 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (R) and in period 3 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1). Between periods was a wash-out period of at least 7 days. arm 13: Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2), in period 2 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1) and in period 3 as oral solution solved in 20 mL water with 240 mL of water after an overnight fast (R). Between periods was a wash-out period of at least 7 days. arm 14: Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1), in period 2 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (R) and in period 3 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2). Between periods was a wash-out period of at least 7 days. arm 15: Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1), in period 2 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2) and in period 3 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (R). Between periods was a wash-out period of at least 7 days.
Interventions: intervention 1: BI 474121 tablet intervention 2: Placebo tablet intervention 3: BI 474121 oral solution intervention 4: Placebo solution
Intervention descriptions: intervention 1: BI 474121 tablet intervention 2: Placebo tablet intervention 3: BI 474121 oral solution intervention 4: Placebo solution

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c28123079-06
EudraCT No.
2019-002358-22
BI Trial No.
1411-0001
BI Investigational
Medicinal Product
BI 474121
Title
A randomised, single-blind, placebo-controlled trial to investigate 
safety, tolerability, and pharmacokinetics of single rising oral 
doses of BI 474121 administered as oral solution and tablets to 
healthy male subjects (SRD part), and a randomised, open-label, 
single-dose, three-way cross-over bioavailability comparison of 
BI 474121 as tablet versus oral solution and tablet with and 
without food (BA part)
Lay Title
A study in healthy men to test how the body takes up and 
tolerates different doses of BI 474121, and whether it makes a 
difference if BI 474121 is taken as a tablet or a drink.
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: 
Principal 
Investigator
Phone:
Fax:
Status
Final Protocol (Revised Protocol (based on global amendment 5)
Version and Date
Version: 6.0
Date: 08 October 2020
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© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
24 October 2019
Revision date
08 October 2020
BI trial number
1411-0001
Title of trial
A randomised, single-blind, placebo-controlled trial to investigate safety, 
tolerability, and pharmacokinetics of single rising oral doses of BI 474121 
administered as oral solution and tablets to healthy male subjects (SRD part), and a 
randomised, open-label, single-dose, three-way cross-over bioavailability 
comparison of BI 474121 as tablet versus oral solution and tablet with and without 
food (BA part)
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
The SRD (single rising dose) part of this trial will be the start of the clinical 
development of BI 474121. Effects of single rising doses on safety, tolerability and 
pharmacokinetics will be assessed as basis for further development.
The relative BA (bioavailability) part is conducted to gain information about the 
effect of food on the relative bioavailability of the BI 474121 tablet formulation and 
the relative bioavailability of tablet versus PfOS to support upcoming clinical 
studies in respect of better trial designs, and to help in the optimization for future 
trial formulation development.
Trial objectives
SRD part
To investigate safety, tolerability and pharmacokinetics following single rising 
doses of BI 474121 
BA part
To investigate the relative bioavailability of the tablet formulation versus oral 
solution as well as the influence of food on the relative bioavailability of the tablet 
formulation


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Trial endpoints
SRD part
Primary endpoint:
To assess safety and tolerability of BI 474121 as the 
percentage of subjects with drug-related adverse events
Secondary endpoints:
AUC0-tz and Cmax of BI 474121
BA part
Primary endpoints:
AUC0-tz and Cmax of BI 474121
Secondary endpoint:
AUC0-of BI 474121
Trial design
SRD part
Single-blind, randomised within dose groups, placebo-controlled parallel-group 
design
BA part
Open-label, randomised, single-dose, intra-individual three-way cross-over  
comparisons of the relative bioavailability of tablet fasted versus oral solution 
fasted, and tablet fasted versus tablet fed
Number of subjects 
total entered
68*
each treatment
SRD part: 
56*(8 per dose group. 6 on active drug and 2 on placebo 
at each of 7 dose levels)
BA part:
12 (all on active drug)
* Additional subjects may be entered in the SRD part 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 56, but is not to exceed 72. The addition of further dose groups 
exceeding the already tested dose levels for the evaluation of safety findings will be subject 
to a substantial CTP amendment requiring approval.
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 45 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product
SRD part: BI 474121 as a powder for oral solution (PfOS, 0.5 mg/mL 
formulation) or uncoated tablets (2.5 mg and 10 mg)
BA part:
BI 474121 as uncoated tablets (2.5 mg tablet or 10 mg tablet), Test
product
BI 474121 as PfOS (5 mL – 2.5 mg or 20 mL – 10 mg), Reference


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dose
SRD part: 0.25 mg and 1 mg as powder for oral solution (PfOS)
2.5, 5, 10, 20, and 40 mg as tablets*
* Based on experience gained during the trial conduct (e.g. preliminary PK 
data), intermediate doses (e.g. 7.5 mg, 15 mg, 30 mg) may be tested provided 
the planned and approved highest dose will not be exceeded. The addition of
further dose groups exceeding the already tested dose levels for the evaluation 
of safety findings will be subject to a substantial CTP amendment requiring 
approval.
BA part:
2.5 mg# as tablet (2.5 mg tablet) and PfOS (5 mL – 2.5 mg) or
10 mg# as tablet (10 mg tablet) and PfOS (20 mL – 10 mg)
# This dose is tentative and can be reduced based on the information 
obtained during the trial. The BA part will only be started if in the SRD part a 
dose at least 4-fold the dose selected for the BA part has shown acceptable 
safety and tolerability. This means, that a dose of 2.5 mg to be used in the BA 
part requires a safe and tolerable dose of at least 10 mg in the SRD part. A dose 
of 10 mg to be used in the BA part requires a safe and tolerable dose of 40 mg 
in the SRD part.
mode of admin.
SRD part: Oral with 240 mL of water in fasted state
BA part:
Food effect
Oral with 240 mL of water under fasted and fed conditions (after a 
high fat/high calorie breakfast)
Relative BA vs PfOS
Oral with 240 mL of water in fasted state
Comparator products
SRD part:
Placebo solution or placebo tablets 
BA part:     Not applicable (no comparator)
dose
SRD part:
Not applicable (matching placebo)
BA part:     Not applicable (no comparator)
mode of admin.
SRD part:
Oral with 240 mL of water in fasted state 
BA part:
Not applicable (no comparator) 
Duration of treatment
SRD part: 1 single dose 
BA part:    3 single doses separated by a washout period of at least 7 days
Statistical methods
SRD and BA part:
Descriptive statistics will be calculated for all endpoints.
BA part: Relative bioavailability will be estimated by the ratios of the geometric 
means (tablet fasted / PfOS fasted, tablet fed / tablet fasted) for the primary and 
secondary endpoints. Additionally, their two-sided 90% confidence intervals (CIs) 
will be provided. This method corresponds to the two one-sided t-test procedure, 
each at a 5% significance level. Since the main focus is on estimation and not 
testing, a formal hypothesis test and associated acceptance range is not specified. 
The statistical model will be an analysis of variance (ANOVA) on the logarithmic 
scale including effects for sequence, subjects nested within sequences, period and 
treatment. CIs will be calculated based on the residual error from the ANOVA. 


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FLOW CHART (SRD PART)
Visit
Day
Planned time (relative to 
drug administration)
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory9
PK blood 
11, 12
PK urine
11.13
12-lead ECG10
Orthostatic testing 15
Continuous ECG 
monitoring
Vital signs (BP, PR)
Questioning for AEs and
concomitant therapy 6
1
-21 to -1
Screening (SCR) 1
xA
x
x
2
-3 to -1
-72:00
08:00
Ambulatory visit
xE7
x
x
1
-1:30
06:30
Admission to trial site
-1:00
07:00
Allocation to treatment2
xC 2,5
x2
x2
x2,14
x2
x2
x2
0:00
08:00
Drug administration
▲
│
▲
│
0:15
08:15
x
│
│
0:30
08:30
x
│
x
│
x
1:00
09:00
x
│
x
│
x
x
1:30
09:30
x
│
x
│
x
2:00
10:00
240 mL fluid intake
x8
│
x
x
│
x
3:00
11:00
x
│
x
│
x
x
4:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
┼
│
x
x
│
▼
x
6:00
14:00
xC
x
│
x
x
x
8:00
16:00
Snack (voluntary)3
x
┼
x
x
x
10:00
18:00
Dinner3
x
│
12:00
20:00
x
┼
x
x
x 
2
24:00
08:00
Breakfast3
xB
x
┼
x
x
x
29:00
13:00
Lunch3
│
x
32:00
16:00
Snack (voluntary)
│
34:00
18:00
Dinner3
x
│
x
x
x
3
48:00
08:00
Breakfast (voluntary)3,
confirmation of fitness and 
discharge from trial site
x
│
▼
x
x
x
4
72:00
08:00
Ambulatory visit
xB
x
x
x
x
5
96:00
08:00
Ambulatory visit
x
x
x
x
5
8- 15
End of trial (EoTrial) 
examination4
xD
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, 12-lead ECG and rhythm strip over at least 15 min, 
safety laboratory (including drug screening), demographics (including determination of body height and weight, 
smoking status and alcohol history, relevant medical history, concomitant therapy and review of inclusion/exclusion 
criteria. Pharmacogenetic samples will be collected if needed.
2.
The time is approximate; procedures are to be performed and completed within the 3 h prior to drug administration. 
Allocation to treatment may be performed at any time following enrolment but must be completed prior to (first) drug 
administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs, and concomitant therapies.
5.
Includes urine drug screening and alcohol breath test at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.


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7.
Safety laboratory to be taken and to be medically evaluated within 74 h prior to administration of study drug; this safety 
laboratory assessment can be omitted if the screening examination is performed on Days -3, -2 or -1. 
8.
One blood sample for stability testing will be taken at this time (refer to Section 5.3.2.4) 
9. 
Letters A, B, C, D and E describe different sets of safety laboratory examinations (see Table 5.2.4: 1).
10. At SCR and EoTrial: ECGs recordings are performed as single ECGs. At SCR the ECG recording includes a 15 min 
rhythm strip. SCR and EoTrial ECGs will not be transferred to central ECG lab. 
ECG recordings scheduled during Visit 2 are performed on Day 1 to Day 3 as triplicate ECGs, and on Day 4 and Day 5 
as single ECGs. All ECGs recorded during Visit 2 will be transferred to the central ECG lab. Recording time points 
may be adapted based on information obtained during the trial. ECG recording will always precede all other study 
procedures scheduled for the same time (see Section 5.2.4). 
11. Sampling times and periods may be adapted based on information obtained during the trial (e.g., due to preliminary PK 
data) including addition of samples and visits as long as the total blood volume removed does not exceed 500 mL per 
subject
12. In dose group 4 (dose level 5 mg) and dose group 7 (dose level 40 mg) including blood sample for metabolite 
identification (refer to Section 5.3.2.2)
13. A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples for 
assessment of PK are to be collected over the stated post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12, 12-24. A further 
urine sample for PK assessment to be collected between 24-48 h.
14. At baseline (i.e. Day 1, prior to drug administration) 3 triplicate ECGs are recorded within approximately one hour. The 
recordings should be separated by approximately 15 minutes between the start of the first ECG recording of
a triplicate and the start of the first ECG recording of the next triplicate ECG.
15. Includes 1st measurement in supine position (~X+5 min), 2nd measurement immediately after standing up (~X+6min), 
3rd measurement after 3 min in a standing position (~X+9 min) 


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FLOW CHART (BA PART)
Period
Visit
Day
Planned time (relative to drug 
administration 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory 7
PK blood
9
12-lead ECG
Vital signs
Questioning for AEs and 
concomitant therapy6
SCR
1
-21 to -
1
Screening 1
xA
x
x
1/2/3
*
2/3/
4
-3 to -1
-72:00
08:00
Ambulatory visit10
XB, 8
x
1
-02:00
06:00
Admission to trial site, allocation to 
treatment2  (visit 2 only)
xB, 2,5
x2
x²
x2
x2
-00:30
07:30
High fat, high calorie breakfast (only in 
treatment T1)
00:00
08:00
Drug administration
00:15
08:15
x
00:30
08:30
x
01:00
09:00
x
01:30
09:30
x
02:00
10:00
240 mL fluid intake 
x
03:00
11:00
x
04:00
12:00
240 mL fluid intake , thereafter lunch3
x
x
x
06:00
14:00
xC
x
08:00
16:00
Snack (voluntary)3
x
10:00
18:00
Dinner3
x
12:00
20:00
x
x
2
24:00
08:00
Confirmation of fitness and discharge 
from trial site, breakfast (optional)3
xB
x
x
x
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x
4
72:00
08:00
Ambulatory visit
x
x
5
96:00
08:00
Ambulatory visit
xB
x
x
Eo
Trial
5
8 - 15
End of trial (EoTrial) examination4
xD
x
x
x
*
Three identical treatment periods separated by a washout phase of at least 1 week between drug administrations
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening and 
infectious serology), demographics (including determination of body height and weight, smoking status and alcohol 
history), relevant medical history, concomitant therapy, and review of inclusion/exclusion criteria.
Pharmacogenetic samples will be collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.


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4.
At the end of trial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. 
5.
Includes urine drug screening and alcohol breath test at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7. 
Letters A, B, C, and D describe different sets of safety laboratory examinations (see Table 5.2.4: 1).
8.
Activities to be performed within 74 hours prior to first administration of study drug; the safety laboratory can be 
omitted, if the screening examination is performed on Days -3, -2 or -1.
9. 
Sampling times and periods may be adapted based on information obtained during the trial (e.g., due to preliminary PK 
data) including addition of samples and visits as long as the total blood volume removed does not exceed 500 mL per 
subject.
10. Safety lab within 74 hours prior to administration of study drug only prior to first treatment (Period 1), replaced by 
safety lab of Day 5 of Period 1 for Period 2 and Day 5 of Period 2 for Period 3. 


