Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Rising Subcutaneous Doses and Multiple Subcutaneous Doses Over 6 Weeks of BI 3006337 in Healthy Male Japanese Subjects (Single-blind, Randomised Within Dose Groups, Placebo-controlled, Parallel Group Design)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

BI-VQD-12774_40-106_AD-11 (8.0)
Clinical Trial Protocol
TITLE PAGE
Document Number: c43161925-02
BI Trial No.
1466-0003
BI Investigational
Medicinal Product
BI 3006337
Title
Safety, tolerability, pharmacokinetics, and pharmacodynamics of 
single rising subcutaneous doses and multiple subcutaneous
doses over 6 weeks of BI 3006337 in healthy male Japanese 
subjects (single-blind, randomised within dose groups, placebo-
controlled, parallel group design)
Lay Title
A study in healthy Japanese men to test how well different doses 
of BI 3006337 are tolerated
Clinical Phase
I
Clinical Trial Leader
Phone: 
FAX: 
 Investigator
Phone: 
FAX: 
Current Version, Date
Version 2.0, 15 Feb 2024
Original Protocol Date
18 Dec 2023
Page 1 of 100
Proprietary confidential information
© 2024 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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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
18 December 2023
Revision date
Not applicable
BI trial number
1466-0003
Title of trial
Safety, tolerability, pharmacokinetics, and pharmacodynamics of single rising 
subcutaneous doses and multiple subcutaneous doses over 6 weeks of BI 3006337 
in healthy male Japanese subjects (single-blind, randomised within dose groups, 
placebo-controlled, parallel group design) 
 Investigator
Trial site
Phone: 
FAX: 
Clinical phase
I
Trial rationale
To assess safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 
3006337 in healthy male Japanese subjects receiving single rising doses (SRD) 
and multiple doses (MD) in order to provide the basis for a clinical development 
of BI 3006337 in Japan.
Trial objectives
To investigate safety, tolerability, pharmacokinetics, and pharmacodynamics
following single rising doses and multiple doses of BI 3006337
Trial endpoints
Primary endpoint: Occurrence of any treatment-emergent adverse event assessed 
as drug-related by the investigator. This is expressed as the percentage of subjects 
treated with investigational drug who experience such an event.
Secondary endpoints:
SRD part: AUC0-∞, Cmax of BI 3006337
MD part: AUCτ,ss, Cmax,ss of BI 3006337
Trial design
Single-blind, randomised within dose groups, placebo-controlled parallel-group 
design
Number of subjects 
total entered
36
on each treatment
SRD part: 24
8 per dose group (6 receiving BI 3006337 and 2 receiving placebo) 
MD part: 12
12 per dose group (9 receiving BI 3006337 and 3 receiving placebo)
* Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g., preliminary PK data), provided the planned 
and approved highest dose will not be exceeded. Thus, the actual number of subjects 
entered may exceed 36, but is not to exceed 48.
Diagnosis
Not applicable

Boehringer Ingelheim
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Main inclusion criteria
Healthy male subjects, age of 18 to 45 years (inclusive) , body mass index (BMI) 
of 18.5 to 25 kg/m2 (inclusive)
Test product
BI 3006337 solution for injection 50 mg/mL 
dose
SRD part: 50 mg, 100 mg, 150 mg
MD part: 150 mg
mode of
administration
subcutaneous (s.c.) after an overnight fast of at least 10 h
Comparator product
Matching placebo
dose
Not applicable
mode of admin.
s.c. after an overnight fast of at least 10 h
Duration of treatment
SRD part: Single dose 
MD part: 6 weeks, once weekly
Statistical methods
Descriptive statistics will be calculated for all endpoints.

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BI-VQD-12774_40-106-AD-11 (8.0)
FLOW CHART
SRD part: DG1 – DG3
Visit
Day
Planned time (relative to trial activities 8) 
[h:min] 
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory15
BI 3006337 in serum
Anti-Drug Antibodies/Neutralizing ADAs 7
Blood biomarker14
Glucose, insulin in plasma
12-lead ECG13
Vital signs (BP, PR, BT)
Questioning for AEs and concomitant 
therapy5
1
-28 to -3
Screening (SCR)1,11
A6
x12
x
2
-2
-41:00
16:00
Admission to trial site4,11
-1
-26:00
07:00
Randomisation10
B
x
x
x
-25:10
07:50
x
-25:00
08:00
Start OGTT
-24:45
08:15
x
-24:30
08:30
x
-24:15
08:45
x
-24:00
09:00
x
-23:30
09:30
x
-23:00
10:00
240 mL fluid intake9
x
-22:00
11:00
x
-21:00
12:00
Lunch9
x
-20:00
13:00
-19:00
14:00
-17:00
16:00
Snack (voluntary)9
-15:00
18:00
-14:00
19:00
Dinner
1
-2:00
07:00
Body weight (BW) 2
C2
x2
x2
x2
x2
x2
x2
0:00
09:00
s.c. injection of
BI 3006337 or placebo
1:00
10:00
x
x
x
1:30
10:30
Light breakfast9
x
x
2:00
11:00
Local tolerability at injection 
site
x
x
x
3:00
12:00
Lunch9
x
x
x
x
7:00
16:00
Snack (voluntary)9
x
x
x
x
10:00
19:00
Dinner
11:00
20:00
x
x
x
x
15:00
24:00
x
x
2
22:00
07:00
Local tolerability at injection 
site
C
22:50
07:50
x
23:00
08:00
Start OGTT
x
x
x
x
x
23:15
08:15
x

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Trial Protocol
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BI-VQD-12774_40-106-AD-11 (8.0)
Visit
Day
Planned time (relative to trial activities 8) 
[h:min] 
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory15
BI 3006337 in serum
Anti-Drug Antibodies/Neutralizing ADAs 7
Blood biomarker14
Glucose, insulin in plasma
12-lead ECG13
Vital signs (BP, PR, BT)
Questioning for AEs and concomitant 
therapy5
2
2
23:30
08:30
x
23:45
08:45
x
24:00
09:00
x
x
x
24:30
09:30
x
25:00
10:00
240 mL fluid intake9
x
x
x
26:00
11:00
x
27:00
12:00
Lunch9
x
x
x
x
x
28:00
13:00
29:00
14:00
31:00
16:00
Snack (voluntary)9
x
x
x
x
33:00
18:00
34:00
19:00
Dinner
35:00
20:00
x
x
x
x
36:00
21:00
Snack (voluntary)9
39:00
24:00
x
x
3
46:00
07:00
Local tolerability at injection 
site
C
47:00
08:00
Breakfast9
x
x
x
x
51:00
12:00
Lunch
55:00
16:00
Snack (voluntary)
58:00
19:00
Dinner9
x
x
x
4
70:00
7:00
Local tolerability at injection 
site
C
72:00
09:00
Breakfast9(voluntary)
x
x
x
x
73:00
10:00
Discharge from trial site
5
96:00
09:00
Ambulatory visit
x
x
x
x
6
120:00
09:00
Ambulatory visit, 
body weight
D
x
x
x
x
x
8
168:00
09:00
Ambulatory visit, local 
tolerability at injection site
C
x
x
x
x
11
240:00
09:00
Ambulatory visit,
body weight
x
x
x
x
15
336:00
09:00
Ambulatory visit
C
x
x
x
x
x
x
22
504:00
09:00
Ambulatory visit,
body weight
E
x
x
x
29
672:00
09:00
Ambulatory visit
E
x
x
x
x
x
3
32 to 40
End of trial (EOT)
examination3
F
x
x
x
x
x

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1.
Subject must be informed and written informed consent obtained prior to starting any SCR procedures. SCR
procedures include physical examination, check of vital signs, ECG, safety laboratory, demographics (including 
determination of body height and weight, smoking status and alcohol history), relevant medical history, 
concomitant therapy, and review of inclusion/exclusion criteria.
2.
The time is approximate; the respective procedures are to be performed and completed within 3 h prior to drug 
administration on Visit 2 Day 1.
3.
End of trial examination includes physical examination (potential injection site reactions), BW, vital signs, ECG, 
safety laboratory, recording of AEs and concomitant therapies.
4.
In addition, a drug SCR and alcohol breath test will be done at this time point.
5.
AEs and concomitant therapies will be recorded throughout the trial but will be specifically asked for at the time 
points indicated in the Flow Chart above.
6.
Including infectious serology test.
7.
Blood sample for anti-drug antibody (ADA) analysis and neutralizing ADAs.
8.
Planned time relative to administration of BI 3006337 or placebo in Visit 2.
9.
If several actions are indicated at the same time point, the intake of meals or liquids will be the last action.
10.
Randomisation will be done following enrolment, the latest prior to administration of trial medication (BI 3006337 or 
placebo) at Day 1 of Visit 2.
11.
COVID-19 Antigen Rapid Test (Nasopharyngeal Swab) at SCR and Day -2 of Visit 2.
12.
The ECG recording must be performed in triplicate ECGs at this time. 
13.
All resulting ECGs will be transferred electronically to the central ECG lab except for SCR and EOT.
14.
Biomarker (BM) samples (refer to Section 5.4)
15.
A, B, C, D, E, & F: safety laboratory sets (refer to section 5.2.3)

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MD part: DG4
Visit
Day
Planned time 
(relative to trial activities 9) 
[h:min]
Approximate clock time
of actual day [h:min]
Event and comment
Safety laboratory19
Acetaminophen in plasma
BI 3006337 in serum
ADAs/Nab8
Blood biomarkers13
Glucose and  insulin in plasma
Blood Biobanking (optional)
12-lead ECG18
C-SSRS examination
Vital signs (BP, PR, BT)
Questioning for AEs and 
concomitant therapy6
1
-28 
to -3
SCR1,3
A4
x17
x
x
2
-2
-41:00
16:00
Admission to trial site3,5
-1
-26:00
07:00
Randomisation11
B7
x
x
x
x
x
-25:10
07:50
x
-25:00
08:00
Start OGTT and 
acetaminophen absorption 
test
-24:45
08:15
x
x
-24:30
08:30
x
x
-24:15
08:45
x
x
-24:00
09:00
x
x
x
x
-23:30
09:30
x
x
-23:00
10:00
240 mL fluid intake10
x
x
x
x
-22:00
11:00
x
x
-21:00
12:00
Lunch10
x
x
x
x
-20:00
13:00
x
-19:00
14:00
x
-17:00
16:00
Snack (voluntary)10
x
-15:00
18:00
x
x
-12:00
19:00
Dinner
1
-1:00
08:00
BW2
x2
x2
x2
x2
x2
x2
x2
0:00
09:00
s.c. injection of
BI 3006337 or placebo
1:30
10:30
x
x
2:00
11:00
Local tolerability at 
injection site12
240 mL fluid intake10
3:00
12:00
x
x
x
x
4:00
13:00
Lunch
7:00
16:00
Snack (voluntary)10
x
x
x
10:00
19:00
Dinner
11:00
20:00
x
x
x
x
15:00
24:00
x
x
2
22:00
07:00
B
x
x
x
x
x
22:50
07:50
x
23:00
08:00
Start OGTT and 
acetaminophen absorption 
test
x
23:15
08:15
x
x
23:30
08:30
x
x

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Visit
Day
Planned time 
(relative to trial activities 9) 
[h:min]
Approximate clock time
of actual day [h:min]
Event and comment
Safety laboratory19
Acetaminophen in plasma
BI 3006337 in serum
ADAs/Nab8
Blood biomarkers13
Glucose and  insulin in plasma
Blood Biobanking (optional)
12-lead ECG18
C-SSRS examination
Vital signs (BP, PR, BT)
Questioning for AEs and 
concomitant therapy6
2
2
23:45
08:45
Local tolerability at 
injection site12
x
x
24:00
09:00
x
x
x
x
24:30
09:30
x
x
25:00
10:00
240 mL fluid intake10
x
x
x
x
26:00
11:00
x
x
27:00
12:00
Lunch10
x
x
x
x
x
28:00
13:00
x
29:00
14:00
x
31:00
16:00
Snack (voluntary)10
x
x
x
x
33:00
18:00
x
x
34:00
19:00
Dinner
35:00
20:00
x
x
x
39:00
24:00
x
x
3
46:00
07:00
Local tolerability at 
injection site12
B
47:00
08:00
Breakfast10
x
x
x
x
x
x
51:00
12:00
Lunch
55:00
16:00
Snack (voluntary)
58:00
19:00
Dinner
4
72:00
09:00
Local tolerability at 
injection site12,
Breakfast (voluntary)10,
Discharge from trial site
B
x
x
x
x
x
8
168:00
09:00
Ambulatory visit15
s.c. injection of
BI 3006337 or placebo
x
170:00
11:00
Local tolerability at 
injection site12
B
x
x
x
15
336:00
09:00
Ambulatory visit15
s.c. injection of
BI 3006337 or placebo
B7
x
338:00
11:00
Local tolerability at 
injection site12
x
x
x
x
18
408:00
09:00
Ambulatory visit, local 
tolerability at injection 
site12
B
x
x
x
x
x
22
504:00
09:00
Ambulatory visit15
s.c. injection of
BI 3006337 or placebo
x
506:00
11:00
Local tolerability at 
injection site12
x
x
x
x
29
672:00
09:00
Ambulatory visit15
s.c. injection of
BI 3006337 or placebo
x
x
674:00
11:00
Local tolerability at 
injection site12
B
x
x
x
x