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART (SRD PART) ...........................................................................5
FLOW CHART (BA PART)..............................................................................7
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS.......................................................................................... 14
1.
INTRODUCTION.................................................................................... 17
1.1
MEDICAL BACKGROUND............................................................................17
1.2
DRUG PROFILE...............................................................................................17
Residual Effect Period..........................................................................22
1.2.6
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................22
1.3.2
Maximum dose.........................................................................24
1.3.2.2
Escalation scheme (SRD part) .............................................................26
1.3.3
Escalation scheme (guided by preliminary PK analysis (see 
1.3.3.1
Section 7.4)).............................................................................26
Preliminary PK analysis...........................................................26
1.3.3.2
Dose selection for food effect study (BA part)....................................27
1.3.4
1.4
BENEFIT - RISK ASSESSMENT ...................................................................27
Expected benefit for the target population.........................................27
1.4.1
Procedure-related risks ........................................................................27
1.4.2
Drug-related risks and safety measures..............................................27
1.4.3


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2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 31
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......31
Main objectives......................................................................................31
2.1.1
Primary endpoint..................................................................................31
2.1.2
Secondary endpoint ..............................................................................31
2.1.3
Safety and tolerability..............................................................32
2.2.2.1
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 34
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................34
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................36
3.3
SELECTION OF TRIAL POPULATION ......................................................37
Main diagnosis for trial entry..............................................................37
3.3.1
Inclusion criteria...................................................................................37
3.3.2
Exclusion criteria ..................................................................................38
3.3.3
Withdrawal of subjects from treatment or assessments ...................39
3.3.4
Discontinuation of trial treatment............................................40
3.3.4.1
Withdrawal of consent to trial participation ............................40
3.3.4.2
Discontinuation of the trial by the sponsor..............................41
3.3.4.3
Replacement of subjects .......................................................................41
3.3.5
4.
TREATMENTS........................................................................................ 42
4.1
INVESTIGATIONAL TREATMENTS ..........................................................42
Identity of the Investigational Medicinal Products ...........................42
4.1.1
Selection of doses in the trial and dose modification .........................43
4.1.2
Method of assigning subjects to treatment groups ............................44
4.1.3
Drug assignment and administration of doses for each subject .......44
4.1.4
Blinding and procedures for unblinding ............................................46
4.1.5
Blinding46
4.1.5.1
Unblinding and breaking the code...........................................47
4.1.5.2
Packaging, labelling, and re-supply ....................................................47
4.1.6
Storage conditions.................................................................................47
4.1.7
Drug accountability ..............................................................................47
4.1.8
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................48
Other treatments and emergency procedures....................................48
4.2.1
Restrictions............................................................................................48
4.2.2
Restrictions regarding concomitant treatment .........................48
4.2.2.1
Restrictions on diet and life style.............................................48
4.2.2.2


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4.3
TREATMENT COMPLIANCE.......................................................................49
5.
ASSESSMENTS....................................................................................... 50
5.1
ASSESSMENT OF EFFICACY.......................................................................50
5.2
ASSESSMENT OF SAFETY............................................................................50
Physical examination ............................................................................50
5.2.1
Vital signs...............................................................................................50
5.2.2
Orthostatic tests ....................................................................................50
5.2.3
Safety laboratory parameters..............................................................51
5.2.4
Electrocardiogram................................................................................53
5.2.5
12-lead resting ECG.................................................................53
5.2.5.1
Continuous ECG monitoring ...................................................55
5.2.5.2
Assessment of adverse events...............................................................56
5.2.6
Definitions of adverse events...................................................56
5.2.6.1
Adverse event ............................................................56
5.2.6.1.1
Serious adverse event ................................................56
5.2.6.1.2
AEs considered ‘Always Serious’.............................57
5.2.6.1.3
Adverse events of special interest .............................57
5.2.6.1.4
Intensity (severity) of AEs.........................................58
5.2.6.1.5
Causal relationship of AEs ........................................58
5.2.6.1.6
Adverse event collection and reporting ...................................59
5.2.6.2
AE collection.............................................................59
5.2.6.2.1
AE reporting to the sponsor and timelines ................60
5.2.6.2.2
Information required..................................................60
5.2.6.2.3
Pregnancy ..................................................................60
5.2.6.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................60
Assessment of pharmacokinetics .........................................................60
5.3.1
Methods of sample collection...............................................................61
5.3.2
Blood sampling for pharmacokinetic analysis.........................61
5.3.2.1
Blood sampling for metabolism analysis.................................61
5.3.2.2
Urine sampling for pharmacokinetic analysis..........................62
5.3.2.3
Additional blood sample for stability-testing ..........................63
5.3.2.4
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................65


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6.
INVESTIGATIONAL PLAN.................................................................. 66
6.1
VISIT SCHEDULE............................................................................................66
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................66
Screening period....................................................................................66
6.2.1
Treatment period ..................................................................................67
6.2.2
Follow-up period and trial completion ...............................................68
6.2.3
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 69
7.1
STATISTICAL DESIGN – MODEL ...............................................................69
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................69
7.3
PLANNED ANALYSES....................................................................................69
Primary endpoint analyses...................................................................71
7.3.1
Secondary endpoint analyses ...............................................................72
7.3.2
Safety analyses.......................................................................................73
7.3.4
7.4
INTERIM ANALYSES .....................................................................................74
7.5
HANDLING OF MISSING DATA ..................................................................75
Safety......................................................................................................75
7.5.1
Pharmacokinetics..................................................................................76
7.5.2
7.6
RANDOMISATION ..........................................................................................76
7.7
DETERMINATION OF SAMPLE SIZE ........................................................76
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 78
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................78
8.2
DATA QUALITY ASSURANCE .....................................................................79
8.3
RECORDS..........................................................................................................79
Source documents .................................................................................79
8.3.1
Direct access to source data and documents.......................................80
8.3.2
Storage period of records.....................................................................81
8.3.3
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................81
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......81
Collection, storage and future use of biological samples and 
8.5.1
corresponding data ...............................................................................81
8.6
TRIAL MILESTONES .....................................................................................82
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................82
9.
REFERENCES......................................................................................... 84
9.1
PUBLISHED REFERENCES...........................................................................84


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9.2
UNPUBLISHED REFERENCES.....................................................................85
10. APPENDICES .......................................................................................... 86
10.1
RECONSTITUTION INSTRUCTIONS .........................................................86
Drug supplies overview.........................................................................86
10.1.1
Required equipment and dosing aids – overview...............................86
10.1.2
Reconstitution procedure.....................................................................87
10.1.3
Reconstitution procedure for the preparation of the active BI 
10.1.3.1
474121 oral solution 0.5 MG/ML............................................87
Solvent for  oral solution for use as placebo solution..............87
10.1.3.2
ILLUSTRATION OF RECONSTITUTION PROCEDURE ...........88
10.1.4
In-use stability.......................................................................................89
10.1.5
Mode of application ..............................................................................89
10.1.6
General remarks - important! .............................................................90
10.1.7


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
Aet1-t2
Amount of analyte eliminated in urine over the time interval t1 to t2
AMP
Auxiliary Medicinal Product
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
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
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
CLR, t1-t2
Renal clearance of the analyte in plasma from the time point t1 to t2
Cmax
Maximum measured concentration of the analyte in plasma
Cmin
Minimum measured concentration of the analyte in plasma
CML
Clinical Monitor Local
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture


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EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
fet1-t2
Fraction of administered drug excreted unchanged in urine over the time 
interval from t1 to t2
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IPD
Important Protocol Deviation
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRT,ex
Mean residence time of the analyte in the body, extravascular
PD
Pharmacodynamic(s)
PE
Polyethylene
PfOS
Powder for reconstitution of an oral solution
PIB
Powder in the bottle
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
PTS
Peak-trough swing
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
RR
Respiratory rate


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SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
T
Test product or treatment
TMF
Trial master file
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vss
Apparent volume of distribution at steady state after intravascular 
administration
Vz
Apparent volume of distribution during the terminal phase after 
intravascular administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
XTC
Ecstasy


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1.
INTRODUCTION
BI 474121 is a PhosphoDiEsterase 2 (PDE2) inhibitor that is being developed for the 
symptomatic treatment of mild to moderate Alzheimer’s disease (AD) and cognitive 
impairment associated with schizophrenia (CIAS).
1.1
MEDICAL BACKGROUND
AD and schizophrenia are chronic, severe, and disabling brain disorders affecting both men 
and women. Available symptomatic treatments for AD consist of acetylcholinesterase 
inhibitors (AChEIs) and memantine which, however, are widely acknowledged as having 
very limited efficacy. More effective symptomatic treatment remains a major unmet medical 
need. Existing treatment options for schizophrenia (i.e., first- and second-generation 
antipsychotics) are primarily efficacious in treating positive symptoms, but have limited 
efficacy for treating the cognitive and negative symptoms of the disorder. No pharmacologic 
therapies have been approved for the symptomatic treatment of the cognitive impairment seen 
in patients with schizophrenia. 
1.2
DRUG PROFILE


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Residual Effect Period
1.2.6
The Residual Effect Period (REP) of BI 474121, when measurable drug levels and/or 
pharmacodynamic effects are still likely to be present, is not known for this first-in-human 
trial. Conservatively, a minimum observation period of at least 5-fold estimated t1/2 has been 
selected, and thus a REP of 7 days is assumed, i.e. the individual subject’s end of trial is on 
Day 8-15 following dosing with investigational drug at the earliest (see Flow Charts).  
1.3
RATIONALE FOR PERFORMING THE TRIAL
The SRD part (single rising dose part) of this trial will be the start of the clinical 
development of BI 474121. Effects of single rising doses on safety, tolerability and 
pharmacokinetics will be assessed as basis for further clinical development in patients with 
cognitive impairment due to AD and schizophrenia.
The BA part (bioavailability part) will generate pharmacokinetic information under fed 
conditions versus the fasted state to support dose regimen in future clinical trials.


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Maximum dose
1.3.2.2
The maximum dose in the SRD part of this trial is 40 mg (see Section 1.3.3.1), and this dose 
will not be exceeded in this trial. Dose escalation will be guided by preliminary PK analysis 
(see Section 1.3.3 and 7.4).
Although, as stated above, a minimum daily dose of about 2.5 mg is predicted to achieve 
therapeutic systemic exposure of BI 474121 at steady state (projected Cmax,ss of 24 nM and 
AUC0-24,ss of 308 nM*h) it is planned to explore higher doses / exposures for several reasons: 
First, subsequent clinical studies in patients may show that the required therapeutic doses and 
exposures are significantly higher than predicted. Also, higher doses / exposures might be 
required for more severe disease states of obesity (different volumes of distribution) or in 
patients with various concomitant diseases. While higher doses and exposures may still be 
well tolerated, they provide a larger magnitude of therapeutic effects.


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Further, testing of doses higher than 2.5 mg is justified to account for uncertainties in 
translation from preclinical data to human, i.e. actual PK parameters may deviate from 
predicted values, e.g.

Bioavailability may be (significantly) less than predicted

Clearance may be higher than predicted

Half-life may be shorter than predicted

Pharmacokinetics may be non-linear with less than dose-proportional increase
Eventually, even if the therapeutic dose turns out to be as low as 2.5 mg, higher than 
therapeutic doses and exposures are typically explored in the well-controlled clinical 
environment of first-in-man trials if supported by non-clinical safety data, in order to provide 
a sufficient safety margin for subsequent trials, e.g.

To cover exposures possibly be reached in trials with multiple dosing and 
accumulation

To cover exposures possibly be seen in trials in patients with impaired excretion 
function, such as renal / hepatic impairment, where substantial increases in exposure 
may be seen

To cover exposures possibly be achieved in subsequent drug-drug interaction trials

To derive a safe supra-therapeutic dose for a tQT trial or achieve high enough 
exposures during SRD trial to waive a tQT trial 
For this trial, a 40 mg dose has been selected as maximum dose. This dose is predicted to 
result in a Cmax of 285 nM and AUC0-24 of 2,850 nM*h in humans. These exposures are 4.2-
fold (Cmax) and 4.0-fold (AUC0-24) below the exposure caps defined above (see Section 
1.3.2.1) and the 40 mg dose will only be administered if predicted geometric mean values of 
Cmax or AUC0-24 do not exceed the defined exposure limits, otherwise dose escalation will be 
stopped at lower doses.
A dose of 40 mg is predicted to result in exposures that are 4.2-fold (Cmax) and 4-fold (AUC0-
24) below the exposures achieved in rats at NOAEL and 15.3-fold (Cmax) and 12.6-fold 
(AUC0-24) below the exposures achieved in Cynomolgus monkey at NOAEL.


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Escalation scheme (SRD part)
1.3.3
Escalation scheme (guided by preliminary PK analysis (see Section 7.4))
1.3.3.1
Escalation scheme has been chosen such that the assumed therapeutic dose is reached at the 
third dose level with higher escalation factors (not more than 4-fold) at the lower dose levels 
and not more than 2-fold at the higher dose levels. 
Table 1.3.3.1: 1 shows the planned dose escalation, the escalation factors, and the predicted 
systemic exposures. These are calculated based on predicted therapeutic exposures (see 
Section 1.2.2) assuming linear kinetic.
Table 1.3.3.1: 1
Dose escalation scheme, escalation factors and BI 474121 exposure in 
plasma predicted based on preclinical data
Dose level 
[#]*
Dose of 
BI 474121 [mg]
Escalation factor from 
previous dose level
Predicted 
Cmax [nM]
Predicted AUC0-24
[nM*h]
1
0.25
1.78
17.8
2
1
4.0
7.12
71.2
3
2.5
2.5
17.8
178.1
4
5
2
35.6
356.2
5
10
2
71.25
712.5
6
20
2
142.5
1,425
7
40
2
285
2,850
* A dose level (= dose group) will only be administered if the treatment in the preceding dose 
group(s) was safe and showed acceptable tolerability and if the systemic exposure of the next 
dose (gMean values for AUC0-24 and Cmax, guided by preliminary PK analysis) is expected to 
not exceed the maximum acceptable exposure (see Section 1.3.2.1). Moreover, dose 
escalation will be stopped in case individual observed exposure values in one subject exceed 
the maximum acceptable exposure. For escalations up to dose level 2 (inclusive), preliminary 
PK data are not needed (see also Section 7.4).
Preliminary PK analysis
1.3.3.2
Dose escalation will be guided by preliminary PK analysis with the following aims:
-
Ascertaining that adequate exposures are reached in this trial as a basis for further 
development of BI 474121, 
-
Ascertaining that the expected gMean exposure values of the next dose group do not 
exceed the maximum acceptable exposure in order to protect subjects’ safety, and
-
Ascertaining that dose escalation is stopped in case observed exposure values of a 
single subject exceed the maximum acceptable exposure.
For details, see Sections 3.3.4.3 and 7.4. 


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Dose selection for food effect study (BA part)
1.3.4
BI 474121 has not been administered to humans. Due to this very early stage of clinical 
development it remains open which dose  will correspond with a therapeutic dose in patients. 
Therefore two optional dose levels (2.5 mg or 10 mg) are planned for the BA part with the 
aim to select the highest possible dose strength. A dose of 2.5 mg to be used in the BA part 
requires that an at least 4-fold higher dose of the SRD part (i.e. at least 10 mg) shows 
acceptable safety and tolerability. A dose of 10  mg to be used in the BA part requires that in 
the SRD part the maximum dose of 40 mg shows acceptable safety and tolerability.
1.4
BENEFIT - RISK ASSESSMENT
Expected benefit for the target population
1.4.1
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 474121 as 
treatment for CIAS as well as for symptomatic treatment of mild to moderate AD. 
Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.
Procedure-related risks
1.4.2
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, syncope, and, in rare cases, in transient inflammation of the wall of the vein, 
or nerve injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an 
indefinite period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures
1.4.3
Factors of risk may derive from particular knowledge or the lack thereof, regarding (1) the 
mode of action, (2) the nature of the target, (3) the relevance of animal models and/or (4) 
findings in non-clinical safety studies.


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Safety measures
The following safety measures will be applied in order to minimise the risk for healthy 
volunteers:

Dose selection is based on a sound preclinical package including 4-week toxicological 
studies (see Section 1.2.3) and non-clinical pharmacology data (Section 1.2.1).


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
Careful selection of starting dose in the SRD part of the trial as described in 
Section 1.3. 

Dose escalation in the SRD part of the trial will be shallow with an increase of no 
more than 2-fold beyond the predicted human therapeutic dose of 2.5 mg of 
BI 474121.

Measurement of BI 474121 plasma concentrations and preliminary determination of 
PK parameters in the SRD part of the trial (Cmax, AUC0-24, see Section 7.3.4). For 
precautionary reasons, drug plasma concentrations in this healthy volunteer trial will 
not exceed the geometric mean (gMean) Cmax of 657 nM for Cmax and 6,201 nM*h for 
AUC0-24(see Section 2.1). Dose escalation will be stopped if the Cmax or AUC0-24 of at 
least 1 subject of one dose group exceeds or if the estimated systemic exposure (group 
gMean values) of the next dose level is expected to exceed the maximum acceptable 
exposure (see Section 7.3.4).

For safety reasons, each dose group of 8 subjects (6 on active, 2 on placebo) in the 
SRD part of the trial will be divided in three cohorts with staggered inclusion of 
subjects (see Section 3.1 for details). The first drug administration of cohort 2 and the 
first drug administration of cohort 3 will be no earlier than 22 hours after first drug 
administration in the previous cohort. Within each cohort, drug administrations will 
be separated by at least 10 min. This design ensures that between first and second 
active dose of each dose level there is a time interval of at least 22 hours. This time 
interval is expected to be sufficient to detect relevant first acute effects of BI 474121.
In the BA part of the trial, 12 subjects will be dosed in one cohort with no minimum 
time interval defined between dosing. 

An extensive safety laboratory will be performed in both trial parts (see 
Section 5.2.3). This will also include sensitive serum markers to early detect skeletal 
muscle injury.

A ECG monitoring up to Day 5 (96 h post dose in the SRD part of the trial) will be 
performed to cover the anticipated period of highest drug exposure. Continuous ECG 
measurement will be performed over 4 hours post dose in the SRD part of the trial. 
Dose escalation in the SRD part of the trial would be stopped as soon as at least 2 
subjects at one dose level showed relevant QT prolongation (see Section 3.3.4.2 for 
details).

In the SRD part of the trial, orthostatic testing will be performed prior to and 
following study drug administration at the time points indicated in the Flow Chart to 
assess hemodynamic effects of BI 474121. Dose escalation will be stopped if clinical 
symptoms will be observed in more than 1 subject (severe) or more than 3 subjects 
(moderate) in one dose group.

Only if the respective dose of BI 474121 was safe and showed acceptable tolerability 
and if no stopping criterion was met (see Section 3.3.4.2), the next higher dose will be 
given not earlier than 7 days (up to dose group 3) or 14 days (from dose group 4
onwards) after first dosing of the previous dose group (referring to the 1st subject of 
each respective dose group) in the SRD part of the trial. A documented Safety Review 
must take place prior to each dose escalation (see Section 3.1).


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
The subjects will stay at the trial site for at least 48 hours after study drug 
administration in the SRD part of the trial and for at least 24 hours after study drug 
administration in the BA part of the trial. Based on an anticipated half-life of 
BI 474121 of 18.6 hours, this is expected to cover the period of highest risk / peak 
effect.

During in-house confinement, the subjects will be under medical observation and 
thoroughly monitored for both expected and unexpected adverse events.
Conclusion
In summary, although not tested in humans to date, BI 474121 has the potential to become an 
oral treatment for cognitive deficits in patients with schizophrenia and AD, both indications 
with a large medical need. 
Based upon preclinical data for BI 474121 as well as the implemented safety measures
described above, healthy subjects will not be exposed to undue risks in relation to the
important information expected from this trial as a basis for further clinical development of
this compound. 
Healthy volunteers are not expected to have any direct benefit from participation in this FIH
clinical trial with BI 474121. Considering the medical need for an effective treatment in
schizophrenia and AD, the sponsor considers that the benefit outweighs the potential risks 
and justifies exposure of healthy human volunteers.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
2.1.1
The main objectives of this trial are to investigate safety, tolerability and pharmacokinetics
(PK) of BI 474121 in healthy male subjects following oral administration of single rising 
doses.
Primary endpoint
2.1.2
The primary endpoint for assessment of safety and tolerability of BI 474121 is the percentage 
of subjects with drug-related adverse events (SRD part).
The following pharmacokinetic parameters will be determined if feasible (BA part): 

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
Secondary endpoint
2.1.3
The following pharmacokinetic parameters will be determined if feasible:
SRD part:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
BA part:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)


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Safety and tolerability
2.2.2.1
Safety and tolerability of BI 474121 will be assessed based on:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring (SRD part only)

Vital signs (blood pressure, pulse rate, orthostatic test (SRD part only))


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
SRD part
This single-rising dose trial is designed as single-blind within dose groups, randomised, and 
placebo-controlled within parallel dose groups.
It is planned to include 56 healthy male subjects in this part of the trial. The subjects will be 
assigned to 7 groups consisting of 8 subjects per group; the groups will be dosed sequentially
(see Table 3.1: 1). The investigator is allowed to alter the scheduled dose groups (e.g., add 
low and/or intermediate dose groups) on the basis of experience gained during the study (for 
instance, based on preliminary PK data), provided the planned and approved highest dose is 
not exceeded. Thus, the actual number of subjects entered may be more than 56, but is not to 
exceed 72. Such changes may be implemented via non-substantial CTP amendments. The 
addition of further dose groups exceeding the already tested dose levels for the evaluation of 
safety findings is subject to a substantial CTP amendment requiring approval.
Within each dose group, 6 subjects will receive BI 474121 and 2 will receive placebo. Only 
one dose is tested within each dose group. For safety reasons, each dose group will consist of
3 cohorts.
The trial medication will be administered in the following order: For the first 4 subjects 
(cohort 1 and 2) the treatment order will be ‘active’ – ‘placebo’ – ‘active’ – ‘active’, while 
the following 4 subjects (cohort 3) will be randomised to 3x ‘active’ and 1x ‘placebo’ 
The second subject on active per dose group will be treated not earlier than 22 hours after the 
first subject on active (minimum time interval between 1st subject of cohort 1 [sentinel 
subject] and 1st of cohort 2). This is expected to be sufficient to detect relevant acute effects 
of BI 474121 in the sentinel subject based on an anticipated half-life of BI 474121 of 
approximately 19 hours prior to exposing more volunteers to BI 474121 at the respective 
dose level. In all cohorts, a time interval of at least 10 min will be maintained between 
dosings of individual subjects.
The dose groups to be evaluated are outlined in Table 3.1: 1 below.


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Table 3.1: 1
Dose groups
Dose Group
1
2
3
4
5
6
7
Dose (mg)
0.25
1
2.5
5
10
20
40
Number of subjects
8
8
8
8
8
8
8
Subjects receiving placebo
2
2
2
2
2
2
2
Subjects receiving BI 474121
6
6
6
6
6
6
6
The dose groups will be dosed consecutively in ascending order, and a time interval of at 
least 3 days will be maintained between the last drug administration to subjects in the 
previous dose group and the first drug administration to subjects in the subsequent dose 
group. Moreover, a time interval of at least 7 days will be maintained for DG 1 to 3 and 14 
days for DG 4 to 7 between the first drug administration to subjects in the previous dose 
group and the first drug administration to subjects in the subsequent dose group. The decision 
to treat the next dose group will be based upon safety, tolerability and pharmacokinetic data 
(for details refer to Section 7.4) of the preceding dose groups. The next dose group will only 
be treated if, in the opinion of the investigator, no safety concerns have arisen in the 
preceding dose groups (i.e. no dose-limiting events occurred), and if none of the pre-specified 
trial-specific stopping criteria have been met (refer to Section 3.3.4.2).
A documented safety review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested anytime by the Principal Investigator (or 
an authorised deputy) or the sponsor of the study (for instance, due to the occurrence of any 
unforeseen adverse events). 
Although no formal Safety Review meeting will take place within a given dose group, safety 
will be continuously monitored during this trial, and an individual will only be dosed in the 
absence of any safety concern (i.e. no dose-limiting events occurred) and if none of the pre-
specified trial-specific stopping criteria have been met (refer to Section 3.3.4.2).
At minimum, data from 4 subjects on active drug need to be available for escalation to a 
higher dose. For the minimum dataset with regards to preliminary PK data, see Section 7.4.
The minimum data set for review consists of the following:

AEs in the current and preceding dose groups up to at least 48 h post dosing, 
including clinically relevant findings from ancillary safety testing listed below (Note: 
AEs may be ongoing at the time of Safety Reviews and AE information may be 
subject to change prior to Database Lock)

Results from 12-lead ECG and continuous ECG monitoring in the current and 
preceding dose groups up to at least 24 h (DG 1 to 3) or 48 h (DG 4 to 7) post dosing

Vital signs and results from the orthostatic tests in the current and preceding dose 
groups up to at least 24 h post dosing

Clinical laboratory tests in the current and preceding dose groups up to 24 h post 
dosing

Preliminary PK data for the selected time as per Section 7.4


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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 Clinical Trial Leader (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs, and out-of-range 
laboratory results (if considered clinically significant). In addition and depending on the 
results and findings, suitable experts from the sponsor or external institutions may be 
consulted on an as needed basis. In these cases expert recommendations will be documented 
in the minutes of the Safety Review and considered for the decision making. Dose escalation 
will only be permitted if no safety concerns exist neither in the opinion of the Principal 
Investigator (or an authorised deputy) nor the Clinical Trial Leader (or an authorised deputy). 
Safety Reviews can be conducted face-to-face or by video/telephone conference. The Clinical 
Trial Leader is responsible for the organisation and minutes of the reviews. Minutes will be 
signed off by the Principal Investigator (or an authorised deputy) and Clinical Trial Lead (or 
an authorised deputy), and will be filed in the ISF and TMF.
BA part
The BA part will be performed as randomised, open-label, three-way, six-sequence, cross-
over trial in healthy male subjects in order to assess (1) the relative bioavailability of the 
tablet relative to PfOS (both administered under fasted conditions) and (2) the relative 
bioavailability of the tablet administered under fed and fasted conditions. The subjects will be 
randomly allocated to the 6 treatment sequences. The treatments will be one 2.5 mg or one 10 
mg tablet administered in the fasting and fed state, after a standardised high-fat, high-calorie 
breakfast, as well as 2.5 mg or 10 mg PfOS administered in the fasting state. For details refer 
to Section 4.1.4.
There will be a wash out period of at least 7 days between the treatments. 
A total of 12 healthy male subjects is planned to participate in the BA part.
An overview of all relevant activities is provided in the Flow Chart. For visit schedule and 
details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
SRD part:
For single-rising dose trials, the sequential rising dose design described in Section 3.1 is 
viewed favourably under the provision not to expose the subjects involved to undue risks.
Single-blind conditions regarding the subject’s treatment (active or placebo) are maintained 
within each dose group. However, subjects and investigators will be aware of the dose of 
drug administered. The disadvantage of the trial design is a possible observer bias with regard 
to the dose-dependent effects; in addition, the sequential dosing of groups could potentially 
result in time-related effects. However, as such 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.


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It is standard in single or multiple rising dose trials involving healthy volunteers to include a 
placebo group to control for safety and tolerability of the trial medication. Each dose group 
consists of 8 subjects, with 6 on active treatment and 2 on placebo. For data analysis 
purposes, the placebo control group will include all subjects of all dose groups treated with 
placebo. Six subjects per active treatment group are generally considered to be sufficient for 
the exploratory evaluation of pharmacokinetics. 
BA part:
For relative bioavailability trials, the cross-over design is preferred due to its efficiency: since 
each subject serves as his own control, the comparison between formulations or treatments is 
based on a comparison within subjects rather than between subjects. This trial design 
therefore removes intersubject variability from the comparison between formulations or 
treatments [cf. R94-1529].
3.3
SELECTION OF TRIAL POPULATION
It is planned that 56 healthy male subjects will enter the SRD part and 12 subjects the BA
part of the study. In the SRD part, the actual number of subjects entered may exceed 56
subjects if additional intermediate or lower doses are tested (see Section 3.1). Subjects will be 
recruited from the volunteers' pool of the trial site. Subjects can only participate either in the 
SRD or in the BA part of the trial.
Only male subjects will be included in the trial because no data on reproductive toxicology 
are available at this time.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
Main diagnosis for trial entry 
3.3.1
The study will be performed in healthy subjects.
Inclusion criteria
3.3.2
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-
lead ECG, and clinical laboratory tests 
2. Age of 18 to 45 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4. Signed and dated written informed consent prior to admission to the study, in 
accordance with GCP and local legislation


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Exclusion criteria
3.3.3
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination 
(including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by 
the investigator
2. Repeated measurement of systolic blood pressure outside the range of 100 to 
140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse 
rate outside the range of 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be 
of clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the 
investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological 
or hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with 
the pharmacokinetics of the trial medication (except appendectomy or simple hernia 
repair)
7. Diseases of the central nervous system (including but not limited to any kind of 
seizures or stroke), and other relevant neurological or psychiatric disorders
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial 
medication or its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc 
interval prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation 
in another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 24 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms or any other relevant ECG finding at screening)


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21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance,
because the subject is not considered able to understand and comply with study 
requirements, or has a condition that would not allow safe participation in the study 
23. Male subjects with WOCBP partner who are unwilling to use a highly effective 
method of birth control from time point of administration of trial medication until 30 
days thereafter. Highly effective methods of birth control are:
- Male subject is sexually abstinent
- Male subjects is vasectomised (vasectomy at least 1 year prior to enrolment), plus
condom in male subject
- Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
- Use of progestogen-only hormonal contraception by female partner that inhibits 
ovulation (only injectables or implants), plus condom in male subject
- Use of combined (estrogen and progestogen containing) hormonal contraception by 
female partner that prevents ovulation (oral, intravaginal or transdermal), plus
condom in male subject
- Female partner is surgically sterilised (including hysterectomy)
- Female partner is postmenopausal, defined as no menses for 1 year without an 
alternative medical cause (in questionable cases a blood sample with FSH above 40 
U/L and estradiol below 30 ng/L is confirmatory)
Sperm donation is not allowed from the time point of drug administration until 30 
days thereafter.
24. ALT (alanine transaminase), AST (aspartate transaminase), or serum creatinine 
exceed upper limit of normal range at screening, confirmed by a repeat test
25. Orthostatic hypotension during orthostatic testing at Day -3, that the investigator 
considers to be of clinical relevance (only applicable for SRD part).
26. During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection.
For study restrictions, refer to Section 4.2.2.
Withdrawal of subjects from treatment or assessments
3.3.4
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR.


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At the time of discontinuation, a complete end of trial examination will be performed, if 
possible, and the information will be recorded in the CRF. If the discontinuation occurs 
before the end of the REP (see Section 1.2.6), the discontinued subject should if possible be 
questioned for AEs and concomitant therapies at or after the end of the REP in order to 
ensure collection of AEs and concomitant therapies throughout the REP, if not contrary to 
any consent withdrawal of the subject.
Since the risks of drug exposure of a (pregnant) female partner of a male study participant via 
the seminal fluid are yet unknown, adequate contraception as outlined in Section 3.3.2 is a 
prerequisite for participation in the study.
Discontinuation of trial treatment
3.3.4.1
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial 
treatment, without the need to justify the 
decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing 
or able to adhere to the trial requirements in the future 
3. The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of 
total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be 
followed up according to the DILI checklist provided in the ISF
6. The subject has a serious adverse reaction or a severe non-serious adverse reaction
(applies to BA part).
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and section 6.2.3.
Withdrawal of consent to trial participation
3.3.4.2
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see section 3.3.4.1 above.