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Visit
Day
Planned time 
(relative to trial activities 9) 
[h:min]
Approximate clock time
of actual day [h:min]
Event and comment
Safety laboratory19
Acetaminophen in plasma
BI 3006337 in serum
ADAs/Nab8
Blood biomarkers13
Glucose and  insulin in plasma
Blood Biobanking (optional)
12-lead ECG18
C-SSRS examination
Vital signs (BP, PR, BT)
Questioning for AEs and 
concomitant therapy6
2
36
840:00
09:00
Ambulatory visit15
s.c. injection of
BI 3006337 or placebo
x
842:00
11:00
Local tolerability at 
injection site12
B
x
x
x
x
43
1007:00
08:00
Admission to trial site, 
BW3,5
x
1008:00
09:00
s.c. injection of
BI 3006337 or placebo
x
x
1010:00
11:00
Local tolerability at 
injection site12
240 mL fluid intake10
B
x
1011:00
12:00
x
x
x
x
1012:00
13:00
Lunch
1015:00
16:00
Snack (voluntary)10
x
x
x
1018:00
19:00
Dinner
1019:00
20:00
x
x
x
x
1023:00
24:00
x
x
44
1030:00
07:00
Local tolerability at 
injection site12
x
x
x
x
x
1030:50
07:50
x
1031:00
08:00
Start OGTT and 
acetaminophen absorption 
test
x
1031:15
08:15
x
x
1031:30
08:30
Local tolerability at 
injection site12
x
x
1031:45
08:45
x
x
1032:00
09:00
x
x
x
x
1032:30
09:30
x
x
1033:00
10:00
240 mL fluid intake10
x
x
x
x
1034:00
11:00
x
x
1035:00
12:00
Lunch10
x
x
x
x
x
1036:00
13:00
x
1037:00
14:00
x
1039:00
16:00
Snack (voluntary)10
x
x
x
x
1041:00
18:00
x
x
1042:00
19:00
Dinner
1043:00
20:00
x
x
x
1047:00
24:00
x
x
45
1054:00
07:00
Local tolerability at 
injection site12
1055:00
08:00
Breakfast10
x
x
x
x
x
1059:00
12:00
Lunch
1063:00
16:00
Snack (voluntary)
1066:00
19:00
Dinner

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Visit
Day
Planned time 
(relative to trial activities 9) 
[h:min]
Approximate clock time
of actual day [h:min]
Event and comment
Safety laboratory19
Acetaminophen in plasma
BI 3006337 in serum
ADAs/Nab8
Blood biomarkers13
Glucose and  insulin in plasma
Blood Biobanking (optional)
12-lead ECG18
C-SSRS examination
Vital signs (BP, PR, BT)
Questioning for AEs and 
concomitant therapy6
2
46
1080:00
09:00
Breakfast (voluntary)10,
Discharge from trial site
B7
x
x
x
x
x
50
1176:00
09:00
Ambulatory visit
x
x
3
64 to 
74
End of trial (EOT) 
examination16, 
Ambulatory visit 
A
x
x
x
x14
x
x
x
x
1.
Trial participants must be informed and written informed consent obtained prior to starting any SCR procedures. At 
SCR, the medical examination will include demographics, height, and BW, 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 (Temperature, BP, PR), 12-lead ECG, laboratory tests, and a 
physical examination.
2.
The time is approximate; the respective procedures are to be performed and completed within 3 h prior to drug 
administration on Day 1 of Visit 2. 
3.
COVID-19 Antigen Rapid Test (Nasopharyngeal Swab) will be performed at SCR and prior to each admission to site.
4.
Including infectious serology test.
5.
In addition, a drug SCR and alcohol breath test will be done at this time point.
6.
AEs and concomitant therapies will be recorded throughout the trial but will be specifically asked for at the time points 
indicated in Flow Chart above.
7.
TSH will only be collected at this time.
8.
Blood samples for ADA/Nab analysis.
9.
Planned time relative to administration of BI 3006337 or placebo at Visit 1.
10. If several actions are indicated at the same time point, the intake of meals or liquids will be the last action.
11. Randomisation will be done following enrolment and the latest prior to administration of trial medication (BI 3006337 
or placebo) at Day 1 of Visit 2.
12. Local tolerability (refer to Section 5.2.5.1)
13. BM samples (refer to Section 5.4)
14. Only blood samples for biobanking will be collected at EOT visit
15. For ambulatory visits, kits assignment must be performed the day before the visit, otherwise the IMP will not be ready 
for administration.
16. End of trial examination includes physical examination (potential injection site reactions), BW, vital signs, ECG, safety 
laboratory, recording of AEs and concomitant therapies.
17. The ECG recording must be performed in triplicate ECGs at this time. 
18. All resulting ECGs will be transferred electronically to the central ECG lab except for SCR and EOT.
19. A & B: safety laboratory sets (refer to section 5.2.3)

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
SRD part: DG1 – DG3........................................................................................4
MD part: DG4 .....................................................................................................7
TABLE OF CONTENTS ................................................................................ 11
ABBREVIATIONS AND DEFINITIONS..................................................... 16
1.
INTRODUCTION.................................................................................... 19
1.1
MEDICAL BACKGROUND............................................................................19
1.2
DRUG PROFILE...............................................................................................20
1.2.1
Nonclinical pharmacology....................................................................20
1.2.2
Toxicology..............................................................................................21
1.2.3
Nonclinical pharmacokinetics..............................................................21
1.2.4
Clinical experience in humans.............................................................22
1.2.5
Residual Effect Period..........................................................................24
1.2.6
Drug product.........................................................................................24
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................24
1.4
BENEFIT - RISK ASSESSMENT ...................................................................25
1.4.1
Benefits...................................................................................................25
1.4.2
Risks .......................................................................................................25
1.4.3
Discussion...............................................................................................28
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 29
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......29
2.1.1
Main objectives......................................................................................29
2.1.2
Primary endpoint..................................................................................29
2.1.3
Secondary endpoints.............................................................................29
2.2.2.1
Safety and tolerability..............................................................30
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 34
3.1
OVERALL TRIAL DESIGN............................................................................34
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................36
3.3
SELECTION OF TRIAL POPULATION ......................................................36
3.3.1
Main diagnosis for trial entry..............................................................36

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3.3.2
Inclusion criteria...................................................................................37
3.3.3
Exclusion criteria ..................................................................................37
3.3.4
Withdrawal of subjects from treatment or assessments ...................39
3.3.4.1
Withdrawal from trial treatment ..............................................39
3.3.4.2
Withdrawal of consent to trial participation ............................40
3.3.4.3
Discontinuation of the trial by the sponsor and dose stopping 
criteria .....................................................................................40
3.3.5
Replacement of subjects .......................................................................41
4.
TREATMENTS........................................................................................ 42
4.1
INVESTIGATIONAL TREATMENTS ..........................................................42
4.1.1
Identity of the Investigational Medicinal Products ...........................42
4.1.2
Selection of doses in the trial and dose modification .........................42
4.1.3
Method of assigning subjects to treatment groups ............................42
4.1.4
Drug assignment and administration of doses for each subject .......43
4.1.5
Blinding and procedures for unblinding ............................................44
4.1.5.1
Blinding....................................................................................44
4.1.5.2
Unblinding and breaking the code...........................................45
4.1.6
Packaging, labelling, and re-supply ....................................................45
4.1.6.1
BI 3006337 and placebo ..........................................................45
4.1.7
Storage conditions.................................................................................45
4.1.8
Drug accountability ..............................................................................46
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................46
4.2.1
Other treatments and emergency procedures....................................46
4.2.1.1
Non-investigational medicinal product....................................48
4.2.1.1.1 Acetaminophen Syrup ...............................................48
4.2.1.1.2 TRELAN-G75 ...........................................................48
4.2.2
Restrictions............................................................................................49
4.2.2.1
Restrictions regarding concomitant treatment .........................49
4.2.2.2
Restrictions on diet and lifestyle..............................................50
4.3
TREATMENT COMPLIANCE.......................................................................50
5.
ASSESSMENTS....................................................................................... 51
5.1
ASSESSMENT OF EFFICACY.......................................................................51
5.2
ASSESSMENT OF SAFETY............................................................................51
5.2.1
Physical examination ............................................................................51
5.2.2
Vital signs...............................................................................................51
5.2.3
Safety laboratory parameters..............................................................51
5.2.4
Electrocardiogram................................................................................57
5.2.4.1
12-lead resting ECG.................................................................57
5.2.5
Other safety parameters.......................................................................59
5.2.5.1
Local tolerability......................................................................59
5.2.5.2
Suicidality assessment .............................................................59

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5.2.6
Assessment of adverse events...............................................................60
5.2.6.1
Definitions of adverse events...................................................60
5.2.6.1.1 Adverse event ............................................................60
5.2.6.1.2 Serious adverse event ................................................60
5.2.6.1.3 AEs considered ‘Always Serious’.............................61
5.2.6.1.4 Adverse events of special interest .............................61
5.2.6.1.5 Intensity (severity) of AEs.........................................62
5.2.6.1.6 Causal relationship of AEs ........................................62
5.2.6.2
Adverse event collection and reporting ...................................63
5.2.6.2.1 AE collection.............................................................63
5.2.6.2.2 AE reporting to the sponsor and timelines ................64
5.2.6.2.3 Pregnancy ..................................................................64
5.2.6.2.4 Hypoglycaemia..........................................................64
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................65
5.3.1
Assessment of pharmacokinetics .........................................................65
5.3.2
Methods of sample collection...............................................................65
5.3.2.1
Blood sampling for BI 3006337 pharmacokinetic analysis.....65
5.3.2.2
Blood sampling for ADA/Nab analysis ...................................65
5.3.4
Pharmacokinetic – pharmacodynamic relationship..........................66
5.4
ASSESSMENT OF BIOMARKERS................................................................66
5.4.1
Biochemical and cellular biomarkers..................................................66
5.4.2
Methods and timing of sample collection............................................66
5.5
BIOBANKING ...................................................................................................67
5.5.1
Methods and timing of sample collection............................................67
5.6
OTHER ASSESSMENTS .................................................................................67
5.6.1
Oral glucose tolerance test ...................................................................68
5.6.1.1
Sampling for OGTT.................................................................68
5.6.1.1.1 Plasma glucose ..........................................................68
5.6.1.1.2 Plasma insulin............................................................69
5.6.2
Acetaminophen absorption test ...........................................................69
5.6.2.1
Plasma sampling for acetaminophen absorption test...............69
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................70
6.
INVESTIGATIONAL PLAN.................................................................. 71
6.1
VISIT SCHEDULE............................................................................................71
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................71

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6.2.1
Screening period....................................................................................71
6.2.2
Treatment period ..................................................................................71
6.2.3
Follow-up period and trial completion ...............................................72
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 73
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................73
7.2
PLANNED ANALYSES....................................................................................73
7.2.1
General considerations.........................................................................73
7.2.1.1
Analysis sets.............................................................................73
7.2.1.2
Pharmacokinetics.....................................................................74
7.2.1.3
Biomarkers...............................................................................74
7.2.2
Primary endpoint analyses...................................................................75
7.2.3
Secondary endpoint analyses ...............................................................75
7.2.5
Safety analyses.......................................................................................77
7.2.6
Other analysis........................................................................................78
7.2.7
Interim analyses ....................................................................................78
7.3
HANDLING OF MISSING DATA ..................................................................79
7.3.1
Safety......................................................................................................79
7.3.2
Pharmacokinetics..................................................................................79
7.3.3
Biomarkers/pharmacodynamics..........................................................79
7.4
RANDOMISATION ..........................................................................................79
7.5
DETERMINATION OF SAMPLE SIZE ........................................................79
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 81
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................81
8.2
DATA QUALITY ASSURANCE .....................................................................82
8.3
RECORDS..........................................................................................................82
8.3.1
Source documents .................................................................................82
8.3.2
Direct access to source data and documents.......................................83
8.3.3
Storage period of records.....................................................................83
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................84
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......84
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................84
8.6
TRIAL MILESTONES .....................................................................................84
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................85

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9.
REFERENCES......................................................................................... 86
9.1
PUBLISHED REFERENCES...........................................................................86
9.2
UNPUBLISHED REFERENCES.....................................................................88
10. APPENDIX ............................................................................................... 89
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)...............89
10.1.1 Columbia-Suicide Severity Rating Scale (C-SSRS) Screening.........89
10.1.2 Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last 
Visit.........................................................................................................92
11. DESCRIPTION OF GLOBAL AMENDMENT................................... 95
11.1
GLOBAL AMENDMENT 1 .............................................................................95

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ABBREVIATIONS AND DEFINITIONS
ADA
Anti-drug Antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Transaminase
ALP
Alkaline Phosphatase
API
Active Pharmaceutical Ingredient
AST
Aspartate Transaminase
%AUCtz-∞
Percentage of AUCtz-∞obtained by extrapolation
AUC
Area under the Curve
AUC0-10h
Area under the concentration-time curve of the analyte in serum over the 
time interval from 0 to 10 h
AUC0-24h
Area under the concentration-time curve of the analyte in serum over the 
time interval from 0 to 24 h
AUC0-168h
Area under the concentration-time curve of the analyte in serum over the 
time interval from 0 to 168 h
AUC0-∞
Area under the concentration-time curve of the analyte in serum over the 
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in serum over the 
time interval from 0 to the last quantifiable data point
AUCt1-t2
Area under the concentration-time curve of the analyte in serum over the 
time interval t1 to t2
BALP
Bone-specific Alkaline Phosphatase
BI
Boehringer Ingelheim
BMI
Body Mass Index (weight divided by height squared)
BP
Blood Pressure
BW
Body Weight
CA
Competent Authority
Cavg
Average concentration of the analyte in serum at steady state over a uniform 
dosing interval τ
CI
Confidence Interval
CL
Total clearance of the analyte in serum after intravascular administration
CL/F
Apparent clearance of the analyte in serum after extravascular administration
Cmax
Maximum measured concentration of the analyte in serum
Cmax,ss
Maximum measured concentration of the analyte in serum during steady 
state
Cmin
Minimum measured concentration of the analyte in serum
Cmin,ss
Minimum measured concentration of the analyte in serum during steady 
state
COVID-19
Corona Virus Disease 2019
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CRO
Contract Research Organization
CT
Computer Tomography
CTL
Clinical Trial Leader

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CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CTX
Carboxy-terminal Collagen Crosslinks
DEXA
Dual-Energy X-Ray Absorptiometry
DG
Dose Group
DILI
Drug Induced Liver Injury
DIO
Diet-induced
ECG
Electrocardiogram
ECGPCS
ECG pharmacokinetic concentration set
EDTA
Ethylenediaminetetraacetic acid
EOT
End of Trial
ES
Enrolled set
EudraCT
European Clinical Trials Database
FC
Fragment Crystallizable
FGF21
Fibroblast Growth Factor 21
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
GI
Gastrointestinal
GLP-1
Glucagon-like Peptide 1
GLP1R
Glucagon-like Peptide 1 Receptor
HMW
High Molecular Weight
HR
Heart Rate
IB
Investigator’s Brochure
ICH-GCP
International Conference of Harmonization – Good Clinical Practice
IEC
Independent Ethics Committee
iPD
Important Protocol Deviation
IRB
Institutional Review Board
ISF
Investigator Site File
ka
Absorption rate constant
z
Terminal rate constant of the analyte in serum
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
micro-CT
Micro-Computer Tomography
MRTex
Mean residence time of the analyte in the body after extravascular
administration
MTC
Medullary Thyroid Carcinoma
NAFLD
Non-alcoholic Fatty Liver Disease
NASH
Non-alcoholic Steatohepatitis
NOAEL
No Observed Adverse Effect Level
OC
Osteocalcin
OGTT
Oral Glucose Tolerance Test
P1NP
Procollagen Type 1 N-terminal Propeptide
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)

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PKS
PK parameter analysis set
PP
Polypropylene
PR
Pulse Rate
q2d
Every second day
QRS
Time between start of the Q-wave and the end of the S-wave in an 
electrocardiogram
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)
qw
Weekly (once a week)
R
Reference treatment
REP
Residual Effect Period
RPM
Report Planning Meeting
RR
Time between two R-waves in an electrocardiogram
SAE
Serious Adverse Event
SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2
s.c.
Subcutaneous
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SRD
Single-Rising Dose
t1/2
Terminal half-life
TAA
Thioacetamide
T-BIL
Total Bilirubin
TC
Total Cholesterol
TG
Triglycerides
TGFß
Transforming Growth Factor beta
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in serum
TMF
Trial Master File
TS
Treated set
TSAP
Trial Statistical Analysis Plan
TSTAT
Trial Statistician
tz
Time of last measurable concentration of the analyte in serum
ULN
Upper Limit of Normal
Vss
Apparent volume of distribution at steady state after intravascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) has a prevalence of about 20 to 30% in the 
general population of Western countries and is rapidly becoming the most common liver 
disease worldwide [R15-5365]. While simple hepatic steatosis can have a benign non-
progressive course, about 10% of patients with NAFLD progress to non-alcoholic 
steatohepatitis (NASH). As the disease progresses, significant fibrosis develops in 37 to 41% 
of patients within 15 years. According to the National Institute of Health, NASH is believed 
to be the most common cause of liver cirrhosis [R15-6070], and the 12th leading cause of 
death in the United States [R15-6057]. Patients with NASH are also at increased risk of 
hepatocellular carcinoma, even in the absence of cirrhosis [R15-5365]. By 2023, about 
13 million patients are projected to have NASH with advanced stages of fibrosis. The risk of 
liver-related death in Western patients with NASH ranges from 10% over 13.7 years to 18% 
over 18.5 years [P13-02280].
Neither approved NASH-targeted therapy nor effective disease modifying regimens are 
currently available. Treatment is focused on addressing comorbidities from metabolic 
syndrome. Moreover, while lifestyle modifications – including weight loss and exercise – are 
recommended across different phenotypes and considered the mainstay initial treatment for 
NASH, they are difficult to achieve and maintain.
The test product BI 3006337 is a long-acting dual GLP-1 and FGF21 receptor agonist. By 
combining activities of GLP-1 and FGF21 in one molecule (dual GLP-1/FGF21 receptor 
agonist), BI 3006337 is expected to address multiple disease-related components of NASH 
by:

Reducing liver cell injury (steatosis, oxidative stress) and hepatic inflammation

Reducing fibrosis and

Improving glucose metabolism and insulin resistance
GLP-1 is a gut-derived incretin hormone with glucose-lowering features achieved by 
inducing insulin secretion and reducing the production of glucagon. It also suppresses 
appetite and retards gastric emptying.
GLP1R agonists are one of the newer classes of medications for the treatment of adults with 
type 2 diabetes and/or obesity. The GLP1R agonist class first became available in 2005 in the 
United States with the approval of short-acting exenatide by the FDA. There are now several 
GLP1R agonists (mostly for s.c. application) available for the treatment of type 2 diabetes 
and obesity. In clinical studies in patients with NASH, liraglutide, a long-acting GLP-1
agonist, achieved resolution of NASH without worsening of fibrosis in 39% (9/23) of patients 
compared with 9% (2/22) in the placebo group after 48 weeks of treatment. Improvements in 
steatosis and hepatocyte ballooning were greater in the liraglutide group, but no differences 
were seen in lobular inflammation and overall non-alcoholic fatty liver disease (NAFLD)
activity score [R16-3177]. Additionally, GLP-1 analogue semaglutide, administered once-
daily, was associated with histological NASH resolution in a phase 2b trial [R21-0690] in 
patients with NASH F2-3, although its effects on fibrosis (including in patients with 

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compensated cirrhosis) have not been proven [R23-2928]. A phase 3 trial is ongoing 
[NCT04822181].
The FGF family of hormones mediates metabolic functions and tissue repair and 
regeneration. FGF21, a non-mitogenic hormone, is a key regulator of energy metabolism. It 
increases energy expenditure, reduces hepatic triglyceride, and improves insulin sensitivity 
[R19-2360]. Several FGF21-class molecules have been tested in humans, and several are still 
in different stages of clinical development for the treatment of type 2 diabetes or NASH. In 
clinical studies involving patients with NASH, a long acting FGF21 analogue efruxifermin 
showed beneficial effects on steatosis, inflammation, and fibrosis. Efruxifermin was 
associated with significant improvement vs. placebo in NASH resolution (76% vs. 15%, p
<0.001) and 1-stage fibrosis improvement (41% vs. 20%, p<0.05) after 24 weeks of treatment 
in patients with NASH F2-3 [R23-0311]. The Phase IIb trial in patients with NASH 
compensated cirrhosis is ongoing [NCT05039450].
Dual GLP-1/FGF21 receptor agonism is therefore expected to reduce liver cell injury 
(steatosis, oxidative stress, and release of aminotransferases) and hepatic inflammation. 
While sustained resolution of steatohepatitis could result in subsequent reduction of fibrosis, 
a dual agonist is also expected to have direct anti-fibrotic effects via FGF21 mediated 
attenuation of TGFß signaling and hepatic stellate cell activation as recently described [R20-
0498]. In addition, a dual GLP-1/FGF21 receptor agonist should improve insulin resistance as 
a root cause of liver steatosis and inflammation.
Overall, the clinical data available from literature on the separate components (GLP-1 and 
FGF21 agonists) are supportive for the development of BI 3006337 in patients with NASH.
1.2
DRUG PROFILE
The test product BI 3006337 is a dual GLP-1/ FGF21 receptor agonist designed for the 
treatment of NASH. It is a GLP-1 and FGF21 antibody FC fusion protein of the 
IgD/IgG4 subclass, that binds to and activates the function of GLP-1 and FGF21 receptors.
1.2.1
Nonclinical pharmacology
BI 3006337 is a highly potent dual GLP-1/FGF21 agonist. In preclinical models of NASH, BI 
3006337 significantly improved multiple disease-related components. In the DIO-NASH 
mice model, BI 3006337 treatment resulted in a superior weight loss compared with a mono-
GLP 1 agonist dulaglutide. BI 3006337 reduced liver fat content, and decreased steatosis, 
lobular inflammation, and ballooning resulting in significant improvement of the mean 
NAFLD activity score (NAS). While improvements in liver histology may reflect the effect 
of BI 3006337 on body weight, anti-fibrotic effects of BI 3006337 in the chemically induced 
rat TAA fibrosis model are weight-loss independent. BI 3006337 treatment (30 nmol/kg) 
resulted in significant reduction of hepatic hydroxyproline content compared with mono-GLP 
1 treatment groups, providing a compelling rationale for positioning BI 3006337 in NASH 
patients with fibrosis.
There were no BI 3006337 related adverse findings in neurological, cardiovascular, 
respiratory, and renal function assessments. BI 3006337 effects on gastrointestinal function 
are expected pharmacodynamics effects and are therefore not considered adverse. These 

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effects weakened during the course of the treatment and did not produce adverse outcomes on 
the overall animal health, implicating an acceptable and manageable safety profile for clinical 
trials.
Further details are shown in the IB Section 5.1.
1.2.2
Toxicology
GLP-1 agonists stimulate glucose-dependent insulin secretion, inhibit food intake and/or 
suppress appetite, slow gastric emptying, and increase satiety [R18-2829] whilst FGF21 
agonists induce increased energy expenditure ([R20-0504, R20-0506]) and are known 
metabolic regulators of glucose and lipid metabolism ([R20-0508]). Consistent with the 
modes of action, BI 3006337 treatment-related findings were directly or indirectly 
(consequential responses due to the decreased food intake, body weight loss and decreased 
body weight gain) attributable to the expected pharmacological effects of BI 3006337, a GLP 
1/FGF21 dual agonist.
The most prominent treatment-related effects were gastrointestinal effects including body 
weight loss and decreased body weight gain which were associated with the reduced food 
consumption. The extent of the effect on body weight was the most pronounced during the 
first week of the treatment period, after which animals started gaining weight (rat) or there 
was general weight stasis or only minimal weight gain for the remainder of the treatment 
period (monkey). Similar effects including emesis have been shown with other GLP-1
agonists and the up-titration method has been used to improve tolerability in the clinical 
trials.
Anticipated with the possible role of FGF21 signaling in skeletal homeostasis [R19-2365], 
there was a trend of slight decreases in bone formation markers (BAP and OC) in monkeys, 
but no changes in bone resorption marker (CTX-1), bone density (DEXA and micro-CT), or 
microscopic correlates. Although these slight changes were minimal in magnitude and not 
considered adverse, it is recommended that the potential effect on bone mass be monitored by 
serum bone biomarkers and bone densitometry assessment during the clinical trials with 
longer duration.
In summary, the toxicology package did not indicate any adverse systemic toxicities nor 
embryo-fetal toxicity with sufficient margins to the exposures expected at the dose levels in 
this MD trial. Therefore, the nonclinical safety data support the chronic administration of 
BI 3006337 to men and women with childbearing potential.
For details, please see IB Sections 5.3 and 8.3.
1.2.3
Nonclinical pharmacokinetics
Two enzyme-linked immunosorbent assay (ELISA) assays were designed to measure full 
length and therefore active components of the molecule (GLP1 and FGF21). The 
pharmacokinetics (PK) of BI 3006337 was dose linear after i.v. and s.c. dosing in mice, rats, 
Cynomolgus monkeys, and minipigs. The ka and bioavailability (F) in non-clinical animals 
were species-dependent during the single dose PK studies. BI 3006337 is expected to be 
primarily distributed to blood and interstitial fluid. Dedicated metabolism studies have not 
been performed. BI 3006337 is expected to undergo protein catabolism in animals and 

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humans to peptides and amino acids. The molecular weight of BI 3006337 is 104 kDa, which 
is above the renal filtration cut-off threshold (around 60 kDa). BI 3006337 is not expected to 
have significant renal filtration. Differential PK profiles were observed in mice and 
Cynomolgus monkeys only. Mice showed a slightly higher exposure to active GLP1 than to 
active FGF21. Monkeys showed a substantially shorter PK profile for active GLP1 than for 
active FGF21. The cause of the discrepancies in the exposure between GLP1 and FGF21 is 
unknown.
1.2.4
Clinical experience in humans
The first clinical trial in humans exposed to BI 3006337 (trial 1466-0001, single rising dose 
[SRD] study) is clinically completed (CTR under preparation) and available data showed that
s.c. administration of single doses of BI 3006337 was safe and well-tolerated up to 150 mg.
Investigator defined drug-related AEs were reported for a small proportion of subjects 
receiving BI 3006337 (7 out of 61 subjects receiving BI 3006337 11.5%). The incidence of 
drug related AEs was not dose dependent and the drug-related AEs were reported as follows:
gastrointestinal disorders (diarrhoea or abdominal discomfort) were observed in two subjects 
from BI 3006337 group. Injection site reaction with mild severity was reported as AE in one 
subject only. AEs referring to elevated pancreatic enzymes were reported in 4 subjects 
(6.6%): pancreatic enzymes increased (both lipase and amylase) in 1 subject, lipase increased 
in 2 subjects and amylase increased in 1 subject. An AE of lipase increased was also reported 
in 1 subject (5.3 %) in the placebo group but was considered not related to BI 3006337 by the 
investigator. There were no severe drug-related AEs, and the majority of AEs was resolved 
before the end of the study. No hepatotoxicity (protocol specific AE of special interest) was 
reported for all participants and no clinically significant findings were reported for vital signs.
One subject in the 150 mg DG experienced a QRS complex abnormal in the ECG, which was 
reported as an AE but was not considered related to BI 3006337 by the investigator. 
[c39685874].
After single subcutaneous dosing, median tmax was generally early, in the range of 7 to 15 h, 
except for 100 mg where median tmax was 61.5 h. AUC0-∞and Cmax increased dose 
proportionally (overall dose range 0.2 to150 mg). Inter-individual variability in Cmax and 
AUC0-∞was high (gCV >50%) and moderate (30% <gCV <50%), respectively. Half-lives t1/2
(gMeans) ranged from 42.8 to 73.3 h (1.8 to 3.1 days) with moderate inter-individual 
variability.
Results from an exploratory ANOVA model indicated no effect of 150 mg BI 3006337 on 
acetaminophen’s absorption. The exploratory OGTT showed a reduction of glucose AUC0-2
at 150 mg BI 3006337 in comparison with placebo whereas changes in insulin and C-peptide 
were not different between 150 mg BI 3006337 and placebo.
Body weight did not change under BI 3006337 single dose treatment. However, at the highest 
doses of BI 3006337 increased HMW adiponectin levels were observed. The highest overall
increases were seen at 100 mg and 150 mg with +89 and 81% placebo-corrected HMW 
adiponectin increases from baseline at 336 h (Day 14) after single s.c. administration of BI
3006337. In addition, a decrease in triglyceride levels was observed at 168 h post dosing with 
-46, -36, and -35% compared with baseline for 50, 100 and 150 mg BI 3006337. However, 
when corrected for the placebo response only the difference at 50 mg remained significant.