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Discontinuation of the trial by the sponsor
3.3.4.3
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (#5, #6 and #7 mandatory discontinuation criteria) :
1. Failure to meet expected enrolment goals 
overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information
invalidating the earlier positive benefit-risk assessment.
3. Violation of GCP, or the CTP impairing the appropriate conduct of the trial.
4. The sponsor decides to discontinue the further development of the investigational 
product
5. Dose escalation in the SRD part or treatment in the BA part will be stopped if at least 
2 subjects on active treatment at one dose level (SRD part) or 2 subjects in the BA 
part have relevant individual QT prolongations, i.e. a QTc increase of greater than 
60 ms from baseline and/or an absolute QT or QTc greater than 500 ms, as confirmed 
by a repeat ECG recording.
6. Dose escalation in the SRD part will be stopped, if the Cmax or AUC0-24 of at least 1 
subject of one dose group increases above the following exposure thresholds or if the 
estimated gMean exposure is expected to exceed a Cmax of 657 nM or an AUC0-24 of 
6,201 nM*h. In this case, one or two additional dose levels lower than the planned 
next dose level may be given, as long as the expected gMean exposure values of the
interim dose do not exceed these exposure thresholds. Estimation will be done based 
on preliminary PK results of preceding dose groups (see Section 7.4)
7. Occurrence of severe non-serious adverse events considered as drug-related by the 
investigator in 2 subjects of the same dose group (8 subjects) in the SRD part, or 3
subjects of the BA group (12 subjects), or occurrence of at least one drug-related 
serious adverse event. Moreover, dose escalation in the SRD part will be terminated if 
more than 3 of the actively dosed subjects at one dose level show drug-related and 
clinically relevant adverse events of at least moderate intensity.
Replacement of subjects
3.3.5
In case that
-
in the SRD part, one dose group is completed by less than 4 subjects on active 
treatment (due to e.g. drop-outs or recruitment reasons) or,
-
in the BA part, more than two subjects do not complete the trial,
the Clinical Trial Leader together with the Trial Pharmacokineticist and the Trial Statistician 
are to decide, if and how many subjects will be replaced. A replacement subject will be
assigned a unique trial subject number, and will be assigned to the same treatment (SRD part) 
/ treatment sequence (BA part) as the subject he replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product has been manufactured by BI Pharma GmbH & Co. KG. 
Identity of the Investigational Medicinal Products
4.1.1
The characteristics of the two test products are given below:
Powder for oral solution
Substance:
BI 474121
Pharmaceutical formulation: Powder for oral solution
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
0.5 mg/mL
Posology:
SRD Part 1-0-0 (0.5 mL=0.25 mg, 2 mL=1 mg)
BA Part 1-0-0 (5 mL=2.5 mg or 20 mL=10 mg)
Route of administration:
oral
Duration of use:
Single dose 
Detailed instructions for reconstitution are given in Appendix 10.1.
BI 474121 2.5 mg tablet
Substance:
BI 474121
Pharmaceutical formulation: Uncoated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
2.5 mg
Posology:
SRD: 1-0-0 (DG3), 2-0-0 (DG4)
BA part: 1-0-0 (optional, see section 1.3.4)
Route of administration:
oral
Duration of use:
Single dose 


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BI 474121 10 mg tablet
Substance:
BI 474121
Pharmaceutical formulation: Uncoated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
10 mg
Posology:
SRD: 1-0-0 (DG5), 2-0-0 (DG6), 4-0-0 (DG7)
BA part 1-0-0 (optional, see section 1.3.4)
Route of administration:
oral
Duration of use:
Single dose 
The characteristics of the reference product (placebo) are given below:
Tablet formulation
Substance:
Matching placebo in size and weight to 2.5 and 10 mg tablet
Pharmaceutical formulation: Uncoated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
--
Posology:
Matching to the test product (1-0-0 [DG4, DG5], 2-0-0 [DG6], 
4-0-0 [DG7])
Route of administration:
oral
Duration of use:
Single dose
Powder for oral solution
Substance:
Not applicable, solvent only
Pharmaceutical formulation: Solvent only
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
--
Posology:
SRD Part 1-0-0 (0.5 mL, 2 mL)
BA Part 1-0-0 (5 mL)
Route of administration:
oral
Duration of use:
Single dose 
Selection of doses in the trial and dose modification
4.1.2
For the SRD part, oral doses in the range of 0.25 mg to 40 mg have been selected in order to
assess the safety and tolerability of BI 474121 in healthy male volunteers, and to investigate
the PK of this PDE2 inhibitor. The selected doses cover a safe starting dose in the sub-
therapeutic range, the estimated therapeutic range and potentially supra-therapeutic doses
within the levels determined by pre-clinical investigations (see Section 1.2 for details).
The intra-individual comparison of the BA part investigating the relative bioavailability of
tablet fasted versus tablet fed are planned to be conducted with a dose of 2.5 mg or 10 mg as 
it is assumed that one of these doses covers the therapeutic range and might be used in the 
further clinical development (see Section 1.2).


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Method of assigning subjects to treatment groups
4.1.3
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate in the SRD part of the trial will be 
recruited to dose groups (3 cohorts per dose group) according to their temporal availability.
As soon as enough subjects are allocated to 1 of the up to 21 dose cohorts, 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. Because the study includes healthy subjects from a homogenous 
population, relevant imbalances between the dose groups are not expected.
Subjects will be assigned to treatments (active treatment or placebo) in the SRD part or to 
treatment sequences in the BA part of the trial prior to the first administration of trial 
medication. For this purpose, the respective randomisation lists will be provided to the trial 
site in advance. Numbers of the randomization lists will be allocated to subjects by drawing 
lots. Subjects are then assigned to treatment (SRD part) or treatment sequences (BA part) 
according to the randomisation list. Once a subject number has been assigned, it cannot be 
reassigned to any other subject. 
The randomisation procedure is described in Section 7.6.
Drug assignment and administration of doses for each subject
4.1.4
SRD part
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of units / 
dose volume for placebo corresponds to the number of units / dose volume of the 
corresponding dose level.
Table 4.1.4: 1
BI 474121 and placebo treatments, oral administration
Dose
group
Substance
Pharmaceutical 
form
Unit strength
Number of units / dose volume 
per administration
Total daily
dose
1
BI 474121
oral solution
0.5 mg/mL
0.5 mL
0.25 mg 
2
BI 474121
oral solution
0.5 mg/mL
2 mL
1 mg
3
BI 474121
uncoated tablet
2.5 mg
1 tablet
2.5 mg
4
BI 474121
uncoated tablet
2.5 mg
2 tablets
5 mg
5
BI 474121
uncoated tablet
10 mg
1 tablet
10 mg
6
BI 474121
uncoated tablet
10 mg
2 tablets
20 mg
7
BI 474121
uncoated tablet
10 mg
4 tablets
40 mg
1-7
Placebo*
oral solution
DG1 to DG2
uncoated tablet
DG3 to DG7
--
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups 
The Investigator can decide at any time to discontinue dosing or to decrease the dose 
escalation by adding intermediate doses in case of intolerability or due to safety concerns.


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For oral solution, the medication for dosing (active treatment and placebo) will be prepared 
by qualified medical study personnel at the trial site under the responsibility of the 
investigator according to the instructions provided in Appendix 10.1.
Administration of trial medication will be performed after subjects have fasted overnight;
fasting is to start no later than 10 h before the scheduled dosing. The investigator (or 
authorised designee) will administer the trial medication as an oral dose together with about 
240 mL of water to subjects who are in a standing position. During the first 4 h after drug 
administration, subjects are not allowed to lie down (i.e. no declination of the upper body of 
more than 45 degrees from upright posture except for medical examination) or to sleep. For 
drug administration, the so-called four-eye principle (two-person rule) should be applied. For 
this, an authorised employee of the trial site should witness the administration of trial 
medication, and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot 
be ensured otherwise.
Subjects will be kept under close medical surveillance until 48 h following drug 
administration.
BA part:
This part is a three-way, 6-sequence, cross-over design. The treatment consists of one 2.5 mg 
or 10 mg tablet administered under fed (Test 1, T1) and fasted (T2) conditions as well as of 5 
mL or 20 mL oral solution (R) administered under fasted conditions. All 12 subjects will 
receive the three treatments in randomised order. The treatment sequences and the treatments 
to be evaluated are described in Section 3.1.
The trial medication will be administered to the subjects, while in a 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 the trial medication, if correct dosage cannot be assured 
otherwise.
For the treatment (uncoated tablet, powder for oral solution), administration will be 
performed following an overnight fast starting no later than 10 h before scheduled dosing. 
For the test treatment (T1), a high fat, high caloric meal will be served starting exactly 30 min 
before drug administration. The meal must be completely consumed prior to drug 
administration. The composition of the standard high-fat, high-caloric meal will be in 
compliance with FDA guidance “Food-effect Bioavailability and Fed Bioequivalence Studies 
[R03-2269] as detailed in Table 4.1.4: 2.


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Table 4.1.4: 2
Composition of the high-fat, high-caloric meal
Ingredients
kcal
2 chicken eggs (whole content) for scrambled eggs
192
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum1
984
1 The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal as 
carbohydrate, and 500 to 600 kcal as fat.
During the first 4 h after drug administration, subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture except for 
medical examination) or to sleep.
The treatments will be separated by a wash-out period of at least 7 days.
Subjects will be kept under close medical surveillance until 24 h after drug administration.
Blinding and procedures for unblinding
4.1.5
Blinding
4.1.5.1
SRD part
The trial is designed single-blind. The treatments administered (active or placebo) will be 
blinded to subjects, but will be known to the investigators (outcome assessors). Only the 
current dose level will be known to the subjects due to the rising dose design.
A single–blind design is considered acceptable because the potential bias in this type of study 
seems to be low and according to study procedures it is assured that the investigator's 
knowledge of the next treatment does not influence the decision to enter a subject.
All trial data will be handled open label. This means that trial functions of the sponsor are 
unblinded (including clinical trial leader, data manager, statistician, bioanalyst, 
pharmacokineticist, pharmacometrician, drug metabolism scientist as well as dedicated 
personnel of the trial site). 
Within the central ECG lab, the staff involved with interval measurements and assessments
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.
Access to the randomisation schedule will be controlled and documented by a signed 
confidentiality statement, which will be stored in the TMF. 


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BA part
The BA part will be handled in an open fashion throughout (that is, during the conduct, 
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations. 
Emergency envelopes will not be provided, since the treatments (only active drug) of all 
subjects are known in this open-label trial.
Unblinding and breaking the code
4.1.5.2
SRD part
As this trial will be conducted single-blind, subjects’ treatment assignments will be known to
investigators. Therefore, no emergency envelopes will be provided.
BA part
As the BA part will be conducted open-label, subjects’ treatment assignments will be known 
to subjects and investigators. Therefore, no emergency envelopes will be provided.
Packaging, labelling, and re-supply
4.1.6
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the
title page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
Storage conditions
4.1.7
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
Drug accountability
4.1.8
The investigator or designee will receive the investigational drugs from the sponsor when the 
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Approval/notification of the regulatory authority,  e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator


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
Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused trial medication will be disposed of locally by the trial site upon written 
authorisation of the trial clinical monitor. Receipt, usage, and disposal of trial medication 
must be documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
Other treatments and emergency procedures
4.2.1
There are no special emergency procedures to be followed. No additional treatment is
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
Restrictions
4.2.2
Restrictions regarding concomitant treatment
4.2.2.1
In principle, no concomitant therapy is allowed. However, in case of adverse events in need 
of treatment, the investigator can authorise symptomatic therapy. All concomitant or rescue 
therapies will be recorded (including time of intake on study days) on the appropriate pages 
of the CRF.
Restrictions on diet and life style
4.2.2.2
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before investigational drug intake (on Day 1 of visit 2 in the SRD part of the trial 
and on Day 1 of visits 2,3 or 4 in the BA part of the trial) until lunch on respective trial days, 
fluid intake is restricted to the milk served with breakfast (in the BA part of the trial [see 
Table 4.1.4: 2]), the water administered with the investigational drug, and an additional 


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240 mL of water served at 2 h and 4 h post-dose (mandatory for all subjects). From lunch 
until 24 h post-dose, fluid intake is restricted to 3 litres. 
During the days of urine collection in the SRD part of the trial, total fluid intake should be at 
least 1.5 litres and should not exceed 3.5 litres.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 4 days before the first administration of trial medication until after the last PK 
sample of each study period is collected. 
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 12 h before until 24 h after administration of investigational 
trial medication.
Smoking is not allowed during in-house confinement while admitted to the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/or urinary excretion of trial medication will provide additional confirmation of
compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable. No efficacy endpoints will be evaluated in this trial.
5.2
ASSESSMENT OF SAFETY
Physical examination
5.2.1
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported),
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR), 12-lead ECG (including rhythm strip of at least 15 minutes in 
SRD part), laboratory tests, and a physical examination. At the end of trial examination, it 
will include review of vital signs, 12-lead ECG, laboratory tests, and a physical examination. 
Vital signs
5.2.2
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap Pro 100, 
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.
Orthostatic tests
5.2.3
At the time points indicated in the Flow Chart orthostatic tests will be performed. Subjects 
should have spent at least 5 min in the supine position before blood pressure and pulse rate 
will be measured the first time. Further 2 measurements will be performed immediately after 
standing up and after 3 min in a standing position. All recordings shall be made using the 
same type of blood pressure recording instrument described in 5.2.5.1 on the same arm if 
possible. 
The term “Orthostatic dysregulation” will be used to describe adverse events that occur
during orthostatic testing. Typical symptoms of orthostatic dysregulation are dizziness,
diaphoresis, tachycardia (PR >100 bpm) or even fainting (which is reflected in the
assessment of AE intensity). 
At the time points given in the Flow chart the following sequence of measurements should be 
adhered: 12 lead-ECG and vital signs will be done before blood sampling. Orthostatic testing 
will be done after blood sampling. While standing up the subject will be accompanied by 
medical staff.


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Safety laboratory parameters
5.2.4
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 10 h
(not on Day 1 of the SRD and BA part at 6 h after dosing). For retests, at the discretion of the 
investigator or designee, overnight fasting is not required. The parameters that will be 
determined are listed in Tables 5.2.4: 1 and 5.2.4: 2. Reference ranges will be provided in the 
ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively, and considered clinically relevant by the investigator.
Table 5.2.4: 1
Routine laboratory tests
Functional lab 
group
BI test name [comment/abbreviation]
A
E
B
C
D
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
Reticulocytes, absol.
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
--
X
Automatic WBC 
differential, 
absolute
Neutrophils, absol.; Eosinophils, absol.; Basophils, absol. ;
Monocytes, absol.; Lymphocytes, absol.
X
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands;  Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
--
X
X
--
--
--
--
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated]
Myoglobin
Lactic Dehydrogenase
Lipase
X
X
X
X
X
X
X
X
X
X
X
X
--
--
X
X
X
X
X
--
X
X
X
X
X
X
X
X
X
--
X
--
--
--
--
X
X
X
X
--
X
X
X
X
X
X
X
X
X
X
A: parameters to be determined at Visit 1 (screening examination) 
E: parameters to be determined at Visit 2 on Days -3, -2 or -1 (laboratory assessment can be omitted if 
screening examination is performed on Days -3, -2 or -1; for time points refer to Flow Chart)
B: parameters to be determined at Visit 2 of the SRD part and Visit 2 - 4 of the BA part (for time points refer to 
Flow Chart)


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C: parameters for monitoring of skeletal muscle to be determined at Visit 2 of the SRD part and Visit 2 - 4 of the 
BA part (for time points refer to Flow Chart)
D: parameters to be determined at Visit 5 of the SRD part or Visit 5 of the BA part (end of trial examination)
Table 5.2.4: 1
Routine laboratory tests (cont).
Functional lab group
BI test name [comment/abbreviation]
A
E
B
C
D
Hormones
Thyroid Stimulating Hormone 
X
--
--
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
C-Reactive Protein (Quant)  
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
--
X
X
X
--
--
X
--
--
--
X
X
X
X
X
--
X
--
--
--
--
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
--
--
Electrolytes
Sodium
Potassium
Chloride
Calcium
X
X
X
X
X
X
--
X
X
X
X
X
--
--
--
--
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
E: parameters to be determined at Visit 2 on Days -3, -2 or -1 (laboratory assessment can be omitted if 
screening examination is performed on Days -3, -2 or -1; for time points refer to Flow Chart)
B: parameters to be determined at Visit 2 of the SRD part and Visit 2 - 4 of the BA part (for time points refer to 
Flow Chart)
C: parameters for skeletal muscle monitoring to be determined at Visit 2 of the SRD part and Visit 2 - 4 of the 
BA part (for time points refer to Flow Chart)
D: parameters to be determined at Visit 5 (end of trial examination) 
The tests listed in Table 5.2.4: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests at screening only. Drug 
screening will be performed at screening and prior to each treatment period.