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Single s.c. doses of BI 3006337 did not appear to affect bone formation (BALP, OC) and 
bone resorption (CTX-1) biomarkers. Small effects regarding a lowering of P1NP in the 50 
and 100 mg dose groups could be detected, however the P1NP values remained still in the 
reference range reported for healthy subjects.
In addition, ADA was assessed pre-dose, 2 weeks after dosing, 4 weeks after dosing and at 
the end-of-trial visit in 1466-0001. Preliminary data up to 150 mg are available. A total of 7 
of 61 subjects receiving BI 3006337 had a positive ADA response. Of these 7 subjects, 4 had 
pre-existing antibodies and 3 subjects (1 subject in dose group 2 mg, 1 subject in dose group 
50 mg, and 1 subjection in dose group 150 mg) had treatment-induced antibodies at the end-
of-trial visit. Titres ranged from 21 to 42. Three of 19 placebo-dosed subjects had an ADA 
response. All 3 placebo-dose subjects had pre-existing antibodies. Titres ranged from 21 to 
336. There was no indication of an association between the development of ADAs in some 
healthy subjects and the overall reported AEs [c39685874].
Further, experience with the single pharmacologically active components of BI 3006337 is 
available. The GLP1R agonist class first became available in 2005 in the United States with 
the approval of short-acting exenatide by the FDA. There are now several GLP1R agonists 
(mostly for s.c. application) available for the treatment of type 2 diabetes and/or obesity. In 
healthy volunteers, GLP1R agonists do not increase the risk of hypoglycaemia, even after 
prolonged fasting. Among the most common adverse effects for the GLP-1 class are nausea, 
vomiting, diarrhoea, headache, and HR increases, which did not impact the cardiac safety of 
the class. Several GLP1R agonists even demonstrated cardiac benefits in long-term cardiac 
outcome studies. First degree atrioventricular block was described for GLP1R agonists in 
clinical trials as well as in the prescribing information for liraglutide (Saxenda) and 
dulaglutide (Trulicity) [R22-1865, R22-1871, R22-1870]. Other cardiac conduction disorders 
such as right or left bundle branch block were reported for liraglutide (Saxenda) [R22-1865].
In clinical trials, there were more cases of pancreatitis among GLP1R-agonist treated patients 
than among placebo-treated patients. Pancreatitis was also reported from marketed use. If 
pancreatitis is suspected, GLP-1 agonists should be discontinued. They should be used with 
caution in patients with a history of pancreatitis. The incidence of acute gallbladder disease in 
clinical trials was greater among GLP1R treated patients compared with placebo in clinical 
trials. There have been post marketing reports of acute renal failure and worsening of chronic 
renal failure in patients treated with GLP1R agonists, with a majority of reported events 
occurring in patients who had experienced nausea, vomiting, diarrhoea, or dehydration. 
Suicidal behavior and ideation have been mentioned in the US prescribing information for 
liraglutide (Saxenda) [R22-1865] and semaglutide (Wegovy) [R21-3011].
As the human relevance of GLP1R-induced rodent thyroid C-cell tumours has not been 
determined, according to US Pis GLP1R agonists are contraindicated in patients with a 
personal or family history of Medullary Thyroid Carcinoma (MTC) and in patients with 
Multiple Endocrine Neoplasia syndrome type 2 (MEN 2, [R22-1865, R22-1867, R22-1871, 
R21-3011, R22-1874]).
Several FGF21-class molecules have been tested in humans, and several are still in different 
stages of clinical development for the treatment of type 2 diabetes or NASH. The most 
frequently reported AEs in studies with FGF21 agonists were gastrointestinal (diarrhoea and 
nausea), which were generally mild and did not require treatment. Effects of FGF21 agonists 

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on HR or BP are conflicting, with studies from pegbelfermin, a PEGylated FGF21 agonist, 
and with efruxifermin, a long-acting Fc-FGF21 fusion protein, showing no obvious changes
[R20-0507, R22-0899, R22-4307], while a 2017 trial of an intravenously administered, long-
acting FGF21 analogue showed increases in BP and HR [R20-0509].
1.2.5
Residual Effect Period
Residual effect period (REP) is the period after the last dose with measurable drug levels 
and/or with still likely to be present PD effects. The estimated REP of BI 3006337 in humans 
is 3 weeks. 
1.2.6
Drug product
For a more detailed description of the BI 3006337 profile, please refer to the current IB
[c30782091].
1.3
RATIONALE FOR PERFORMING THE TRIAL
The current trial will be performed to assess the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of BI 3006337 in Japanese male subjects, thus supporting the Phase II 
clinical development program of BI 3006337 in NASH in Japanese patients. Moreover, the 
trial will be performed to gain PK information at steady state exposure.
BI 3006337 is a dual GLP-1/FGF21 receptor agonist being developed for the treatment of 
compensated cirrhosis due to NASH to prevent a first clinical decompensating event and 
improve all-cause survival. Both GLP-1 and FGF21 agonists are currently in clinical 
development for this same indication either as monotherapy or as part of combination 
therapies, with promising results.
Cumulative data for BI 3006337 from non-clinical disease models demonstrate treatment 
effects across multiple NASH-relevant pathological aspects, including weight loss, improved 
lipid profile, insulin sensitivity, liver steatosis, hepatic lobular inflammation, and reduced 
hepatocyte injury and liver fibrosis (see the current IB [c30782091]). These results warrant 
clinical development for patients with NASH cirrhosis.
Preliminary data from 26-week chronic toxicity studies showed that there were no adverse 
target organs of toxicity associated with systemic exposures providing high safety margins. 
Overall, the nonclinical safety data support the administration of BI 3006337 to humans for 
up to chronic duration.
Single doses of BI 3006337 have been investigated in healthy male subjects in 
trial 1466-0001. BI 3006337 was administered s.c. at doses of 0.2 mg, 0.5 mg, 1 mg, 2 mg, 
4 mg, 8 mg, 15 mg, 30 mg, 50 mg, 100 mg, and 150 mg. BI 3006337 was safe and well-
tolerated for the doses up to 150 mg.
The multiple rising dose (MRD) and proof of clinical principle (PoCP) trial 1466-0002 is 
currently assessing safety, tolerability, PK and PD, and signs of efficacy of BI 3006337 in 
overweight or obese trial participants.

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The study of exploratory and probable valid biomarkers will be hypothesis-generating or 
supportive to endpoints. Study findings will be used to expand our understanding of the 
mechanism of BI 3006337 action to support subsequent trial designs regarding dose and 
schedule selection.
To address future scientific questions, trial participants will be asked to voluntarily donate 
biospecimens for banking (please see Section 5.5). If the trial participant agrees, banked 
samples may be used for future biomarker research and drug development projects, e.g., to 
identify patients that are more likely to benefit from a treatment or experience an AE, or to 
gain a mechanistic or genetic understanding of drug effects and thereby better match patients 
with therapies.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this study is without any (therapeutic) benefit for the healthy subjects. Their 
participation in the study, however, is of major importance for the development of
BI 3006337 as a s.c. drug, which might improve the therapy in patients with NASH.
Prevention of liver-related complications and reduction of overall mortality are the ultimate 
treatment goals for patients with NASH and advanced fibrosis.
1.4.2
Risks
The trial participants are exposed to the risks of the trial procedures and the risks related to 
the trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and, in rare cases, by transient inflammation of the wall of the 
vein. In addition, in rare cases a nerve might be injured while inserting the venous catheter, 
potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite period. 
The same risks apply to venepuncture for blood sampling.
For SRD part, the total volume of blood withdrawn during the entire trial per trial subject will 
not exceed the volume of a normal blood donation (400 mL) and no health-related risk to the 
trial subjects is expected from this blood withdrawal. For MD part, the total volume of blood 
withdrawn during the entire trial per trial subject will exceed 400 ml but will not exceed 600 
ml. This is acceptable considering the duration of the trial, and no health-related risk to the 
trial subjects is expected from this blood withdrawal.
In the usual Phase I settings, the trial participants stay on site in small groups for several days 
and there is a potential risk for spreading SARS-CoV-2 across the trial participant group or 
site staff. Some trial procedures, e.g., collecting blood samples, recording of ECGs, or 
assessing vital signs, may not allow keeping the recommended distance of 1.5 to 2 meters to 
prevent the transmission of SARS-CoV-2. A risk management procedure has been set up at 
the sites detailing specific cautionary measures (e.g., hygiene rules, wearing of face masks, 
and physical distance), which is filed in the investigator site file (ISF). The local requirements 
may be subject to change and the trial procedures will be adapted accordingly, if applicable.

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Drug-related risks and safety measures
The core safety pharmacology endpoints (cardiovascular, respiratory, and neurological 
function) were evaluated as part of a 26-week GLP repeat dose toxicity study in monkeys.
No mortality or adverse findings were associated with BI 3006337 administration in the 
neurological or respiratory function. Although a trend of BI 3006337 related increase in the 
heart rate was detected, it was considered non-adverse based on the lack of apparent dose-
related relationship and associated effects on other ECG parameters. This and other 
BI 3006337 related non-adverse effects were fully reversible after the 12-week recovery 
period.
The most prominent treatment-related effects were gastrointestinal effects including body 
weight loss and decreased body weight gain, which were associated with the reduced food 
consumption. In monkeys, the extent of the effect on the body weight was the most 
pronounced during the first 5 weeks of the treatment period and during the recovery period, 
marked body weight gain was observed. Similar effects including emesis have been shown 
with other GLP-1 agonists, and the up-titration method has been used to improve tolerability 
in the clinical trials.
Based on the injection site reactions observed in monkeys, local irritation in humans is 
possible. Monitoring the injection site is recommended in human trials.
Anticipated with the possible role of FGF21-signalling in skeletal homeostasis, there was a 
trend of slight decreases in bone formation markers (bone-specific alkaline phosphatase
[BALP] and osteocalcin [OC]) in monkeys, but no changes in bone resorption marker 
(carboxy-terminal collagen crosslinks [CTX-1]), bone density (Dual energy X-ray 
absorptiometry [DEXA] and micro-CT) or microscopic correlates. The nonclinical toxicology 
package did not indicate any adverse toxicities at doses providing high safety margins.
Assuming linear and dose-proportional pharmacokinetics, an accumulation of +10% with 
once weekly dosing (based on a half-life of 45 h) and based on the observed single dose 
parameters Cmax (1290 µg/L) and AUC0-∞(80600 µg*h/L) at 150 mg in trial 1466-0001, the 
steady state parameters at 150 mg are predicted as Cmax,ss =1290 µg/L* 1.1 = 1419 µg/L and 
AUCτ,ss = 80600 µg*h/L. Hence, these predicted exposures at the proposed dose levels in this 
MD trial are covered by sufficient margins in the toxicity studies (IB Section 5.3 and 8.3).
Biological agents have an inherent potential for immune-mediated effects with a variety of 
associated adverse effects, including immediate and delayed reactions. The risk of 
immunogenicity for BI 3006337 has been assessed in the SRD study in humans. So far there 
is no indication of an association between the development of ADAs in some healthy subjects 
and the overall reported AEs. However, the immunogenicity results at this stage of drug 
development, considering the low number of subjects and the short duration of the single-
dose trials, should be interpreted with caution. ADA generation and immunogenicity-related 
safety monitoring will continue in future trials with BI 3006337. Due to the s.c. 
administration, local intolerabilities may occur. Trial participants are exposed to risks of trial
procedures and risks related to the exposure to the trial medication.
Non-clinical safety pharmacology studies with BI 3006337 have neither identified adverse 
effects on respiratory nor cardiovascular function that would imply an increased risk in 
context of the COVID-19 pandemic. Based on the mechanism of action, BI 3006337 is not 

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expected to promote malfunction of the immune system resulting in an increased risk of 
progression of COVID-19 infection.
The following safety measures will be applied in this trial to minimize the risk for the trial 
participants:

Careful dose selection (refer to Section 4.1.2)

Preliminary measurement of BI 3006337 serum concentrations and preliminary 
determination of PK parameters

Subjects with conditions that may pose a safety risk in the trial will be excluded (refer 
to Section 3.3.3)

An extensive safety laboratory will be performed with special focus on full blood 
exam also including bone turnover biomarkers

For safety reasons, the drug administrations of each cohort in SRD part will be 
separated by at least 72 h (between last trial subject in the current cohort and first trial 
participant of the next cohort) to cover the period of highest risk/peak effect. 