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Table 5.2.4: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
7410,
 True M,
, or 
similar) will be performed prior to each treatment period, and may be repeated at any time 
during the study at the discretion of an investigator or designee. The results will not be 
included in the CTR.
The laboratory tests listed in Tables 5.2.4: 1 and 5.2.4: 2 will be performed at 
, with the exception of 
drug screening tests. These tests will be performed at the trial site using M-10/14-PDT test or 
comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
Electrocardiogram
5.2.5
12-lead resting ECG
5.2.5.1
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System,
 at the time points given in the Flow Chart. Electrode placement will be performed 
according to the method of Wilson, Goldberger and Einthoven modified by Mason and Likar 
(hips and shoulders instead of ankles and wrists). Precise electrode placement will be marked 
with an indelible mark on the skin to allow reproducible placement throughout the study.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled 
for the same time (except for blood drawing from an intravenous cannula that is already in 
place) to avoid compromising ECG quality.


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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 Charts.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database.
Storing
All ECGs will be stored electronically on the Muse Cardiology Information System (
 
.
ECGs recorded during visit 2 of the SRD part will be evaluated by a central lab, while ECG 
recordings during the BA part will be only evaluated locally.
Data transfer
In the SRD part of the trial, for time points specified in the Flow Chart, ECGs will be 
transferred electronically to the central ECG lab
for 
evaluation and/or storage except for ECGs from screening and EoTrial visits which will not 
be transferred. 
In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded.
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).
Evaluation
a) Central ECG lab
Central ECG lab evaluation will be performed post-study for the first of three 
replicate ECGs per time point on Days 1 to Day 3 and for the single ECGs on Day 4 
and 5. This will include the determination of cardiac QRS-axis as assessed by the 
ECG machine’s algorithm as well as the intervals RR, PR, QRS and QT measured 
semi-automatically.
Heart rate (HR) and the QT interval corrected for HR (QTc, e.g. QTcF and QTcB) 
will be determined by the sponsor (see TSAP for details).
All semi-automatic interval measurements in one subject will be performed on the 
same lead. The intervals will be measured from four cardiac cycles (beats) in lead II. 
If lead II shows a flat T wave or is not measurable for any reason, lead V5 will be 
used, or if that lead is not measurable, then lead I will be used. The lead actually used 
will be reported in the CTR. For automatic interval measurements no lead will be 


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provided. After quality control, the fiducial point markings will be reviewed by the 
cardiologist assigned to the study.
Morphological analyses of the ECGs will be performed by a board-certified 
cardiologist or equivalent who is to evaluate only the first of three replicate 12-lead 
ECGs recorded per time point on Days 1 to Day 3 and the single ECGs on Days 4 and 
5.
The ECG interpretation will include an overall assessment (normal, abnormal 
clinically relevant, abnormal clinically not relevant, not evaluable) and findings with 
respect to e.g. rhythm, conduction, presence of myocardial infarction, ST-segment, T-
wave, and presence of U-wave. Basis of the terminology used for the evaluation is the 
 EG standard findings list as specified in the data transmission agreement.
For blinding arrangements see Section 4.1.5. 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 the 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].
b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of 
cardiac safety during the study, the QT and QTcB values generated by the 
computerised ECG system or their manual corrections by the investigators will be 
used. In doubtful cases (SRD part), 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 abnormality will be monitored carefully and, 
if necessary, the subject will be removed from the trial and will receive the appropriate 
medical treatment. 
Continuous ECG monitoring
5.2.5.2
Continuous ECG monitoring will be only conducted during the SRD part. 
Cardiac rhythm (including heart rate) will be monitored by means of continuous 3-lead ECG 
recording using the CARESCAPE Monitor B450 (
) for at 
least 15 min before drug administration (for baseline assessment) and for 4 h following drug 
administration). This continuous ECG monitoring supports the early detection of adverse 


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events such as clinically relevant bradycardia, tachycardia, or arrhythmia at the trial site. 
Beyond this clinical evaluation at the trial site, no further data collection or analyses are 
performed based on continuous ECG monitoring.
ECG data from continuous ECG recording will not be transferred to the clinical trial 
database. Abnormal findings during continuous ECG recording will be recorded as AEs if 
judged clinically relevant by the Investigator.
Assessment of adverse events
5.2.6
Definitions of adverse events
5.2.6.1
Adverse event
5.2.6.1.1
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
5.2.6.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 

Requires inpatient hospitalisation  

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 


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convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
5.2.6.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.6.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
eDC system. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.


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Intensity (severity) of AEs
5.2.6.1.5
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
5.2.6.1.6
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged


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Adverse event collection and reporting
5.2.6.2
AE collection
5.2.6.2.1
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial:
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF


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AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no 
further information can be obtained.
Pregnancy
5.2.6.2.4
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
5.3.1
Date and clock times of drug administration and pharmacokinetic sampling will be recorded.
Exact times of plasma sampling will be derived from the study management system 
ClinBase™ and documented in the CRFs by the medical personnel or sent as electronic files
to the trial data manager. The actual sampling times will be used for determination of 
pharmacokinetic parameters.


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PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. as a result of 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.
Methods of sample collection
5.3.2
Blood sampling for pharmacokinetic analysis
5.3.2.1
For quantification of BI 474121 concentrations in plasma, approx. 2.7 mL of blood will be 
drawn from an antecubital or forearm vein into an K2-EDTA (potassium ethylenediamine-
tetraacetic acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. 
Blood will be withdrawn either by means of an indwelling venous catheter or by 
venepuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x 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 of plasma. 
The process from blood collection until transfer of plasma aliquots into the freezer should be 
completed in less than 90 min, with interim storage of blood samples and aliquots on ice. The 
time each aliquot was placed in the freezer will be documented. Until transfer on dry ice to 
the analytical laboratory, the aliquots will be stored upright at approximately -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 approximately -20°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. Further information such as matrix and analyte may also be provided. 
Plasma samples will be transferred to
 :
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g., for stability testing or assessment of metabolites). However, only data 
related to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations, but not later than 5 years after the CTR is 
archived.
Blood sampling for metabolism analysis
5.3.2.2
Additional K2-EDTA plasma samples for the identification of drug metabolites will be 
investigated in the 5 mg and 40 mg dose group. Based on the knowledge gained during the 
trial conduct, e.g. from preliminary PK results, the dose group may be modified to a different 
one. The change will be implemented via a non-substantial CTP amendment.
The blood samples will be drawn at the same time points as PK samples on Day 1 to 5 (see 
Flow Chart). At each of these times, 2.7 mL blood will be needed for metabolite analysis. 
The blood samples will be processed in the same way as the PK samples (see Section 
5.3.2.1). However, the plasma obtained (approximately 1 mL) will be transferred into a single


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polypropylene tube. Samples will be stored at approximately -20°C or below until transfer to 
the metabolism laboratory.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, 
planned sampling time and ‘MetID’. 
Plasma samples dedicated to metabolism investigation are transferred to:
Only data related to the parent compound and its metabolites will be acquired. Evaluation of 
drug metabolism will be reported separately and will not be included in the CTR. The study 
samples will be discarded after completion of the experiments but not later than 5 years after 
the CTR has been archived. 
Urine sampling for pharmacokinetic analysis
5.3.2.3
A blank urine sample will be collected before administration of trial medication (within 3h 
before drug dosing) and two 0.5 mL aliquots will be retained to check for analytical
interference by concomitant or rescue medication. 
All urine voided during the sampling intervals indicated in the Flow Chart will be collected in 
2 L polyethylene (PE) containers and stored at about 2° to 8° C. Subjects are told to empty 
their bladders at the end of each sampling interval. In order to facilitate urine sampling, 
subjects will be advised to drink at least 100 mL water before the end of each urine sampling 
interval.
The urine weight/volume for each collection interval will be documented (however, no 
correction for the specific gravity of urine is done; i.e., 1 L is defined to be equal to 1 kg).
Urine containers will be stored at about 2° to 8° C between sampling times. Two 0.5 mL 
aliquots will be stored in polypropylene (PP) tubes for bioanalytical measurements. If more 
than one collection container is used in an interval, the contents of all containers are to be 
mixed before aliquots are prepared. Mixing should be done by transferring the entire content 
of all collection containers into a single polyethylene) (PE)/PP or glass container, and stirring 
the mixed fractions for about 1 min (manually or using a stir bar or other stirring device made 
of PE, PP, Teflon, or glass).
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned collection time. Further information, such as matrix and analyte may also be 
provided. 
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at 
approximately -20°C or below at the trial site. The second aliquot will be transferred after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory, the 
urine samples will be stored at approximately -20°C or below until analysis.


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Urine samples will be transferred to
:
After completion of the trial, the urine samples may be used for further methodological 
investigations (e.g., for stability testing or assessment of metabolites). However, only data 
related to the analyte and/or its metabolite(s) will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations but not later than 5 years after the CTR has been archived.
Additional blood sample for stability-testing
5.3.2.4
In order to assess the stability of the analyte in whole blood, one additional blood sample will 
be obtained from all subjects of dose group 5 mg. Based on the knowledge gained during the 
trial conduct, e.g. from preliminary PK results, the chosen timing or dose group may be 
changed to a different one. The change will be implemented via a non-substantial CTP 
amendment.
Approximately 2.4 mL blood will be drawn from an antecubital or forearm vein into two 
1.2 mL K2-EDTA-blood drawing tubes at the time indicated in the Flow Chart (immediately 
after the drawing of a regular blood PK sample, which means that no additional venous 
puncture will be necessary).
From each K2-EDTA tube, one aliquot will be generated:

One aliquot (‘stability reference’) will be centrifuged within 10 min after collection. 
Centrifugation will last for approximately 10 min (at approximately 2000 x g to 
4000 x g and 4 to 8 °C), plasma will be separated and transferred into a freezer

The second aliquot (‘stability test’) will be stored for about 4 h at room temperature 
and ambient light conditions (storage time must be documented) and will then be 
centrifuged and stored as for the first aliquot. 
At a minimum, the aliquots should be labelled with BI trial number, administered drug, 
subject number, planned sampling time, and whether the sample is the ‘stability reference’ or 
‘stability test’ sample.
Until transfer to the analytical laboratory, both aliquots will be stored at approximately
-20 °C or below at the trial site. Both aliquots will be provided to the responsible bioanalyst 
together with the information about sample handling (i.e., storage time of stability test sample
at room temperature). After receipt, the aliquots will be stored at the bioanalytical laboratory 
at approximately -20°C or below until analysis.
The plasma samples for stability testing will be transferred to


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The results of the analysis of these samples will not be reported in the CTR but will be used 
for bioanalytical assay validation and therefore included in the corresponding method 
validation report. The remaining sample volume will be discarded at latest upon completion
of the method validation report.


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5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.3 are 
generally used assessments of drug exposure. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration (including blank values for PK and biomarkers).
The acceptable deviation from the scheduled time for vital signs, ECG, start of first RR 
measurement in orthostatic tests, laboratory tests will be ± 15 min for the first 4 h after trial 
drug administration, ± 30 min thereafter on Day 1, ± 60 min on Day 2 and ± 120 min from 48 
h post administration onwards.
Starting from 48 h post administration a deviation from the scheduled time for PK and 
biomarker sampling as well as for AE questioning of ± 120 min is acceptable.
If several activities are scheduled at the same time point in the Flow Charts, ECG should be 
the first and meal the last activity. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on physiological 
parameters (except orthostatic testing).
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 will be recorded and used for the determination of 
pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Screening period
6.2.1
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study. For information 
regarding laboratory tests (including drug and virus screening), ECG, vital signs, and 
physical examination, refer to Sections 5.2.3 to 5.2.5. Genotyping will be performed in those 
volunteers whose genotypes have not been previously determined (for details, see Section 
5.6.1). 


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Treatment period
6.2.2
SRD Part:
Within 3 days before Day 1 of Visit 2 (but no later than Day -1), subjects will visit the trial
site in the morning in an ambulatory fashion for assessment of safety laboratory parameters
and orthostatic testing.
In the morning of Day 1 of Visit 2 subjects will be admitted to the trial site and drug
screening and alcohol breath test will be performed. Each subject will receive one dose of
trial medication (BI 474121 or placebo) at Visit 2.
Trial medication will be taken orally by each subject under direct supervision of the
investigator or
designee. Details on treatments and procedures of administration are
described in Section 4.1.4. After administration of investigational drug, subjects will remain
under close medical surveillance for at least 48 h after investigational drug administration.
Subjects will then be allowed to leave the trial site on Day 3 after formal assessment and
confirmation of their fitness by the Investigator or a designee.
On all other study days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma and urine samples for PK
analysis, refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.3
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from
screening until the end of trial examination.
BA part:
In the BA part, each subject is expected to participate in 3 treatment periods. At least 1 week
will separate drug administrations in the first and second treatment periods.
In the morning of Day 1 of Visit 2, 3 and 4 subjects will be admitted to the trial site and drug 
screening and alcohol breath test will be performed.
Subjects will receive one 2.5 mg or one 10 mg dose of BI 474121 as tablet or oral solution in
each treatment period. Tablets will be administered with or without high-fat, high-calorie 
breakfast.
Trial medication will be taken orally by each subject under direct supervision of the
investigator or
 designee. Details on treatments and procedures of administration are
described in Section 4.1.4. After administration of investigational drug, subjects will remain
under close medical surveillance for at least 24 h. Subjects will then be allowed to leave the


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trial site on Day 2 after formal assessment and confirmation of their fitness by the
Investigator or a designee. On all other study days, subjects will be treated in an ambulatory 
fashion.
For details on time points and procedures for collection of plasma samples for PK analysis,
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.3
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from
screening until the end of trial examination.
Follow-up period and trial completion
6.2.3
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.2 to 5.2.6.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
SRD part:
The main objectives of this trial will be assessed by calculating descriptive statistics for 
safety as well as for PK parameters, which will be compared between the treatment groups. 
Further analyses of these endpoints comprise the power model for assessment of dose 
proportionality.
BA part:
The main objectives of this part of the trial are to investigate the relative bioavailability of 
BI 474121 given as tablet under fed condition (Test 1, T1) compared with BI 474121 given 
as tablet under fasted condition (Test 2, T2) as well as the relative bioavailability of
BI 474121 given as tablet under fasted condition (T2) compared with BI 474121 given as oral 
solution under fasted condition (Reference, R) on the basis of the primary and secondary 
pharmacokinetic endpoints, as listed in Section 2.1.2 and Section 2.1.3.
This part of the trial is designed to allow intra-subject comparisons and will be evaluated 
statistically by use of a linear model for logarithmically transformed PK endpoints.
7.2
NULL AND ALTERNATIVE HYPOTHESES
SRD part:
It is not planned to test any statistical hypotheses in this study.
Any confidence intervals computed are to be interpreted in the perspective of the exploratory 
character of the study; i.e., confidence intervals are considered as interval estimates for 
effects.
BA part:
The relative bioavailability of BI 474121 will be estimated by the ratios of the geometric 
means (T1/T2, T2/R), and their corresponding 2-sided 90% confidence intervals (CIs) will be 
provided. This method corresponds to the two one-sided t-test procedure, each at the 5% 
significance level. Since the main focus is on estimation and not testing, a formal hypothesis 
test and associated acceptance range is not specified.
7.3
PLANNED ANALYSES
Analysis sets
For both parts, statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomised and 
treated with at least one dose of study drug. The treatment assignment will be 


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determined based on the first treatment the subjects received. The treated set will be 
used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one primary or secondary PK endpoint that was 
not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK 
non-evaluability (as specified in the following subsection ‘Pharmacokinetics’). Thus, 
a subject will be included in the PKS, even if he contributes only one PK parameter 
value for one period to the statistical assessment. Descriptive and model based 
analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be specified in the Integrated Quality and Risk Management Plan, iPDs 
will be identified no later than in the Report Planning Meeting, and the iPD categories will be 
updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and Section 2.2.2.2 for drug BI 474121 
will be calculated according to the relevant SOP of the Sponsor (001-MCS-36-472). 
Plasma and urine (in the SRD part of the trial) concentration data and parameters of a subject
will be included in the statistical pharmacokinetic (PK) analyses if they are not flagged for 
exclusion due to a protocol deviation relevant to the evaluation of PK (to be decided no later 
than in the Report Planning Meeting) or due to PK non-evaluability (as revealed during data 
analysis, based on the criteria specified below). Exclusion of a subject’s data will be 
documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma and urine (in the SRD part of the trial) concentrations and/or parameters of a subject 
will be considered as non-evaluable, if for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

Missing samples/concentration data at important phases of PK disposition curve.
In addition, plasma concentrations and/or parameters of a subject will be considered as non-
evaluable in the BA part of the trial, if for example

The subject experiences emesis at any time during the labelled dosing interval.