A thorough ECG monitoring during in-house days and additionally on selected 
ambulatory visits

Although the risk of hypoglycaemic episodes is considered to be low for BI 3006337 
because of its mode of action (induction of glucose-dependent insulin-secretion), 
blood glucose will be monitored within predefined intervals after administration of 
the trial medication (see Flow Chart)

The trial participants will be monitored for vital signs and local tolerability at the 
injection site

During the stay on site, the trial participants will be under medical observation and 
thoroughly monitored for AEs such as systemic hypersensitivity reactions including 
anaphylactic reaction (refer to Section 4.1.4 and 4.2.1)

A documented safety review of all available safety data will be conducted at least 
prior to proceeding to multiple dose part.

In addition, a screening of SARSCoV2 has been implemented to be performed as part 
of the safety assessments at the screening visit (Visit 1). Trial participants positive in 
the results for this virus are not eligible for the trial in accordance with exclusion 
criterion 19 and will be excluded from the trial. During the ambulatory visits, trial 
participants are allowed to enter the site only after it was confirmed that trial 
participants do not have any signs or symptoms of infection (e.g., fever).
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure trial 
participants´ safety; see also Section 5.2.6.1.4.
Consistent with the FDA draft guidance intitled “Suicidal Ideation and Behavior:
Prospective Assessment of Occurrence in Clinical Trials,” due to a potential centrally 
mediated mechanism of action of the compound, prospective assessment of suicidal ideation 
and behaviour is included in the MD part of this trial.

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1.4.3
Discussion
In summary, BI 3006337 has the potential to become a s.c. treatment for NASH. Based on the 
mode of action, the pharmacological targets, the clinical experience of the separate 
components, and the nonclinical toxicology data as well as the implemented safety measures 
described above, trial participants 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. As of today, no pharmacological treatment has been approved for the 
treatment of NASH, particularly also for the more advanced fibrosis stages of NASH, which 
constitute a population with high unmet medical need. Therefore, the sponsor considers that 
the benefit outweighs the potential risks and justifies exposure to trial participants.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objectives of this trial are to investigate safety, tolerability, pharmacokinetics (PK), 
and pharmacodynamics (PD) of BI 3006337 in healthy male subjects following s.c.
administration of single rising doses and multiple doses over 6 weeks. 
2.1.2
Primary endpoint
The primary endpoint to assess safety and tolerability of BI 3006337 is the occurrence of any 
treatment-emergent adverse event assessed as drug-related by the investigator. This is 
expressed as the percentage of subjects treated with investigational drug who experience such 
an event.
2.1.3
Secondary endpoints
The following pharmacokinetic parameters will be determined if feasible:
SRD part:

AUC0-∞(area under the concentration-time curve of the analyte in serum over the time 
interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in serum)
MD part (after the last dose):

AUCτ,ss (area under the concentration-time curve of the analyte in serum over the 
dosing interval tau at steady state) after the last dose in Week 6

Cmax,ss (maximum measured concentration of the analyte in serum at steady state) after 
the last dose in Week 6

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2.2.2.1
Safety and tolerability
Safety and tolerability of BI 3006337 will be assessed based on:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure (BP), pulse rate (PR), and intra-axillary body temperature
(BT))

Local tolerability assessed by investigator

Columbia-Suicide Severity Rating Scale (C-SSRS) (MD part)

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
This single-rising dose and multiple dose trial is designed as blinded to subject (refer to 
Section 4.1.5), randomised, and placebo-controlled within parallel dose groups.
SRD part:
It is planned to include a total of 24 healthy male subjects in the single dosing part. The 
subjects will be assigned to 3 groups consisting of 8 subjects per group; the groups will be 
dosed sequentially (see Figure 3.1: 1). However, the addition of further dose groups for the 
evaluation of safety findings is subject to a substantial CTP amendment and requires approval 
by the competent authority.
MD part:
It is planned to include a total of 12 healthy male subjects in the multiple dosing part (see 
Table 3.1: 1).  Within this dose group, 9 subjects will receive BI 3006337 and 3 will receive 
placebo. Only one dose is tested within each dose group.
The trial schedule and design are depicted in Figure 3.1:1 below.
Figure 3.1: 1 Trial design
The dose groups to be evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups
Dose Group
1
2
3
4
Dose (mg)
50
100
150
150
Number of subjects
8
8
8
12
Subjects to receive placebo
2
2
2
3
Subjects to receive BI 3006337
6
6
6
9
In SRD part, the 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. The decision to treat the next dose group will be based upon safety of all the preceding 
dose groups. The next dose group will only be treated if, in the opinion of the investigator, no 
Dose Group 1
50 mg SD
Dose Group 4
150 mg MD
Dose Group 2
100 mg SD
Dose Group 3
150 mg SD

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safety concerns have arisen in the preceding dose groups, and if none of the pre-specified 
trial-specific stopping criteria have been met (refer to Section 3.3.4.1 and 3.3.4.3).
The decision proceeding to MD part will be based upon safety and tolerability of all the 
preceding dose groups in SRD part. MD part will only be treated if, in the opinion of the 
principal investigator and clinical trial leader (CT Leader), no safety concerns have arisen in 
the preceding dose groups, and if none of the pre-specified trial-specific stopping criteria 
have been met (refer to Section 3.3.4.1 and 3.3.4.3).
At minimum, data from 4 subjects who received active drug in each dose group need to be 
available for escalation to a higher dose. The minimum data set for review consists of the 
following:

AEs in the current and preceding dose groups up to at least 72 h after injection
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 at the site, as provided in the preliminary cardiac safety 
summary reports by the central ECG laboratory (see Section 5.2.4) in the current and 
preceding dose groups up to at least 72 h after start of injection

Vital signs in the current and preceding dose groups up to at least 72 h after injection

Clinical laboratory tests in the current and preceding dose groups up to at least 72 h 
after injection

Check of criteria for stopping subject treatment as per Section 3.3.4.1
A documented safety review of all available safety data will be conducted at least prior to 
proceeding to MD part. Safety reviews can be conducted face-to-face or by video/telephone 
conference. The CT 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 the CT 
Leader (or an authorised deputy) and will be filed in the investigator site file (ISF) and trial 
master file (TMF).
Furthermore, an unscheduled safety review meeting can be requested anytime by the 
principal investigator or the sponsor of the trial (for instance, due to the occurrence of any 
unforeseen adverse events).
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.

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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For single-rising dose and multiple dose trials, the sequential rising dose design described in 
Section 3.1 is widely established in Phase I clinical development and includes adequate 
measures to ensure subjects’ safety.
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 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.
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. 
SRD part: Each dose group consists of 8 subjects, with 6 randomised to active treatment, and 
2 randomised to placebo. For data analysis purposes, the placebo control group will include 
all subjects of all dose groups treated with placebo. 6 subjects per active treatment group are 
generally considered to be sufficient for the exploratory evaluation of pharmacokinetics. 
MD part: Each dose group consists of 12 subjects, with 9 randomised to active treatment, and 
3 randomised to placebo. For data analysis purposes, the placebo control group will include 
all subjects of all dose groups treated with placebo. 9 subjects per active treatment group are 
generally considered to be sufficient for the exploratory evaluation of pharmacokinetics. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 24 healthy males in SRD part and 12 healthy males in MD part will enter 
the trial. The actual number of subjects entered may exceed the total of 36 if additional 
intermediate doses are tested (see Section 3.1). Subjects will be recruited from the volunteers' 
pool of the trial site.
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.
3.3.1
Main diagnosis for trial entry 
The trial will be performed in healthy subjects.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.

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3.3.2
Inclusion criteria
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) Japanese ethnicity, according to the following criteria: born in Japan, have lived outside 
of Japan < 10 years, and have parents and grandparents who are Japanese
3) Age of 18 to 45 years (inclusive) 
4) BMI of 18.5 to 25.0 kg/m2 (inclusive) 
5) Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
6) Subjects who agree to minimise the risk of making their partner pregnant by fulfilling any 
of the following criteria starting from the start of injection of trial medication until 30 
days after end of injection of trial medication:
-
Use of adequate contraception, any of the following methods plus condom: 
intrauterine device, combined oral contraceptives that started at least 2 months 
prior to the first drug administration
-
Vasectomized (vasectomy at least 1 year prior to enrolment)
-
Surgical sterilization (including bilateral tubal occlusion, hysterectomy or bilateral
oophorectomy) of the subject’s female partner
-
Female partner is postmenopausal, defined as no menses for 1 year without an 
alternative medical cause
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1) Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2) Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or PR outside the range of
50 to 90 bpm at screening visit
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) Clinically relevant 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)

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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) Relevant chronic or acute infections (including positive result for human 
immunodeficiency virus (HIV), hepatitis A virus, hepatitis B virus, hepatitis C virus, and 
syphilis infection at screening)
10) History of tuberculosis (TB) or positive finding in interferon-gamma release assay 
(IGRA)
11) Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin
12) History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
13) 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)
14) 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
15) Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
16) Inability to refrain from smoking during in-house confinement
17) Alcohol intake (from signing of ICF to EOT)
18) Drug abuse or positive drug screening
19) Positive result for COVID-19 Antigen Rapid Test (Nasopharyngeal Swab) or clinical 
symptoms suggestive for this disease at screening visit
20) Blood donation of more than 200 mL within 30 days or 400 mL within 12 weeks, or 
plasmapheresis and platelet apheresis within 2 weeks prior to planned administration of 
trial medication or intended blood donation during the trial
21) Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
22) Inability to comply with the dietary regimen of the trial site
23) A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms in males or any other relevant ECG finding at screening
24) A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
25) 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 

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In addition, the following trial-specific exclusion criteria apply:
26) Male subjects with sperm donation from the administration of trial medication until 30 
days after administration of trial medication
27) Personal of family history of medullary thyroid carcinoma or history of multiple 
endocrine neoplasia syndrome type 2
28) Delayed gastric emptying (gastroparesis) or history of pancreatitis or bone disorders, bone 
trauma, fracture, and previous bone surgery in the last 2 months as well as subjects with 
risk for osteoporosis
29) GLP-1-agonist or FGF21-agonist treatment in the last 6 months prior to SCR
30) Any lifetime history of suicidal behaviour, any suicidal ideation of type 2 to 5 on the C-
SSRS in the past 12 months prior to screening (MD part only)
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may withdraw or may be removed from trial treatment or may withdraw consent to 
trial participation as a whole (‘withdrawal of consent’) with quite 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, trial data will be included in the CRF and will be reported in the CTR.
Following removal or withdrawal, a complete end-of-trial examination should be performed.
If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.6), the 
subject should, if possible, be questioned for AEs and concomitant therapies at or after the 
end of the REP to ensure collection of AEs and concomitant therapies throughout the REP, if 
not contrary to any consent withdrawal of the subject.
3.3.4.1
Withdrawal from trial treatment
An individual subject will be withdrawn from trial treatment if:
1) The subject wants to withdraw from trial treatment. The subject will be asked to explain 
the reasons but has the right to refuse to answer
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, the safety of the 
subject cannot be guaranteed as he / she 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

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4) The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events (AEs), or diseases)
5) An AE or clinically significant laboratory change, or abnormality occurs that the 
investigator assesses as warranting discontinuation of treatment. This may include cases 
of sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP >180/100 
mmHg), clinically relevant changes in ECG requiring intervention, or unexplained 
hepatic enzyme elevations at any time during the trial
6) 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
7) Occurrence of signs of suicidal behaviour or ideation (see section 5.2.5.2)
8) Occurrence of pancreatitis
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
If new safety information becomes available, Boehringer Ingelheim will review the benefit-
risk-assessment and, if needed, pause or discontinue the trial treatment for all subjects or take 
any other appropriate action to guarantee the safety of the trial subjects.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor and dose stopping criteria
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (if reason 4 is met, the trial should be discontinued immediately):
1) Failure to meet expected enrolment goals overall or at a particular trial site
2) The sponsor decides to discontinue the further development of the investigational product
3) Deviation from GCP, or the CTP, or the contract with BI impairing the appropriate 
conduct of the trial
4) New toxicological findings, serious AEs, or any safety information invalidating the 
earlier positive benefit-risk assessment (see Section 3.3.4.1)
The dose escalation of BI 3006337 will be stopped if:
5) More than 50% of the subjects at one dose level show drug related and clinically relevant 
adverse events of moderate or severe intensity, or if at least two subjects of the same dose 

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group have drug-related severe non-serious adverse events, or if at least one drug-related 
serious adverse event is reported  
6) At least 2 subjects who received active treatment at one dose level have relevant 
individual QT prolongations, i.e., a QTc increase of greater than 60 ms from baseline in 
connection with absolute QT or QTc greater than 500 ms, as confirmed by a repeat ECG 
recording
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
If some subjects do not complete the trial (including subjects non-evaluable for PK), they 
may be replaced if considered necessary to reach the objective of the trial. Subjects who 
withdraw or are withdrawn from treatment or assessments because of a drug-related adverse 
event will not be replaced. The Clinical Trial Leader together with the Trial Pharmacologist 
and the Trial Statistician are to decide if and how many subjects will be replaced. A 
replacement subject will be assigned a unique trial subject number and will be assigned to the 
same treatment as the subject he replaces.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Substance:
BI 3006337
Pharmaceutical formulation: Solution for injection
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
50 mg/mL (100 mg per vial)
Posology:
Single dosing
Mode of administration:
s.c.
Duration of use:
SRD part: Single dose, MD part: 6 weeks q.w. dosing 
The characteristics of the reference product (placebo) are given below:
Substance:
Placebo of BI 3006337
Pharmaceutical formulation: Solution for injection
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Not applicable
Posology:
Single dosing
Mode of administration:
s.c.
Duration of use:
SRD part: Single dose, MD part: 6 weeks q.w. dosing 
4.1.2
Selection of doses in the trial and dose modification
The doses in the trial were selected on the bases of the data obtained from Caucasian SRD 
trial (1466-0001) to allow ethnic comparison in PK and safety. 
The doses selected for this trial cover the subtherapeutic as well as the estimated therapeutic 
range and include a safety margin (see Section 1.2).
4.1.3
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups
according to their temporal availability. As soon as enough subjects are allocated to a dose 
group, the following subjects will be allocated to one of the other dose groups. Therefore, the 
allocation of subjects to dose groups 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.

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Subjects will be assigned to treatments (active treatment or placebo) prior to the first 
administration of trial medication. For this purpose, the randomisation scheme will be 
provided to the trial site in advance. Numbers of the randomisation scheme will be allocated 
to subjects with “first come first served” principle. Subjects are then assigned to treatment 
according to the randomisation scheme.
The randomisation procedure is described in Section 7.4.
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The dose volume for 
placebo corresponds to dose volume of the corresponding dose level.
Table 4.1.4: 1
BI 3006337 and placebo treatments, s.c. administration
Dose
group
Substance
Pharmaceutical form
Unit 
strength
Total dose
per 
injection
1
BI 3006337
Solution for injection
50 mg/mL
50 mg
2
BI 3006337
Solution for injection
50 mg/mL
100 mg
3
BI 3006337
Solution for injection
50 mg/mL
150 mg
4
BI 3006337
Solution for injection
50 mg/mL
150 mg
1-4
Placebo*
Solution for injection
--
--
* Subjects receiving placebo are equally distributed across dose groups 
The syringes containing the s.c. solutions for administration (BI 3006337 or placebo) will be 
prepared by qualified medical study personnel at the trial site under the responsibility of the 
investigator according to Instruction for Preparation and Administration of Parenteral study 
medication provided by the sponsor. The investigator can decide at any time to discontinue 
dosing in case of intolerability or safety concerns.
BI 3006337 or placebo will be administered by the investigating physician or authorised 
designee to the subject by s.c. injection into a lifted skin fold of the abdominal wall while 
lying in supine position. The injection needle has to be placed at a 45-degree angle and 
injected into the skin fold over at least 15 seconds. Skin is sanitized before injection. For 
administration, syringe sizes dependent on administered volume (e.g., Inject®-F/Inject®, B. 
Braun Melsungen, will be used. If the volume exceeds 2 mL the dose will be divided into two 
syringes and will be injected into two different injection sites on the same side of the 
abdominal wall. In the MD part, the subsequent doses should be administered on the alternate 
side of the abdominal wall. Following s.c. injection, the subject should remain in a supine
position for at least 30 minutes. Injection sites will be specified by naming the quadrant of the 
abdomen in which the injection will be done (upper right quadrant; upper left quadrant; lower 
left quadrant; lower right quadrant).
For drug administration, the so-called four-eye principle (two-person rule) should be applied. 
For this, one authorised employee of the trial site should witness the administration of trial 
medication, and – if applicable – its preparation (e.g., reconstitution), if correct dosage cannot 
be ensured otherwise.

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Administration of BI 3006337 or placebo will be performed by the investigator or authorised 
designee following an overnight fast, which is to start no later than 10 h before the scheduled 
dosing until at least 1,5h after dosing. Water may be consumed ad libitum except for 1 hour 
before and 1.5 hours after drug administration. Predefined meals will be served as outlined in 
Flow Chart.For restrictions with regard to diet, see Section 4.2.2.2.
In SRD part, subjects will be kept under close medical surveillance until at least 72 h after 
drug administration.
In MD part, subjects will be kept under close medical surveillance until at least 72 h after 
drug administration during hospitalisation and until at least 2 h after drug administration at
the ambulatory visits. Hypersensitivity reactions should be treated according to medical 
standards (see Section 4.2.1).
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
The trial is designed single-blind. The treatments administered (BI 3006337 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.
The table below summarises the masking/blinding level of individual functions, roles and 
responsibilities involved in the trial. 
Table 4.1.5.1: 1
Blinding level of individual functions
Role/function
Timing of Unblinding / receiving access to the treatment information 
(including rationale)
Subject/Participant
This trial is blinded to the subject /participant. The subject/participant’s 
treatment information will be provided to the site after the trial has 
completed.
Investigator/Site Staff
The randomisation scheme will be provided to the trial site prior to 
randomisation for preparation of medication.
Sponsor trial team
As requested during trial conduct. 
Bioanalytical Staff
As requested for analysis of bioanalytical samples.
Pharmacologist/
Pharmacometrician
As requested for analysis of pharmacokinetic, pharmacodynamic data or 
Pharmacometric modelling.

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Table 4.1.5.1: 1
Blinding level of individual functions (cont.)
Role/function
Timing of Unblinding / receiving access to the treatment information 
(including rationale)
ECG laboratory
Within the central ECG lab, the staff involved with interval 
measurements will be blinded with respect to subject, treatment, 
recording date and time as well as planned time points of the ECGs. The 
staff involved with the morphological analyses will be blinded with 
respect to treatment. For the quality control of the measurements, certain 
members of the ECG evaluation team will review the entire portfolio of 
ECG measurements for each subject blinded to date, time, and time 
point.
For preliminary cardiac safety reports for dose escalation decisions the 
central lab will be fully blinded.
During the time a role/function is blinded according to the table above, the randomisation 
schemes and medication kit lists (i.e., the treatment information) are kept restricted by the 
global Randomisation Team per Sponsor SOP.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.5.2
Unblinding and breaking the code
As this trial will be conducted single blind fashion, subjects’ treatment assignments will be 
known to investigators. Therefore, no emergency envelopes will be provided.
4.1.6
Packaging, labelling, and re-supply
4.1.6.1
BI 3006337 and placebo
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with the principles of Good Manufacturing Practice (GMP). 
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. Examples of the labels will be available in 
the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area 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 

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Clinical Research Associate (as provided in the list of contacts) is to be contacted 
immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the Institutional Review Board (IRB)

Availability of a signed and dated clinical trial contract between the sponsor or 
delegate and the investigational site

Approval/notification of the regulatory authority, e.g., competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
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 return 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 returned to the sponsor. Receipt, usage, and disposal of 
trial medication must be documented on the appropriate forms. Account must be given for 
any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Except for acetaminophen administration to perform the acetaminophen absorption test (see 
Section 4.2.1.1.1) and glucose administration to perform the OGTT (see Section 4.2.1.1.2) , 
no additional treatment is planned. However, in case of AEs in need of treatment, the 
investigator can authorize symptomatic therapy. In those cases, trial participants will be 
treated as necessary and, if required, kept under supervision at the trial site or transferred to a 
hospital until all medical evaluation results have returned to an acceptable level.

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Prolonged or severe gastrointestinal (GI) events
There are no special emergency procedures to be followed. Most frequent AEs of GLP-1 and 
FGF21 receptor agonists are nausea and vomiting. In case of prolonged or severe vomiting, 
the investigator will monitor serum creatinine, if deemed necessary. If nausea or vomiting are 
not amenable to conservative management, anti-emetics (e.g., dimenhydrinate, 
metoclopramide, granisetron, or ondansetron) may be administered at the investigator’s 
discretion.
Hypoglycaemic events
Symptoms of mild to moderate hypoglycaemia, or blood glucose levels below 49 mg/dL 
(measured using a bedside glucose test) can be treated by ingestion of carbohydrates (e.g.,
stepwise in defined amounts of 10 g). Typical clinical signs of mild or moderate 
hypoglycaemia include cold sweats, cool pale skin, nervousness or tremor, anxious feeling, 
unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive 
hunger, temporary vision changes, headache, nausea, and palpitations. Severe hypoglycaemia 
may lead to unconsciousness. Trial participants experiencing hypoglycaemia should remain 
confined until the symptoms have improved and resolved, blood glucose is within or above 
the normal range, and the investigating investigator deems the trial participant safe for 
discharge.
Hypoglycaemic events will be recorded as AEs if symptomatic, or if serum glucose levels 
(local safety laboratory) are below 54 mg/dL or blood glucose levels (bedside test) are below 
49 mg/dL (see Section 5.2.6.2.4).
Suicidality
In case of signals of suicidal ideation or behaviour, the Investigator should discontinue 
treatment with the trial medication, notify the Sponsor and the subject should be referred to 
an appropriate psychiatric clinic.
Systemic hypersensitivity
In case of any systemic hypersensitivity including anaphylactic reaction emerging during or
after injection(s) of trial medication, the investigator should:

Immediately stop further injections for this individual subject

Treat in accordance with severity of the reaction and local standard of care, with
systemic antihistamines, i.v. steroids, and in case of a severe allergic reaction (e.g., 
anaphylactic reaction), epinephrine

Draw a blood sample for the evaluation of IgE, histamine, serum tryptase, and 
complement components (see laboratory manual in the ISF)

Draw a blood sample for the evaluation of ADA
When a delayed hypersensitivity reaction is suspected, please draw a blood sample for
laboratory assessment and evaluate for signs of extra-cutaneous organ involvement. The
decision to discontinue treatment and/or restart treatment after resolution of the reaction
should be based on reaction type and severity.

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4.2.1.1
Non-investigational medicinal product
4.2.1.1.1
Acetaminophen Syrup
Table 4.2.1.1.1:1 below displays the characteristics of the non-investigational medicinal 
product for the acetaminophen absorption test performed in this trial.
Table 4.2.1.1.1:1
Characteristics of Acetaminophen Syrup
Substance:
Acetaminophen Syrup
Pharmaceutical formulation:
Solution
Unit strength:
20 mg per 1 mL
Posology:
Single doses on Day -1, Day 2, and Day 44 of Visit 
2 (MD part only) 
Route of administration:
Oral
Frequency of dosing:
Single doses
Calonal Syrup 2% will be supplied as commercially available product by a public pharmacy
(R23-4465). Transport and storage are under the responsibility of the investigator and must 
comply with the pertinent information in the prescribing information of the drug product used 
in the clinical trial. No additional labelling is planned.
Documentation on the commercial drug product, containing at least the following 
information, must be available on-site in the ISF:

BI trial number

Investigator name

Trade name of drug product

Substance International non-proprietary name

Holder of marketing authorization

Pharmaceutical dosage form, quantity of dosage units

Storage conditions

Use-by date

Batch/lot number

Point of purchase

Date of receipt

Recipient (name and function)
In addition, documentation of drug purchase, including identification of the drug product and 
quantity, must be available at the clinical site and filed in the ISF.
4.2.1.1.2
TRELAN-G75
Table 4.2.1.1.2:1 below displays the characteristics of the non-investigational medicinal 
product for the oral glucose tolerance test performed in this trial.

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Table 4.2.1.1.2:1
Characteristics of TRELAN-G75
Substance:
Carbohydrate solution
Pharmaceutical formulation:
Solution
Unit strength:
75 mg per bottle (225 ml)
Posology:
SRD part: Single doses on Day -1 and Day 2 of 
Visit 2
MD part: Single doses on Day -1, Day 2, and 
Day 44 of Visit 2 
Route of administration:
Oral
Frequency of dosing:
Single doses
TRELAN-G75 will be supplied as commercially available product by a public pharmacy
(R23-4466). Transport and storage are under the responsibility of the investigator and must 
comply with the pertinent information in the prescribing information of the drug product used 
in the clinical trial. No additional labelling is planned.
Documentation on the commercial drug product, containing at least the following 
information, must be available on-site in the ISF:

BI trial number

Investigator name

Trade name of drug product

Substance International non-proprietary name

Holder of marketing authorization

Pharmaceutical dosage form, quantity of dosage units

Storage conditions

Use-by date

Batch/lot number

Point of purchase

Date of receipt

Recipient (name and function)
In addition, documentation of drug purchase, including identification of the drug product and 
quantity, must be available at the clinical site and filed in the ISF.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on trial days) on the appropriate pages of the CRF.