A predose concentration is >5% Cmax value of that subject


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Plasma and urine (in the SRD part of the trial) concentration data and parameters of a subject 
which is flagged for exclusion will be reported with its individual values but will not be 
included in the statistical analyses. Descriptive and inferential statistics of PK parameters will 
be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format as in the bioanalytical report (that is 
to the same number of decimal places provided in the bioanalytical report).
Primary endpoint analyses
7.3.1
SRD part:
The primary endpoint as specified in Section 2.1.2 will be derived according to BI standards.
The analysis will be based on the treated set (TS) and will be descriptive in nature.
BA part:
Primary analysis:
The secondary endpoints (refer to Section 2.1.2) will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/ Pharmacodynamics’ (001-MCS-36-472).
The statistical model used for the analysis of the secondary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be 
logtransformed (natural logarithm) prior to fitting the ANOVA model. This model will 
include effects accounting for the following sources of variation: sequence, subjects within 
sequences, period and treatment. The effect 'subjects within sequences' will be considered as
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment 
k in period j,
=
the overall mean,
i =
the ith sequence effect, i = 1, … , 6
sim =
the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
j = 
the jth period effect, j = 1, 2, 3
k =
the kth treatment effect, k = 1, 2, 3


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eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random 
variables.
Point estimates for the ratios of the geometric means (T1/T2 and T2/R) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Secondary endpoint analyses
7.3.2
SRD part:
The secondary endpoints (refer to Section 2.1.3) will be analysed descriptively. Analyses will 
be performed for the parent drug and for potential metabolites.
BA part:
The secondary endpoints (refer to Section 2.1.3) 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) and will be assessed 
statistically using the same methods as described for the primary endpoints.


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Safety analyses
7.3.4
Safety will be assessed as defined by the endpoints listed in Section 2.1.2 and 2.2.2 based on 
the treated set (TS). Safety analyses will be descriptive in nature and will be based on BI 
standards. 
For all analyses the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. The placebo group in the safety evaluation 
will consist of all subjects treated with placebo, regardless of the dose group in which they 
were treated. The test treatment groups will be compared to the placebo group in a descriptive 


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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.
Measurements (such as ECGs, vital signs, or laboratory parameters) or AEs will be assigned 
to treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment-emergent AEs). 
Therefore, measurements planned or AEs recorded prior to intake of trial medication will be 
assigned to the screening period, those between the trial medication intake and end of REP
(see Section 1.2.6) or next intake of study medication (BA part) will be assigned to the 
treatment period. Events occurring after the REP but prior to trial termination date will be 
assigned to ’follow-up’. These assignments including the corresponding time intervals will be
defined in detail in the TSAP. Note that AEs occurring after the last per protocol contact but 
entered before database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
Additionally, further treatment intervals (called analysing treatments) may be defined in the 
TSAP in order to provide summary statistics for other than above periods, such as combined 
treatments, on-treatment totals, or periods without treatment effects (such as screening and 
post-study intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.6.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as possibly clinically significant values will be highlighted in the listings.
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline. 
SRD part, only:
The ECG variables QT, HR, QTcF, QTcB, PR, QRS, and RR obtained from the centralised 
evaluation of 12-lead ECG recordings will be the basis for the derivation of quantitative and 
categorical ECG endpoints. These endpoints and their analyses will be described in the 
TSAP.
7.4
INTERIM ANALYSES
SRD part:
A preliminary analysis of PK parameters (AUC0-24 and Cmax of BI 474121) provided as 
individual values and geometric means of the first cohort per dose level, will be performed 
for

Dose level 1 before proceeding to dose level 3 (n+2)


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
Dose levels 3, 4, 5 and 6 (n) before proceeding to the next dose level 4, 5, 6, and 7 
(n+1)
(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.)
The pharmacokinetic parameters AUC0-24 and Cmax for BI 474121 will be calculated 
according to the BI SOP 'Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics' (001-MCS-36-472). The non-compartmental analysis 
will be performed using a validated software program such as Phoenix WinNonlinTM 
software (version 6.3 or higher, 
) or SAS® Version 9.4 
(or later version). A quality check of the preliminary data will be performed.
Available information on dose linearity from preceding dose groups will be considered when 
estimating Cmax and AUC0-24 values to be expected for the next higher dose to be 
administered.
In contrast to the final PK calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows. Therefore, minor deviations may occur between preliminary and final results. 
The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without subject identification information. The 
preliminary results will be distributed to the investigator and the trial team. 
Depending on the results of available preliminary PK analyses and the tolerability and safety 
of the compound, changes to the dosing schedule (e.g., additional intermediate doses),) and 
additional PK/PD preliminary analysis may be performed if requested by the Trial Clinical 
Monitor, the investigator, or Trial Clinical Pharmacokineticist. Preliminary PK results will 
not be reported in the CTR.
No inferential statistical interim analysis is planned. However, after completion of each dose 
group the investigator (or his or her deputy) is allowed to postpone further dose progression 
until a preliminary analysis of the data has been performed.
BA part:
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
Safety
7.5.1
It is not planned to impute missing values for safety parameters.


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Pharmacokinetics
7.5.2
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
In the SRD part of the trial, subjects will be randomised within each dose group in a 3:1 ratio
(test treatment to placebo).
In the BA part of the trial, subjects will be randomised to one of 6 treatment sequences in a 
1:1:1:1:1:1 ratio. The block size will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
SRD part:
It is planned to include a total of 56 subjects in this part of the trial. The planned sample size 
is not based on a power calculation. The size of 8 subjects per dose group (6 on active 
treatment, and 2 on placebo) is commonly used in single-rising dose studies of the present 
type and is in general considered as sufficient for the exploratory evaluation of single dose 
safety and pharmacokinetics.
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 
in the SRD part may exceed 56, but will not exceed 72 subjects entered.
BA part:
It is planned to enter a total of 12 subjects in the trial, because this sample size is considered 
sufficient to achieve the aims of this exploratory trial. With this sample size, the following 
precision in estimating the ratio of geometric means (test/reference) can be expected with 
95% probability. Precision is defined as the ratio of upper CI limit to the relative BA 
estimate. Note that the precision is independent of the actual ratio of geometric means.
For this First-in-Man trial, no information on intra-subject variability is available. Therefore, 
Table 7.7: 1 provides an overview on the achievable precision for estimating the ratio of 
geometric means (test/reference) for three different gCV. For illustrative purposes, the 


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expected 90% confidence intervals with 95% coverage probability are displayed for different 
values of geometric mean ratios T/R in the three-period six-sequence crossover design.
Table 7.7: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a 3x3 crossover trial (N=12)
gCV[%]
Precision (upper CI 
limit/relative BA 
estimate)
Ratio1 [%]
90% CI [%]
15
1.141
80
( 70.13,  91.25)
100
( 87.67, 114.07)
125
(109.58, 142.58)
20
1.191
80
( 67.17,  95.28)
100
( 83.97, 119.10)
125
(104.96, 148.87)
25
1.243
80
( 64.38,  99.41)
100
( 80.47, 124.27)
125
(100.59, 155.33)
1Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The calculation was performed as described by Julious [R11-5230] using R Version 3.5.1.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. As a general rule, no trial results should be 
published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the  subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the responsible Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) and competent authority (CA) according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
For subjects enrolled during the COVID-19 crisis: In addition to the study specific informed 
consent, separate written consent will be obtained for testing on SARS-CoV-2 infection.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the
Phase I unit – the 
validated ClinBase
system is used for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as data base. Instead of being entered into CRFs, selected data are directly 
entered into the system.
Source documents
8.3.1
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make three documented attempts to 


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retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number,
and social security number) have properly been removed or redacted to ensure subject
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data are entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
Direct access to source data and documents
8.3.2
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 


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accuracy of the data will be verified by direct comparison with the source documents 
described in section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
Storage period of records
8.3.3
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
the local requirements valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
Collection, storage and future use of biological samples and corresponding 
8.5.1
data
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage


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
A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state.
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered
in the report.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the
, under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a Clinical Trial Monitor, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates, and investigators of participating trial sites
The trial medication will be provided by the 
 
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
).


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Analyses of BI 474121 concentrations in plasma and urine will be performed at
.
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
 for evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI. 
Data management and statistical evaluation will be done by BI or a contract research
organisation appointed by BI, according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2002:1-
9.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER) (2005)
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R16-0366
E14 Implementation Working Group
ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs: questions & 
answers (R3) (current version dated 10 December 2015).
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/E
fficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2016) ; 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (2015)
R18-1409
Gomez L, Breitenbucher JG. PDE2 inhibition: potential for the treatment of
cognitive disorders. Bioorg Med Chem Lett. 2013. 23: 6522–6527.
R13-4518
Hu NW, Ondrejcak T, Rowan MJ. Glutamate receptors in preclinical 
research on Alzheimer's disease: update on recent advances. Pharmacol 
Biochem Behav 100, 855 - 862 (2012)
R13-4521
Lin CH, Lane HY, Tsai GE. Glutamate signaling in the pathophysiology 
and therapy of schizophrenia. Pharmacol Biochem Behav 100, 665 - 677 
(2012)
R10-5092
Cooke SF, Bliss TVP. Plasticity in the human central nervous system. Brain 
129, 1659 - 1673 (2006)
R10-5102
Reymann KG, Frey JU. The late maintenance of hippocampal LTP: 
requirements, phases, 'synaptic tagging', 'late-associativity' and 
implications. Neuropharmacology 52, 24 - 40 (2007)
R09-1400
European Medicines Agency (EMEA). ICH topic M3 (R2) non-clinical 
safety studies for the conduct of human clinical trials and marketing 
authorization for pharmaceuticals: step 4: note for guidance on non-clinical 
safety studies for the conduct of human clinical trials and marketing 
authorization for pharmaceuticals (June 2009, CPMP/ICH/286/95).
http://www.emea.europa.eu (2009)


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R94-1529
Chow SC, Liu JP, Design and Analysis of Bioavailability and 
Bioequivalence Studies. New York: Marcel Dekker Inc (1992)
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group (2010)
R06-1037
Guidance for industry: estimating the maximum safe starting dose in initial 
clinical trials for therapeutics in adult healthy volunteers. U.S. Department 
of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER) (2005)
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
n00269861
. In vitro inhibition of human, rat and monkey 
recombinant phosphodiesterase (PDE) 2A and human recombinant PDE1a, 
1b and 1c by BI 47412. 05 June 2019
c26859057
. Investigator's Brochure BI 474121 Alzheimer's 
Disease and Schizophrenia. 04 October 2019
n00265648
 
. 18B128. BI 474121: 4-week 
oral (gavage) toxicity study in rats
n00271367
. GM20LK. BI 474121. Toxicity Study by Oral Gavage 
Administration to Cynomolgus Monkeys for 4 Weeks Followed by a 4 
Week Recovery Period
n00268539
 Prediction of 
BI 474121 Pharmacokinetics and Therapeutic Dose in Human. 02 August 
2019


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10.
APPENDICES
10.1
RECONSTITUTION INSTRUCTIONS
Drug supplies overview
10.1.1
a) BI 474121 Powder for Oral Solution 40 mg (target solution concentration BI 474121: 
0.5 mg/mL), provided in 100 mL amber glass bottles with plastic screw cap
b) Solvent for Oral Solution 80 mL (HP-ß-Cyclodextrin 100 mg/ml) provided in 100 mL
amber glass bottle with plastic screw cap
Required equipment and dosing aids – overview
10.1.2
a) Mechanical (orbital) shaker for bottles (e.g.
 Typ KL2)
b) Dosing dispensers/syringes and bottle adapters
For the withdrawal of respective volume aliquots from the final Oral Solution to be 
administered, amber
ExactaMed Syringes should be used in a size 
as close as possible to the required dose volume. For this purpose, a range of syringe 
sizes from 1 mL up to 60 mL should be stocked in the trial site.
In order to ease the withdrawal of the oral solution from the glass bottles with the 
amber 
ExactaMed syringes,
bottle adapters and 
dispenser tip caps should be used and stocked in the trial site, preferably 
Adapta Cap Bottle Adapters (E-28 mm) or 
Press-
In Bottle Adapters (PIBATM) 
Possible 
 Med Oral amber dispensers 

ExactaMed amber oral dispenser 1 mL 

ExactaMed amber oral dispenser 3 mL 

ExactaMed amber oral dispenser 5 mL 

ExactaMed amber oral dispenser 10 mL 

ExactaMed amber oral dispenser 20 mL 

ExactaMed amber oral dispenser 60 mL 
Only CE certified syringes are to be used!


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Reconstitution procedure
10.1.3
2 bottle concept, see also Section 10.1.4.
Reconstitution procedure for the preparation of the active BI 474121 oral solution
10.1.3.1
0.5 MG/ML
Necessary materials
a) BI 474121 Powder for Oral Solution 40 mg (target solution concentration 
BI 474121: 0.5 mg/mL), provided in 100 mL amber glass bottles with plastic screw 
cap.
b) Solvent for Oral Solution 80 mL (HP-ß-Cyclodextrin 100mg/ml) provided in 100 mL
amber glass bottles with plastic screw cap.
Reconstitution procedure
Step 1: 
Open the bottle containing the Solvent for Oral Solution 80 mL (HP-ß-
Cyclodextrin 100 mg/ml)
Step 2: 
Transfer the content of the Solvent for Oral Solution 80 mL (HP-ß-
Cyclodextrin 100mg/ml) completely and carefully into the bottle containing 
the BI 474121 Powder for Oral Solution 40 mg
Step 3:
Close the bottle with the plastic screw cap and shake the bottle manually until 
the BI 474121 powder is wetted. Mount the bottle in a horizontal recumbent 
position on a mechanical shaker (e.g.
 Typ KL2) 
Step 4:
Let the bottle shake orbitally for 240 min. at 350 rpm in its horizontal 
recumbent position.
Step 5:
Visually control that the powder is completely dissolved (clear to almost clear 
solution). After complete dissolution the solution is ready for use.
The final BI 474121 Oral Solution concentration is 0.5 mg/mL.
The allowable dose range is from 0.1 mg - 35 mg
Solvent for  oral solution for use as placebo solution
10.1.3.2
Necessary materials
a) Solvent for Oral Solution 80 mL (HP-ß-Cyclodextrin 100mg/ml) provided in 100 
mL amber glass bottles with plastic screw cap.
The Placebo Solution is the Solvent for Oral solution 80 ml (HP-ß-Cyclodextrin 
100mg/ml).


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ILLUSTRATION OF RECONSTITUTION PROCEDURE
10.1.4
The following scheme on the principle followed for the present PfOS formulation, 2-bottle 
concept, should serve as an additional illustration to clarify, how the reconstitution procedure 
for the preparation of the active oral solution has to be performed. 
Active oral solution reconstitution procedure
2-bottle concept: SfOS + PfOS (API)
Component
g/bottle
Function
HP-ß-CD
8.0000
Solubilizer
Water
74.4640
Solvent
82.4640
Component
g/bottle
Function
BI 474121
0.040
Active 
ingredient
Transfer  the complete SfOS
SfOS
Solvent for Oral Solution
Final solution for
administration
0.5 mg/mL
PfOS
API powder in bottle
Powder for Oral Solution


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The following picture shows the bottle, the dispenser and the adapter needed to prepare the 
PfOS formulation to clarify the procedure in additional.
In-use stability
10.1.5
The in-use stability of the reconstituted solution is 24 h after its preparation, incl. storage in 
dispensers until administration. Further details are given on the CTS labels.
Mode of application
10.1.6
Withdraw the required volume aliquot to obtain the required doses. In case the complete 
content of a bottle is used, content is administered directly out of the bottle.
Use amber
 ExactaMed syringes for dose withdrawal/administration, and 
subsequently if necessary amber glass bottles for administration of aliquots.
Use
ExactaMed syringes at a volume size as close as possible to the 
volume to be withdrawn.
Please note that it is the responsibility of the CTL to assure that appropriate supplies are used 
for administration of a dose, based on guidance in the clinical trial protocol, and dosing is 


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limited to the allowed dosing range for a specific dose formulation as stated in this 
Reconstitution Instruction.
General remarks - important!
10.1.7
Because of lacking analytical coverage beyond the instructed preparation procedure of the 
different dose formulations no further (external) dilutions of the reconstituted solutions are 
allowed!
The present reconstitution instruction does not contain any advice how to withdraw a specific 
dose from the reconstituted solutions. The specific dose volumes to be withdrawn from the 
described dose formulations in order to obtain a required dose will be calculated and 
documented by Clinical Operations in the Clinical Trial Protocol (CTP) and subsequent 
documents (e.g. work sheets)!


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APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c28123079
6.0
clinical-trial-protocol-version-06
A randomised, single-blind, placebo-controlled trial to investigate safety, tolerability,
and pharmacokinetics of single rising oral doses of BI 474121 administered as oral
solution and tablets to healthy male subjects (SRD part), and a randomised,
open-label, single-dose, three-way cross-over bioavailability comparison of BI
474121 as tablet versus oral solution and tablet with and without foo...
Author-Trial Statistician
08 Oct 2020 13:55 CEST
Author-Clinical Trial Leader
08 Oct 2020 14:43 CEST
Approval-Team Member Medicine
08 Oct 2020 15:35 CEST
Author-Trial Clinical
Pharmacokineticist
09 Oct 2020 01:30 CEST
Approval-
 Medicine
11 Oct 2020 21:06 CEST
Verification-Paper Signature
Completion
14 Oct 2020 09:11 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c28123079
6.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c34992306-01
BI Trial No.:
1411-0001
Title:
A randomised, single-blind, placebo-controlled trial to investigate
safety, tolerability, and pharmacokinetics of single rising oral  doses 
of BI 474121 administered as oral solution and tablets to healthy 
male subjects (SRD part), and a randomised, open-label, single-
dose, three-way cross-over bioavailability comparison of BI 474121 
as tablet versus oral solution and tablet with and without food (BA 
part).
(including Protocol Amendments No.1-5 [c28123079-06]).
Investigational
Product:
BI 474121
Responsible trial 
statistician:
Phone:
Fax:
Date of statistical 
analysis plan:
26 APR 2021 SIGNED 
Version:
1
Page 1 of 41
Proprietary confidential information
2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................8
5.
ENDPOINTS..........................................................................................................9
5.1
PRIMARY ENDPOINTS .....................................................................................9
5.2
SECONDARY ENDPOINTS ...............................................................................9
5.2.1
Key secondary endpoints ......................................................................................9
5.2.2
Secondary endpoints .............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................................13
6.1
TREATMENTS...................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................16
6.3
SUBJECT SETS ANALYSED ...........................................................................17
6.5
POOLING OF CENTRES..................................................................................19
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................19
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................20
7.
PLANNED ANALYSIS ......................................................................................22
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........24
7.2
CONCOMITANT DISEASES AND MEDICATION......................................24
7.3
TREATMENT COMPLIANCE ........................................................................24
7.4
PRIMARY ENDPOINTS ...................................................................................24
7.4.1
Primary analysis of the primary endpoints ......................................................24
7.5
SECONDARY ENDPOINTS .............................................................................26
7.5.1
Key secondary endpoints ....................................................................................26
7.5.2
Other Secondary endpoints................................................................................26
7.7
EXTENT OF EXPOSURE .................................................................................27
7.8
SAFETY ANALYSIS..........................................................................................27
7.8.1
Adverse Events ....................................................................................................27
7.8.2
Laboratory data...................................................................................................29
7.8.3
Vital signs.............................................................................................................29
7.8.4
ECG ......................................................................................................................30
7.8.5
Others ...................................................................................................................32
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............33
9. 
REFERENCES ....................................................................................................34


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11.
HISTORY TABLE..............................................................................................41


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis – SRD part....................................13
Table 6.1: 2
Treatments and labels used in the analysis – BA part ......................................14
Table 6.3: 1
Subject sets analysed ........................................................................................19
Table 6.7: 1
Time schedule of 12-lead ECG recordings (SRD part)....................................21
Table 11: 1
History table .....................................................................................................41


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
website: glossary
Term
Definition / description
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 to the last quantifiable data point
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 to 24 h
BMI
Body mass index
CARE
Clinical Analysis and Reporting Environment
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
CV
Arithmetic Coefficient of Variation
DBLM
Database Lock Meeting
DILI
Drug induced liver injury
ECGPCS
ECG Pharmacokinetic Concentration Set
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
LLT
Lower Level Term
Max
Maximum
MedDRA
Medical Dictionary For Regulatory Activities
Min
Minimum
N
Number non-missing observations
Nobs
Number of observations
os
Oral solution
P10
10th percentile
P90
90th percentile
PKS
PK parameter analysis set
PT
Preferred Term


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Term
Definition / description
Q1
1st quartile
Q3
3rd quartile
QD
Quaque die, once daily
R
Reference
RAGe
Report Appendix Generator system
REP
Residual Effect Period
SD
Standard Deviation
SOC
System Organ Class
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
T
Test
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary


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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 (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or higher,
.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this
TSAP. The following change compared to the protocol will be made:
In CTP section 7.3 the following was defined: Important protocol deviation (iPD) categories
will be specified in the Integrated Quality and Risk Management (IQRM) Plan, iPDs will be
identified no later than in the Report Planning Meeting, and the iPD categories will be
updated as needed. Due to SOP changes, the IPD categories are no longer available in IQRM
plan but included in an Excel spreadsheet (3). The IPD categories originally defined in IQRM
plan were transferred to the IPD specification file. Minor changes regarding the IPD
categories were performed only.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP: 
The primary endpoint for assessment of safety and tolerability of BI 474121 is the percentage 
of subjects with drug-related adverse events (SRD part).
The following pharmacokinetic parameters will be determined if feasible (BA part):

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 2.1.3 of the CTP: 
The following pharmacokinetic parameters will be determined if feasible:
SRD part:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
BA part:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatment, please see 
CTP, Sections 3 and 4.
The SRD part is designed as single-blind within dose groups, randomised, and placebo-
controlled within parallel dose groups. It is planned to include 56 healthy male subjects in this 
part of the trial. The subjects will be assigned to 7 groups consisting of 8 subjects per group (6 
subjects will receive BI 474121 and 2 will receive placebo).
The BA part will be performed as randomised, open-label, three-way, six-sequence, crossover
trial in healthy male subjects. It is planned to include 12 healthy male subjects. The subjects 
will be randomly allocated to the 6 treatment sequences. There will be a wash out period of at 
least 7 days between the treatments.
For details see Table 6.1:1 and Table 6.1:2 below.
Table 6.1: 1
Treatments and labels used in the analysis – SRD part
Treatment
Label in dataset
Short label
P*
Placebo, solution, po, qd
Plc os
Q*
Placebo, tablet, qd
Plc tab
A
BI 474121, 0.5 mg/mL solution, 0.25 mg, po, qd
BI 0.25mg os
B
BI 474121, 0.5 mg/mL solution, 1.0 mg, po, qd
BI 1mg os
C
BI 474121, tablet, 2.5 mg, po, qd
BI 2.5mg tab
D
BI 474121, tablet, 2*2.5 mg, po, qd
BI 5mg tab
E
BI 474121, tablet, 10 mg, po, qd
BI 10mg tab
F
BI 474121, tablet, 2*10 mg, po, qd
BI 20mg tab
G
BI 474121, tablet, 4*10 mg, po, qd
BI 40mg tab
*:
Each placebo group in the safety evaluation will consist of all placebo treated patients in SRD part, regardless of the 
dose group in which they were treated.


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Table 6.1: 2
Treatments and labels used in the analysis – BA part
Treatment
sequence
Short label in dataset
Short label
UVW
BI 474121 10 mg solution / tablet fasted / tablet fed
R/T2/T1
UWV
BI 474121 10 mg solution / tablet fed / tablet fasted
R/T1/T2
VUW
BI 474121 10 mg tablet fasted / solution / tablet fed
T2/R/T1
VWU
BI 474121 10 mg tablet fasted / tablet fed / solution
T2/T1/R
WUV
BI 474121 10 mg tablet fed / solution / tablet fasted
T1/R/T2
WVU
BI 474121 10 mg tablet fed / tablet fasted / solution
T1/T2/R
U=R (Reference treatment)
V=T2 (Test treatment 2)
W=T1 (Test treatment 1)
The short label will be used whenever tables/listings are displayed by treatment sequence. If actual 
treatment is shown the following labels will be used: BI 10mg tab fed, BI 10mg tab fasted, BI 10mg 
solution (e.g. AE tables).
Section 1.2.6 of CTP:
The Residual Effect Period (REP) of BI 474121, when measurable drug levels and/or
pharmacodynamic effects are still likely to be present, is not known for this first-in-human
trial. Conservatively, a minimum observation period of at least 5-fold estimated t1/2 has been
selected, and thus a REP of 7 days is assumed, i.e. the individual subjects end of trial is on
Day 8-15 following dosing with investigational drug at the earliest.
SRD part:
The following study phases will be defined for the analysis of adverse events (AEs):

Screening (ranging from 0:00 h on day of informed consent until first administration 
of study medication)

On treatment (BI/Placebo treatment ranging from the first time of administration of 
study medication until 168 hours (7 days) after the last time of administration of study 
medication)

Follow-up (F/U) (ranging from 168 hours (7 days) after last administration of study 
medication until 0:00 h on day after trial termination date)
BA part:
The following study phases will be defined for the analysis of adverse events (AEs):

Screening (ranging from 0:00 h on day of informed consent until first administration 
of study medication)

On treatment (BI 10mg tab fed / BI 10mg tab fasted / BI 10mg solution) (ranging 
from the first time of administration of study medication until 168 hours (7 days) after 


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the last time of administration of study medication or until time of next drug 
administration (whatever occurs first))

Follow-up (F/U BI 10mg tab fed / F/U BI 10mg tab fasted / F/U BI 10mg solution)
(ranging from 168 hours (7 days) after last administration of study medication until 
0:00 h on day after trial termination date)
Section 7.3.4 of the CTP: Note that AEs occurring after the last per protocol contact but 
entered before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
Displays of AEs will be stratified by dose group as specified in table 6.1:1 and table 6.1:2. 
The following AE displays will be provided in the report:
Section 15.3 of the CTR displays:
In these displays, the on-treatment phase will be analysed (labelled with the name of the study 
treatment (short label in SRD part)). Screening and Follow up phases will not be included in 
this analysis.
The following totals will be provided in addition:

a total over all Placebo treated on-treatment phases (“Plc Total”) – SRD part only

a total over all BI treated on-treatment phases (“BI Total - tab”) – SRD part only

a total over all BI treated on-treatment phases (“BI Total - os”) – SRD part only

a total over all BI treated on-treatment phases (“BI Total”) – SRD part only

a total over all on treatment phases included in this analysis (“Total”)
In Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT only) of the CTR, SRD part and 
BA part will be combined:
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening and Follow up phases will not be included in this analysis.
The following totals will be provided in addition:

a total over all Placebo treated on treatment phases in SRD part (“Plc Total – SRD 
part”)

a total over all BI treated on treatment phases in SRD part (“BI Total – SRD part”)

a total over all on treatment phases in SRD part included in this analysis (“Total –
SRD part”)

a total over all on treatment phases in BA part included in this analysis (“Total – BA 
part”)

a total over all BI treated on treatment phases (“BI Total”)

a total over all on treatment phases included in this analysis (“Total”)


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In Section 15.4 and Appendix 16.2 (Listings) of the CTR displays, screening and follow-up 
periods will be included and no totals will be provided.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewers guide. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (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).
Categories which are considered to be iPDs in this trial were defined in the integrated quality 
and risk management plan (IQRMP) prior to trial initiation. The iPD list was transferred into 
the iPD specification file (due to changes in the SOP) (3). Within this transfer some minor 
adaptations were done to comply with new naming conventions and categorisations. IPDs will 
be identified no later than in the Report Planning Meeting and the iPD categories in the iPD 
specification file will be updated as needed. If any iPDs are identified, they are to be 
summarised into categories and will be captured in the RPM/DBLM minutes (the decision 
log) and in the iPD specification file. The decision on exclusion of subjects from analysis sets 
will be made after discussion of exceptional cases and implications for analyses.
The iPD specification file (e.g. the DV domain specifications) will be stored within the TMF 
in EDMS.
The iPDs will be summarised and listed.


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6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP:
For both parts, statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomised and 
treated with at least one dose of study drug. The treatment assignment will be
determined based on the first treatment the subjects received. The treated set will be 
used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one primary or secondary PK endpoint that was 
not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK 
non-evaluability (as specified in the following subsection ‘Pharmacokinetics’).
Thus, a subject will be included in the PKS, even if he contributes only one PK 
parameter value for one period to the statistical assessment. Descriptive and model 
based analyses of PK parameters will be based on the PKS.
All ECG analyses are performed on the TS, except for the exposure-response analyses, which 
are performed on the ECGPCS defined below.

ECG Pharmacokinetic Concentration Set (ECGPCS): This subject set includes all 
subjects from the TS of the SRD part who provide at least one pair of a valid drug 
plasma concentration and a corresponding (i.e. time-matched) ECG endpoint to be 
used in the exposure-response analyses. For placebo subjects, the plasma 
concentration is set to zero and hence always considered as valid. The decision 
whether a time deviation between PK blood sampling and ECG recording is 
acceptable (and thus whether the pair of values will be used) is to be made no later 
than at the RPM before data base lock. For subjects treated with active drug, the 
decision about concentration value validity needs to be made within the Clinical 
Pharmacology Group.
Pharmacokinetics
The pharmacokinetic parameters for drug BI 474121 listed in TSAP Section 5 will be 
calculated according to BI standard (see BI-KMED-TMCP-MAN-0014 (6)).
Plasma and urine (in the SRD part of the trial) concentration data and parameters of a 
subject will be included in the statistical pharmacokinetic (PK) analyses if they are not 
flagged for exclusion due to a protocol deviation relevant to the evaluation of PK (to be 
decided no later than in the Report Planning Meeting) or due to PK non-evaluability (as 
revealed during data analysis, based on the criteria specified below). Exclusion of a subject’s 
data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken


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
Use of restricted medications
Plasma and urine (in the SRD part of the trial) concentrations and/or parameters of a subject 
will be considered as non-evaluable, if for example

The subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

Missing samples/concentration data at important phases of PK disposition curve.
In addition, plasma concentrations and/or parameters of a subject will be considered as non-
evaluable in the BA part of the trial, if for example

The subject experiences emesis at any time during the labelled dosing interval.