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4.2.2.2
Restrictions on diet and lifestyle
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. 
For s.c. administration of the trial medication (BI 3006337 or placebo), the subject will be 
fasting within at least 10 hours before and 1.5 h after dosing. During this fasting period, 
liquid intake will be limited to water, which may be consumed ad libitum apart from 1 hour 
before and 1.5 h after drug administration. On other days, subjects are allowed to have an 
evening Snack (voluntary).
Furthermore, no food is allowed within at least 12 h before and 4 h after each OGTT or 
intake of acetaminophen for testing gastric emptying.
From 1 h before start of each OGTT/acetaminophen intake until lunch (4h after start), fluid
intake is restricted to the liquid administered with OGTT or acetaminophen, and an additional
240 mL of water served at 2 h after start.
Total fluid intake should be at least 1.5 litres and should not exceed 3.5 litres.
Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products including St. John's wort (Hypericum perforatum) are not permitted starting 
5 days before the BI 3006337 application until the EOT examination.
Alcoholic beverages must not be consumed from signing the ICF until end of treatment 
(EOT). Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks and 
chocolate) are not allowed from 12 h before until 8 h after administration of trial medication 
(BI 3006337 or placebo).
Excessive physical activity (such as competitive sport) should be avoided starting 5 days 
before the BI 3006337 application until the EOT 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 trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable. No efficacy endpoints will be evaluated in this trial.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height, and body weight, 
smoking and alcohol history (alcohol history 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, and intra-axillary body temperature), 12-lead 
ECG, laboratory tests, and a physical examination. At the end of trial examination, it will 
include review of vital signs, 12-lead ECG, laboratory tests, and a physical examination 
including determination of body weight and potential injection site reactions as well as 
recording of AEs and concomitant therapies.
5.2.2
Vital signs
Systolic and diastolic BPs as well as HR (heart rate is considered to be equal to pulse rate) 
will be measured by a BP monitor 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. Intra-axillary 
body temperature will also be measured.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required. The parameters to be assessed are listed in Tables 5.2.3: 1, 5.2.3: 2, and 5.2.3: 3. 
Reference ranges will be provided in the ISF.
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.

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Table 5.2.3: 1
SRD Part: Routine laboratory tests
Functional lab 
group
BI test name [comment/abbreviation]
A
B
C
D
E
F
Haematology
Haematocrit
X
X
X
--
X
X
Haemoglobin
X
X
X
--
X
X
Red Blood Cell Count/Erythrocytes
X
X
X
--
X
X
Reticulocytes, absol.
X
X
X
--
X
X
White Blood Cells/Leucocytes
X
X
X
--
X
X
Platelet Count/Thrombocytes (quant)
X
X
X
--
X
X
Glycosylated haemoglobin A1c (HbA1c)
X
--
--
--
--
--
Automatic WBC 
differential
relative and 
absolute)
Neutrophils
X
X
X
--
X
X
Eosinophils
X
X
X
--
X
X
Basophils
X
X
X
--
X
X
Monocytes
X
X
X
--
X
X
Lymphocytes
X
X
X
--
X
X
Manual 
differential WBC 
(if automatic
differential WBC 
is abnormal)
Neut. Poly (segs); Neut. Poly (segs), relat.; 
Neutrophils Bands; Neutrophils Bands, relat.; 
Eosinophils/Leukocytes; Eosinophils, relat.; Basophils/ 
Leukocytes; Basophils, relat.; Monocytes/ Leukocytes; 
Monocytes, relat.; Lymphocytes/Leukocytes; 
Lymphocytes, relat.
X
X
X
--
X
X
Coagulation
Activated Partial Thromboplastin Time 
X
X
X
--
X
X
Prothrombin time – INR (International Normalization 
Ratio)
X
X
X
--
X
X
Enzymes
AST [Aspartate aminotransferase] /GOT, SGOT
X
X
X
--
X
X
ALT [Alanine aminotransferase] /GPT, SGPT
X
X
X
--
X
X
Alkaline Phosphatase (ALP)
X
X
X
--
X
X
Gamma-Glutamyl Transferase (GGT)
X
X
X
--
X
X
Creatine Kinase [CK]
X
X
X
--
X
X
Creatine Kinase Isoenzyme MB [only if CK is elevated]
X
X
X
--
X
X
Insulin
--
--
--
X
--
--
Lactate Dehydrogenase
X
X
X
--
X
X
Lipase
X
X
X
--
X
X
Amylase
X
X
X
--
X
X
Hormones
Thyroid Stimulating Hormone (TSH)
X
--
--
--
--
--
A: parameters to be determined at Visit 1 (SCR examination) 
B: parameters to be determined at Visit 2 on Day -1
C: parameters to be determined at Visit 2 on Days 1, 2, 3, 4, 8, and 15
D: parameters to be determined at Visit 2 on Day 6
E: parameters to be determined at Visit 2 on Days 22 and 29
F: parameters to be determined at Visit 3 (EOT examination)

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Table 5.2.3: 1
SRD part: Routine laboratory tests (cont.)
Functional lab 
group
BI test name [comment/abbreviation]
A
B
C
D
E
F
Substrates
Glucose
X
X
X
X
--
X
Creatinine
X
X
X
--
--
X
Bilirubin, Total
X
X
X
--
--
X
Bilirubin, Direct
X
X
X
--
--
X
C-Peptide
--
--
--
X
--
--
Protein, Total
X
X
X
--
--
X
C-Reactive Protein (Quant)  
X
X
X
--
--
X
Uric Acid
X
--
X
--
--
X
Cholesterol, total 
X
--
X
--
--
X
Triglyceride
X
--
X
--
--
X
High density lipoprotein (HDL) cholesterol
X
--
X
--
--
X
Low density lipoprotein (LDL) cholesterol
X
--
X
--
--
X
Electrolytes
Sodium
X
X
X
--
--
X
Potassium
X
X
X
--
--
X
Calcium
X
X
X
--
--
X
Inorganic phosphate
X
X
X
--
--
X
Urinalysis (Stix)
Urine Nitrite (qual)
X
X
X
--
--
X
Urine Protein (qual)
X
X
X
--
--
X
Urine Glucose (qual)
X
X
X
--
--
X
Urine Ketone (qual)
X
X
X
--
--
X
Urobilinogen (qual)
X
X
X
--
--
X
Urine Bilirubin (qual)
X
X
X
--
--
X
Urine RBC/Erythrocytes (qual)
X
X
X
--
--
X
Urine WBC/Leucocytes (qual)
X
X
X
--
--
X
Urine pH
X
X
X
--
--
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite 
or protein are 
abnormal in urine)
Only positive findings will be reported (for instance, 
the presence of sediment bacteria, casts in sediment, 
squamous epithelial cells, erythrocytes, leukocytes)
X
X
X
--
--
X
A: parameters to be determined at Visit 1 (SCR examination) 
B: parameters to be determined at Visit 2 on Day -1
C: parameters to be determined at Visit 2 on Days 1, 2, 3, 4, 8, and 15
D: parameters to be determined at Visit 2 on Day 6
E: parameters to be determined at Visit 2 on Days 22 and 29
F: parameters to be determined at Visit 3 (EOT examination)

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Table 5.2.3: 2
MD Part: Routine laboratory tests
Functional lab group
Test name
A
B
Haematology
Haematocrit
X
X
Haemoglobin
X
X
Red Blood Cell Count/Erythrocytes
X
X
Reticulocytes, absol.
X
X
White Blood Cells/Leucocytes
X
X
Platelet Count/Thrombocytes (quant)
X
X
HbA1c
X
X
Automatic WBC 
differential (relative and 
absolute)
Neutrophils
X
X
Eosinophils
X
X
Basophils
X
X
Monocytes
X
X
Lymphocytes
X
X
Manual differential WBC 
(if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), relat.; 
Neutrophils Bands; Neutrophils Bands, relat.; 
Eosinophils/Leukocytes; Eosinophils, relat.; 
Basophils/Leukocytes; Basophils, relat.; 
Monocytes/Leukocytes; Monocytes, relat.; 
Lymphocytes/Leukocytes; Lymphocytes, relat.
X
X
Coagulation
Activated Partial Thromboplastin Time
X
X
Prothrombin time – INR (International 
Normalization Ratio)
X
X
Enzymes
AST/GOT, SGOT
X
X
ALT/GPT, SGPT
X
X
ALP
X
X
GGT
X
X
CK
X
X
CK Isoenzyme MB [only if CK is elevated]
X
X
Insulin
X
X
Lactate Dehydrogenase
X
X
Lipase
X
X
Amylase
X
X
Calcitonin
X
--
Hormones
TSH
X
X*
Urinalysis (Stix)
Urine Nitrite (qual)
X
X
Urine Protein (qual)
X
X
Urine Glucose (qual)
X
X
Urine Ketone (qual)
X
X
Urobilinogen (qual)
X
X
Urine Bilirubin (qual)
X
X
Urine RBC/Erythrocytes (qual)
X
X
Urine WBC/Leucocytes (qual)
X
X
Urine pH
X
X
A: parameters to be determined at Visit 1 (screening examination) and Visit 3 (EOT examination)
B: parameters to be determined at Visit 2 on Day -1, 2, 3, 4, 8, 15, 18, 29, 36, 43, and 46 (*with the exception 
that TSH will only be tested at Day -1, 15, and Day 46)

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Table 5.2.3: 2
MD part: Routine laboratory tests (cont.)
A: parameters to be determined at Visit 1 (screening examination) and Visit 3 (EOT examination)
B: parameters to be determined at Visit 2 on Day -1, 2, 3, 4, 8, 15, 18, 29, 36, 43, and 46 (*with the exception 
that TSH will only be tested at Day -1, 15, and Day 46)
The tests listed in Table 5.2.3: 3 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. Infectious serology test is planned to be performed at screening only. Drug screening 
and COVID-19 Antigen Rapid Test (Nasopharyngeal Swab) will be performed at SCR and
before each admission to the site (Day -2 of Visit 2 for SRD part and Day -2 of Visit 2 and 
Day 43 of Visit 2 for MD part).
Functional lab group
Test name
A
B
Substrates
Glucose
X
X
Creatinine
X
X
Bilirubin, Total
X
X
Bilirubin, Direct
X
X
C-Peptide
X
X
Protein, Total
X
X
C-Reactive Protein (Quant)
X
X
Uric Acid
X
X
Cholesterol, total
X
X
Triglyceride
X
X
High density lipoprotein (HDL) cholesterol
X
X
Low density lipoprotein (LDL) cholesterol
X
X
Electrolytes
Calcium
X
X
Sodium
X
X
Potassium
X
X
Inorganic phosphate
X
X
Urine sediment (microscopic 
examination if erythrocytes, 
leukocytes nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (for 
instance, the presence of sediment bacteria, 
casts in sediment, squamous epithelial 
cells, erythrocytes, leukocytes)
X
X

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Table 5.2.3: 3
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Alcohol
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/Ecstasy
Opiates 
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis A antibodies (qualitative)
Hepatitis B surface antigen (qualitative)1
Hepatitis B core antibody (qualitative)1
Hepatitis B surface antibody (qualitative)1
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
TB test (IGRA: QuantiFERON® Gold assay/T-SPOT®.TB)
Syphilis test (RPR, TP antibody method)
COVID-19 infection
COVID-19 Antigen Rapid Test (Nasopharyngeal Swab)
1 If hepatitis B surface antigen and/or hepatitis B core antibody is positive, subject will be not allowed 
participating in this trial. If hepatitis B surface antibody is positive, hepatitis B surface antigen and hepatitis B 
core antibody is negative, and there is evidence that subject gets hepatitis B virus vaccine, subject will be 
allowed participating in this trial.
To encourage compliance with alcoholic restrictions, a breath alcohol test will be performed 
prior to each treatment period and may be repeated at any time during the trial at the 
discretion of an investigator or designee. The results will not be included in the CTR.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
It is the responsibility of the Investigator to evaluate the laboratory reports. Clinically 
relevant abnormal findings as judged by the Investigator are to be reported as adverse events 
(please refer to Section 5.2.6). 
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4).

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5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph at the time points given in the Flow Chart. Electrode 
placement will be performed according to the method of Wilson, Goldberger and Einthoven 
modified by Mason and Likar (hips and shoulders instead of ankles and wrists). Precise 
electrode placement will be marked with an indelible mark on the skin to allow reproducible 
placement throughout the trial.
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 trial procedures scheduled for 
the same time (except for blood drawing from an intravenous cannula that is already in place) 
to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e., three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. 
Storing
All ECGs will be stored electronically in the system provided by the central ECG lab and 
stored as print outs.
Data transfer
For time points specified in the Flow Chart, ECGs will be transferred electronically to the 
central ECG lab<
> for evaluation (per dose group for 
preliminary data analysis and at the end of trial for final evaluation).
In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded. 
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).

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Evaluation
a) Central ECG lab
Central ECG lab evaluation will be performed per time point as specified in the Flow 
Chart. 
This will include the determination of cardiac QRS-axis as assessed by the ECG 
machine’s algorithm as well as the intervals RR, PR, QRS and QT measured semi-
automatically.
The preliminary cardiac safety summary reports from the central lab, which are 
required for dose escalation meetings, will be based on a statistical analysis of the 
automatically determined cardiac intervals (HR, QT/QTc, PR, and QRS) from the 
respective ECG machines. In case of unreliable measurements, a preliminary manual 
adjudication may be performed and will be noted in the respective report, where 
applicable.
HR and the QT interval corrected for HR (QTc e.g., QTcF and QTcB) will be 
determined by the sponsor (see Trial Statistical Analysis Plan (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 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 locally printed 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 trial, the QT and QTcF values generated by the computerised 
ECG system or their manual corrections by the investigators will be used. In doubtful 
cases, ECGs may be sent upfront (i.e., prior to the regular data transfer) for 
cardiologic assessment by the central lab. In this case, these centrally measured results 
would overrule any other results obtained.