A predose concentration is >5% Cmax value of that subject
Plasma and urine (in the SRD part of the trial) concentration data and parameters of a 
subject which is flagged for exclusion will be reported with its individual values but will not 
be included in the statistical analyses. Descriptive and inferential statistics of PK parameters 
will be based on the PKS.


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Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
Treated set
PKS
ECGPCS
Primary endpoint and further safety 
assessments (incl. ECG)
X
Analyses of PK endpoints 
X
Analyses of PD/biomarker endpoints
X
ECG exposure response analysis
X
Demographic/baseline parameters
X
Important protocol deviations
X
Disposition
X
Exposure
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see BI-KMED-BDS-
HTG-0035) (4).
Missing data and outliers of PK data are handled according to BI standards (see BI-KMED-
TMCP-MAN-0012 (5) and BI-KMED-TMCP-MAN-0014 (6)).
If single cardiac cycles of an ECG (out of the generally four) are missing, the arithmetic mean 
for this single ECG will be computed with the reduced (1, 2 or 3) number of cardiac cycles.
If replicate ECG recordings are missing, the arithmetic means per time point will be computed 
with the reduced number (1 or 2) of recordings.


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For the classification of the on-treatment QTc/QT intervals into ‘no new onset’ / ‘new onset’ 
categories, the handling of missing value is described in Appendix Section 10.1.3.
For subjects on active drug (e.g. post dose time points), missing plasma concentration values 
with ‘BLQ’ in the comment field will be replaced by ½ LLOQ for the exposure-response 
analysis.
For placebo subjects, the missing plasma concentration values will be replaced by 0 for the 
exposure-response analyses. 
For PK analysis, missing data and outliers of PK data are handled according to BI standards 
(6) and (9).”
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
SRD part: The baseline value is defined as the last measurement before first administration of 
trial medication (BI 474121 or Placebo).
BA part: The baseline value is defined as the last measurement before administration of trial 
medication in each treatment period (e.g. ptm -2:00).
For laboratory analysis, the last value on treatment will be defined as the last value during 
corresponding treatment period (usually 96:00h in first and second treatment period). 
Adherence to time windows will be checked via the consistency check listings at the RPM.
Unscheduled measurements of laboratory data and vital signs data will be assumed to be 
repeat measurements of the most recent scheduled measurement (e.g. for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement. 
There will be a centralised evaluation of the 12-lead ECG recordings of the SRD part at the 
time points and for the ECG recordings specified in Table 6.7: 1 below:


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Table 6.7: 1
Time schedule of 12-lead ECG recordings (SRD part)
Visit
Day
Planned time [hh:mm]
(relative to drug 
administration)
Study phase
Central evaluation
1
-21 - -1
Screening
NA
2
1
-01:00
Baseline
first ECG of each of the 
3 triplicate baselines
-00:45
-00:30
00:30
On-treatment
first single ECG of the 
triplicate
01:00
01:30
02:00
03:00
04:00
06:00
08:00
12:00
2
24:00
34:00
3
48:00
4
72:00
Single ECG
5
96:00
Single ECG
5
8-15
End-of-study 
examination
NA
At Screening and End-of-study examination ECG recordings are performed as single ECGs 
and will not be transferred to central ECG lab. Three triplicate ECGs will be recorded as the 
baseline before the first drug administration, but only the first ECG of each of the 3 baseline 
triplicates will be transferred to the database. At all other time points, 1 triplicate ECG will be 
recorded, but only the first single ECG of the triplicate will be transferred to the database. The 
baseline value of an ECG variable is defined as the mean of the ECG variable values prior to 
drug administration.
For the exposure-response analyses, acceptable maximum time deviations between ECG 
recordings and plasma concentration sampling are necessary (see the definition of the 
ECGPCS in Section 6.3). These are defined as 10 min until 1 hour after dosing, 20 min from 
including 1.5 hours up to 12 hours after dosing and as 1 h for time points including 12 hours 
after dosing and later. Pairs with time deviations exceeding those specified above will be 
excluded from exposure-response analyses. When the sampling time of the blood sample or 
the ECG recording is not available, the pair will also be excluded.


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by
and
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Tables and listings will be provided separately for the SRD part and BA part.
Statistical model-based analysis of PK endpoints will 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 endpoints and concentrations will be performed by the 
at 
and will be 
presented in Section 15.6 of the CTR and in Appendix 16.1.13.5.
Descriptive data analysis of PD/biomarker parameters will be performed by 
and will be presented in Section 15.7 of the CTR and Appendix 16.1.13.6.
The format of the listings and tables will follow the BI standards (see BI-KMED-BDS-HTG-
0045 (7)) with the exception of those generated for PK-calculations following BI standards 
for PK/PD analysis (8).
The individual values of all subjects will be listed, sorted by dose group/placebo (SRD part) 
or treatment sequence (BA part), 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 and non-PD parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations and PK parameters, the following descriptive statistics will 
additionally be calculated:
Nobs
number of observations
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile


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The data format for descriptive statistics of concentrations will be identical to the data format 
of the respective concentrations. The descriptive statistics of PK and PD 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 available in 
CRF and will display the number of observations in a category, as well as the percentage (%). 
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.
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 and ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in BI-KMED-TMCP-MAN-0014 “Noncompartmental 
Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies” (6) and BI-KMED-
TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD Data Files” (9).


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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 / treatment sequence and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the 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. Patients without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre under supervision of the investigating physician or a designee. The 
measured plasma concentrations and/or urinary excretion of trial medication will provide 
additional confirmation of compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will
be addressed in the RPM/DBLM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
7.4.1
Primary analysis of the primary endpoints
SRD part: Please refer to Section 7.8.1 for the description of the analysis of the primary 
endpoint.
BA part:
Section 7.3.1 of the CTP: 
Primary analysis:
The primary endpoints (refer to Section 5.1) will be calculated according to the BI Standard 
(see BI-KMED-TMCP-MAN-0014 (6)).
The statistical model used for the analysis of the primary endpoints will be an analysis of
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: sequence, subjects within sequences, 
period and treatment. The effect 'subjects within sequences' will be considered as random, 


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whereas the other effects will be considered as fixed. The model is described by the following 
equation:
yijkm 
= µ + ζi + sim + πj + τk + eijkm,
where
yijkm
= logarithm of response measured on subject m in sequence i receiving treatment k in 
period j,
µ
= the overall mean,
ζi
= the ith sequence effect, i = 1, … , 6
sim
= the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., ni
πj
= the jth period effect, j = 1, 2, 3
τk
= the kth treatment effect, k = 1, 2, 3
eijkm
= the random error associated with the mth subject in sequence i who received 
treatment k in period j.
where sim ~ N(0, 
) i.i.d., eijkm ~ N(0, 
 ) i.i.d. and sim, eijkm are independent random
variables.
Point estimates for the ratios of the geometric means (T1/T2 and T2/R) for the primary
endpoints (see TSAP Section 5.1) and their two-sided 90% confidence intervals (CIs) will be
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) (e.g. log(T1)-
log(T2) or log(T2)-log(R)) will be estimated by the difference in the corresponding adjusted 
means (Least Squares Means). Additionally their two-sided 90% confidence intervals will be 
calculated based on the residual error from the ANOVA and quantiles from the t-distribution. 
These quantities will then be back-transformed to the original scale to provide the point 
estimate and 90% CIs for each endpoint.


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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
Other Secondary endpoints
Section 7.3.2 of the CTP: 
SRD part:
The secondary endpoints (refer to Section 5.2.2) will be analysed descriptively. […]
BA part:
The secondary endpoints (refer to Section 5.2.2) will be calculated according to the BI
Standard (see BI-KMED-TMCP-MAN-0014 (6)) and will be assessed statistically using the 
same methods as described for the primary endpoints.


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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 each drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS, separately for SRD and BA part.
If not stated otherwise, the safety results will be sorted by treatment group (SRD part) or by
actual treatment (BA part).
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
The analyses of AEs will be descriptive in nature and will be based on BI standards as
presented in “Analysis and Presentation of Adverse Event Data from Clinical Trials – Display 
Template” [BI-KMED-BDS-HTG-0041] (10) and [BI-KMED-BDS-HTG-0066] (11). All 
analyses of AEs will be based on the number of subjects with AEs and NOT on the number of 
AEs.
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs occurring between first drug intake till 7 days after last drug intake will be assigned to 


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the randomised treatment. All AEs occurring before first drug intake will be assigned to 
‘screening’ and all AEs occurring after last drug intake + 7 days will be assigned to ‘follow-
up’ (for listings only). For details on the treatment definition, see Section 6.1.
According to ICH E3 (12), in addition to Deaths and serious adverse events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced 
or interrupted). An overall summary of adverse events will be presented. 
The frequency of subjects with AEs will be summarised by treatment, primary system organ
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with
serious AEs, for subjects with drug-related AEs, for subjects with drug-related serious adverse 
events, and for subjects with AESIs. In addition, the frequency of subjects with AEs will be 
summarised by treatment, worst intensity, primary system organ class (SOC) and preferred 
term (PT).
The SOCs and PTs will be sorted by frequency (within SOC). The MedDRA version number
(most recent version) will be displayed as a footnote in the respective output.
According to the clinical study protocol, adverse events of special interest (AESI) will be
analysed:
Section 5.2.6.1.4 of the CTP: The following are considered as AESIs:

Hepatic injury 
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-
fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT, additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
[BI-KMED-BDS-HTG-0042] (13). 
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 possibly 
clinically significant will be flagged in the data listings.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significantly 
abnormal or not (at the RPM at the latest). 
Descriptive statistics of laboratory data including change from baseline will be calculated by 
planned time point based on the worst value of the subject at that planned time point (or 
assigned to that planned time point).
7.8.3
Vital signs
For vital signs (blood pressure and pulse rate), descriptive statistics including change from 
baseline will be calculated by dose group and by planned time point based on the last value of 
the subject at that planned time point (or assigned to that planned time point). In the listing the 
difference from baseline will also be displayed.
Descriptive statistics over time will also be provided for the orthostatic test results (SRD part 
only) to enable checking of orthostatic hypotension occurrence. Subjects should have spent at 
least 5 min in the supine position before blood pressure and pulse rate will be measured the 
first time. Further 2 measurements will be performed immediately after standing up and after 
3 min in a standing position. An orthostatic hypotension is defined as a decline in systolic 
blood pressure of ≥ 20 mmHg or a decline in diastolic blood pressure of ≥ 10 mmHg within 
the first three minutes after standing up.
Clinically relevant findings in vital signs will be reported as AEs.


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7.8.4
ECG
Continuous safety ECG monitoring (by investigator)
Clinically relevant abnormal findings will be reported as adverse events.
No separate listing or analysis of continuous ECG monitoring will be prepared.
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 (SRD part only) will be based on the TS, except the exposure-
response analyses, which are based on the ECGPCS set.
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR, only listings will be provided. Occurrences of notable findings will be flagged.
Comments regarding the ECGs will be listed.
Categorical endpoints
For the categorical endpoints, frequency tables will be provided.
Categorical endpoints will also include morphological findings that might be attributable to 
treatment. In particular, new onsets of findings not present at baseline will be explored. A 
morphological finding observed on treatment that was not reported at baseline will be 
categorized as a ‘new onset’ of this finding.
For all subjects with any notable finding in ECG intervals, a separate listing will be created as 
end-of-text display (based on the same display template as in Appendix 16.2), and the 
corresponding time profiles will be shown.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the absolute 
values and changes from baseline over time of QTcF, HR, QT, PR and QRS. The time 
profiles of mean and SD for the changes from baseline on treatment will be displayed 
graphically by treatment.
For QTcF and HR changes from baseline, the relationship to the corresponding plasma 
concentrations will be evaluated using a random coefficient model. For subjects in the 
ECGPCS, all time points with available ECG endpoints and valid time-matched drug plasma 
concentrations will be included. For the handling of missing values, see Section 6.6.


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The response variable will be the change from baseline in QTcF (QTcF). The placebo 
subjects will be included in the analysis, setting their plasma concentrations to zero.
As a first step, it is investigated if there is a potential delayed or accelerated (e.g. due to 
metabolites) effect of the drug on QTcF. A general visual impression will be provided by 
overlaying time profiles of plasma concentrations and QTcF changes from baseline (QTcF). 
These figures will be generated for each subject (presented in the Statistical Appendix of the 
CTR), as well as for means per treatment group (presented in the End-of-Text part of the 
CTR).
The relationship between BI 474121 plasma concentrations and QTcF changes from baseline 
will be investigated in an exploratory manner using a random coefficient model to estimate 
the difference in means between BI 474121 and placebo of QTcF change from baseline and 
its 90% confidence interval at the geometric mean of Cmax for each dose. Additionally, the 
estimated overall slope with its 90% confidence interval will be provided. The used random 
coefficient model is based on a white paper from Garnett et. al. (14) with QTcF as response 
variable, centered baseline QTc and plasma concentration as continuous covariates and
treatment as fixed categorical effects, and a random intercept and slope for each subject. 
Restricted maximum likelihood estimation will be performed, and the Kenward-Roger 
method will be applied to adjust standard errors and estimate denominator degrees of 
freedom. For more details refer to Section 10.1.4.
For visualization, a scatterplot of the BI 474121 plasma concentration against the following 
individual QTcF values will be provided: For each subject on active treatment and each time 
point, subtract the mean value of all individual observed ΔQTcF values from the placebo 
group for this time point from the individual observed ΔQTcF value for this subject and time 
point. This results in estimates for “individual ΔΔQTcF” values, which should only be used 
for plotting purposes. The corresponding regression line and its pointwise confidence bands 
as well as and the geometric means of Cmax for each dose will additionally be displayed in the 
plot. 
The goodness of fit of the above model will be checked. The visual checks will include the 
inspection of concentration-QTcF quantile plots (14) and residual plots. In case of non-
linearity or if there is evidence for a delayed effect, further models will be explored in order to 
better characterise the PK-ECG relationship.
All of the above described graphical and statistical analyses will be also performed for HR in 
place of QTcF.
Appropriateness of heart rate correction methods of QT interval
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of QTcF interval versus RR interval will be estimated separately for off-drug 
values and active treatment, by applying the random coefficient model described in Section 
10.1.2 using the QTcF and RR variable values per time point. A scatterplot of QTcF vs RR
including the overall regression lines will be included in the Statistical Appendix of the CTR.


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7.8.5
Others
Physical examination
Physical examination findings, including visual inspection of the skin of palms and soles and
oral cavity 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.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information of the SRD part (single-blind) was released for both interim 
analysis according to the details specified in the logistics plan after completion of the 
respective dose groups.
The treatment information of the BA part (open-label) was loaded into the trial database after 
completion of enrolment, i.e. the randomization has been completed.


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9.
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, IDEA for CON.
3.
BI-KMED-BDS-TMP-0059: “iPD specification document (sdtm-dv-domain-
specification)”, template, current version, KMED.
4.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current
version; KMED.
5.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMED.
6.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies”, current version; KMED.
7.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project 
Summaries”, current version; KMED.
8.
BI-KMED-TMCP-OTH-0003: “Graphs and Tables for Clinical Pharmacokinetics and
Pharmacodynamic Noncompartmental Analyses”, current version, KMED.
9.
BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; KMED.
10. BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from
Clinical Trials – Display Template”, current version; KMED.
11. BI-KMED-BDS-HTG-0066: “Analysis and Presentation of AE data from clinical trials”, 
current version, KMED.
12. 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.
13. BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; KMED.
14. R18-0143: 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).


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1 
26-APR-21
None
This is the final TSAP