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Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (if identified at the screening
visit) if judged clinically relevant by the investigator.
Any ECG abnormalities will be monitored carefully and, if necessary, the subject will be 
removed from the trial and will receive the appropriate medical treatment. 
5.2.5
Other safety parameters
5.2.5.1
Local tolerability
Assessment of injection site should be performed after s.c. drug administration, at the 
timepoints indicated in Flow Chart, and more frequently, if deemed necessary by the 
investigator. For assessment, the quadrant of the injection site will be captured in the eSource 
after injection. Local tolerability will be assessed by the investigator or authorised designee 
according to ‘swelling’, ‘induration’, ‘heat’, ‘redness’, ‘pain’, or ‘other findings’. Injection 
site reactions with clinically relevant findings must be recorded as AE. The diameter of the 
affected area will be measured. Digital photography should be used by the investigator to 
document clinically relevant injection site reactions.
5.2.5.2
Suicidality assessment
At the time points, specified in the Flow Chart, potential suicidality or suicidal ideations will 
be assessed using the ‘Columbia-Suicide Severity Rating Scale (C-SSRS). The C-SSRS is a 
semi-structured interview which was developed to assess both suicidal behaviour and suicidal 
ideation to address the need for a summary measure to track change in the severity of 
suicidality across both clinical settings and treatment trials. Two versions of the C-SSRS will 
be used in this study: the ‘Baseline/ Screening’ version and the ‘Since-last-visit’ version. The 
‘Baseline/ Screening’ questionnaire will be used at the Screening visit and the ‘Since-last-
visit’ questionnaire will be used at the rest of the visits including EOT. The C-SSRS 
interview may be administered by any type of physician, psychologist, clinical social worker, 
mental health counsellor, nurse, or coordinator with C-SSRS training. It has a typical duration 
of 5 minutes and causes only a low burden on subjects. At a minimum, the interview consists 
of 2 screening questions related to suicidal ideation and 4 questions related to suicidal 
behaviour and may be expanded to up to 17 items in case of positive responses. Free text 
entries are allowed. The investigator has to directly evaluate the scale and write a report 
considering plausibility and clinical relevance of results. Doubtful outcomes may be repeated, 
or reports may be validated by a consulting psychiatrist. If there is a confirmed positive report 
of suicidal behaviour or suicidal ideation type 2, 3, 4 or 5 after start of trial, the investigator is 
to immediately interview the patient during the clinic visit. If the investigator did not 
administer the C-SSRS leading to the positive report, he/she has to consult a psychiatrist, if 
considered necessary. If the positive report is confirmed, appropriate actions for the patient’s 
safety have to be initiated.
For each report of suicidal ideation type 1, 2 or 3 after start of the trial, the investigator has to 
decide, based on his/her clinical judgment, whether it represents an AE as defined in the 
protocol, and, if it is considered to be an AE, reported it accordingly.

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All C-SSRS reports of suicidal ideation type 4 to 5 and all reports of suicidal behavior must 
be reported as SAEs by the investigator and appropriate actions must be taken.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
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.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 

Requires inpatient hospitalisation, or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the subject and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse

An event that possibly leads to disability will be handled as ‘deemed serious for any 
other reason’ and, therefore, reported as an SAE.

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5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of 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. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described Section 5.2.6.2.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in Section 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.
5.2.6.1.4
Adverse events of special interest
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.
Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is defined by any
of the following alerts (alterations) of hepatic laboratory parameters that occur after the first
dose of IMP: 
1.
AST or ALT elevation ≥3 × ULN and total bilirubin ≥2 × ULN measured at the same 
visit, or in samples drawn within 30 days of each other, OR
2.
AST or ALT elevation ≥3 × ULN and INR ≥1.5 × ULN measured at the same visit, or in 
samples drawn within 30 days of each other, OR
3.
AST or ALT elevation ≥3 × ULN with new onset, or worsening of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%), 
OR
4.
AST or ALT elevation ≥5 × ULN
These laboratory findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF. 
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy,
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without laboratory 
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 

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the criteria of hepatic injury alert, the procedures described in the DILI checklist should be 
followed.
Additionally, with subjects having a normal AST and ALT at baseline, the emergence of an 
isolated AST or ALT elevation between ≥3-fold and <5 × ULN requires repeat testing within 
72 hours. DILI Checklist is not required unless repeat testing trigger alerts 1, 2, 3, or 4.
The following events should lead to immediate discontinuation of trial IMP (active or 
placebo):

Hepatic injury alert number 1, 2 or 3

Hepatic injury alert number 4, if persists >2 weeks

AST or ALT elevation >8 × ULN
Following completion of the DILI Checklist, if the Boehringer Ingelheim IMP cannot be 
excluded as a possible cause of the DILI event, discontinuation should be made permanent 
without rechallenge. If an alternate causality, e.g., acute viral hepatitis, is confirmed by the 
DILI Checklist evaluation, Boehringer Ingelheim IMP may be re-started, if warranted.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
5.2.6.1.6
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, 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)

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
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

There is an alternative explanation (e.g., situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs. 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 to describe an AE more precisely.
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
(the End of Study (EOT) visit): 
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 

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these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF 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 trial treatment related SAEs 
and trial treatment related AESIs of which the investigator may become aware 
of by any means of communication, e.g., phone call. Those AEs should be 
reported on the BI SAE form (see Section 5.2.6.2.2), but not on the CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 
24 hours of becoming aware of the event, the country specific reporting process will be 
provided in the ISF. The same timeline applies if follow-up information becomes available. 
On specific occasions, the Investigator could inform the sponsor upfront via telephone. This 
does not replace the requirement to complete and send 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. All (S)AEs, including those persisting after the individual subject’s end of trial, 
must be followed up until they have resolved, have been sufficiently characterized (e.g., as 
‘chronic’ or ‘stable’), or no further information can be obtained.
5.2.6.2.3
Pregnancy
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 was obtained.
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 form 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.
5.2.6.2.4
Hypoglycaemia
Hypoglycaemic events will be recorded as AEs if symptomatic if serum glucose levels (local 
safety laboratory) are below 54 mg/dL or blood glucose levels (bedside glucose test) are 
below 49 mg/dL.

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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be used for determination of 
pharmacokinetic parameters.
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for BI 3006337 pharmacokinetic analysis
For quantification of BI 3006337 concentrations in serum, 3.5 mL of blood will be drawn 
from an antecubital or forearm vein into a serum (SST_II_Advance_tube) blood drawing tube 
at the times indicated in Flow Chart. 
Details on PK sample collection, processing, handling, and shipment are provided in the 
Laboratory Manual. 
After analysis, the serum samples may be used for further methodological investigations
(e.g., for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. However, only data related to the analyte 
including anti-drug antibodies (if applicable) will be generated by these additional 
investigations. The trial samples will be discarded after completion of the additional 
investigations, but not later than 5 years after the CTR is archived.
5.3.2.2
Blood sampling for ADA/Nab analysis
For assessment of ADA and Nabs to BI 3006337, 3.5 mL of blood will be taken from an 
antecubital or forearm vein into a serum (SST_II_Advance_tube) blood drawing tube at the 
times indicated in Flow Chart. Data regarding Nabs may not be part of the CTR.
Details on ADA and Nab sample collection, processing, handling, and shipment are provided 
in the Laboratory Manual. 
The samples may be used to further characterize ADA/Nab response or to address Health 
Authority questions regarding the results/methodology, however only data related to the 
ADA/Nabs will be generated by these addition investigations. The study samples will be 
discarded no later than 5 years after the final study report has been generated.

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5.3.4
Pharmacokinetic – pharmacodynamic relationship
Exposure-response relationships may be investigated graphically for selected PK parameters
(e.g. Cmax,ss and AUCτ,ss) and selected PD, safety/tolerability endpoints including gastric
emptying, nausea/vomiting, and HR. If it is considered necessary to further investigate a
particular relationship, exposure-response model(s) will be developed. This pharmacometric
analysis will then not be part of the CTR but will be reported separately.
5.4
ASSESSMENT OF BIOMARKERS
5.4.1
Biochemical and cellular biomarkers
Blood samples will be collected for the analysis of exploratory biomarkers at visits specified 
in Flow Chart. The change from baseline measurements may include the following:

Adiponectin (HMW and total)

Glucagon

Markers for bone formation: 

Procollagen Type 1 N-terminal Propeptide (P1NP)

Bone-specific Alkaline Phosphatase (BALP)

Osteocalcin (OC)

Marker for bone resorption:

Carboxy-terminal Collagen Crosslinks (CTX-1)
5.4.2
Methods and timing of sample collection
For the measurement of the exploratory biomarkers, 18 ml of blood will be drawn from an 
antecubital or forearm vein at the time points indicated in the Flow Chart. Blood will be 
withdrawn by means of either an indwelling venous catheter or by venipuncture with a metal 
needle.
The trial samples will be discarded after completion of any investigations, but not later than
2 years after the final trial report has been signed. Any leftover samples or derived material
from pre-specified analyses may be used for method development/validation but will be

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destroyed no later than 2 years after the final trial report has been signed. Exceptions are
remainders of trial samples for which a participant has voluntarily accepted a biobanking
option and has provided a signed ICF (see Section 5.5).
Detailed instructions for biomarker blood sampling, processing, and shipment of the different 
biofluids are provided in a laboratory manual. All lab kit supplies will be provided by the 
central lab vendor designated by the sponsor.
5.5
BIOBANKING
Blood samples will be collected for biobanking. Participation in biobanking is voluntary and 
not a prerequisite for participation in the trial. Biobanking will only occur after a separate 
biobanking informed consent has been given in accordance with local ethical and regulatory 
requirements.
To be able to address future scientific questions, trial participants will be asked to voluntarily
donate biospecimens for banking. If the trial participant agrees, banked samples may be used 
for future biomarker research and drug development projects, e.g., to identify subjects that 
are more likely to benefit from a treatment or experience an AE, or to gain a mechanistic or 
genetic understanding of drug effects and thereby better match subjects with therapies. 
Samples will be stored for testing for a period consistent with local regulations.
5.5.1
Methods and timing of sample collection
Detailed instructions on sampling, preparation, processing, shipment, and storage are 
provided in the laboratory manual. Samples will be collected prior to the IMP administration. 
For sampling timepoints, see Flow Chart.
Approximately 8.5 mL blood will be drawn for DNA, 4 mL for plasma and 8.5 mL serum 
banking purposes. Any analyses on DNA or plasma/serum samples will not be reported in the 
main CTR. Samples will be collected only where all applicable local regulatory and ethics 
approvals have been obtained for biobanking.
5.6
OTHER ASSESSMENTS
As indirect PD responses to study drug administration, glucose and insulin in plasma in the 
OGTT as well as endpoints of acetaminophen in the acetaminophen absorption test (MD part
only) are measured and derived at ‘baseline’ on Day -1 of Visit 2 and post-dose on Day 2 and 
Day 44 (MD part only) of Visit 2.

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Endpoints for the exploratory evaluation of the pharmacodynamics of BI 3006337 are:

Change of plasma glucose, plasma insulin and plasma C-peptide (AUEC0-2 and 
AUEC0-4) during an oral glucose tolerance test (OGTT) following administration of
BI 3006337 relative to placebo and an OGTT conducted at baseline

change from baseline in Homeostasis Model of Assessment regarding insulin 
resistance (HOMA-IR) and regarding β cell function (HOMA-ß) derived from insulin 
and glucose values obtained during OGTT.

Change in acetaminophen absorption (AUC0-10, Cmax and tmax) following 
administration of BI 3006337 relative to placebo and an absorption test conducted at 
baseline as an indirect determination of the gastric emptying rate
5.6.1
Oral glucose tolerance test
An OGTT will be performed on Day -1, Day 2, and Day 44 (MD part only) of Visit 2.
For the OGTT, a commercially available and ready-prepared glucose solution (TRELAN-
G75, see Section 4.2.1.1.2 for details) will be used. Glucose administration will be performed 
following an overnight fast, which is to start no later than 12 h before the scheduled glucose 
intake. Before each OGTT subjects are told to empty their bladders. After blood drawing for 
determination of fasting glucose and insulin in plasma, 225 mL of this glucose solution 
containing 75 g glucose will be swallowed by the subject, while in a sitting or standing
position, under supervision of the investigating physician or an authorised designee.
The glucose solution should be ingested within 3 minutes. At the predefined time points
before and after glucose intake indicated in the Flow Chart, blood samples for the
determination of plasma glucose and insulin will be collected.
Subjects will be kept under close medical surveillance until after at least 4h following glucose 
administration. During the first 4 hours after glucose intake, subjects will be confined to bed 
in a half-supine position unless supine positioning is required for trial-related measurements
(e.g., recording of vital signs). For restrictions with regard to diet see Section 4.2.2.2.
Refer to Sections 5.6.1.1.1 and 5.6.1.1.2 for details on blood collection and sample work-up.
Additionally, the following indices of insulin secretion and sensitivity will be derived:
HOMA-IR and HOMA-β% will be calculated from insulin and glucose values according to
the calculations below:
HOMA − IR = (FPI [mU/L] ∗FPG[mmol/L])/22.5
HOMA − β% = (20 ∗FPI [mU/L]) / (FPG [mmol/L] – 3.5) ∗100.
5.6.1.1
Sampling for OGTT
5.6.1.1.1
Plasma glucose
For determination of plasma glucose, blood samples of 2 mL will be drawn from an
antecubital or forearm vein into NaF (sodium fluoride) blood drawing tubes at times
indicated in the Flow Chart. Blood will be withdrawn by means of either an indwelling
venous catheter or by venipuncture with a metal needle.

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The plasma samples will be discarded after completion of the investigations but not later than 
2 years upon the final study report has been signed. The final instruction of blood sampling 
and processing will be written in a Laboratory Manual.
5.6.1.1.2
Plasma insulin
For quantification of insulin in plasma, 3 mL of blood will be collected from
an antecubital or forearm vein into an K3-EDTA (ethylenediaminetetraacetic acid)-
anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will be
withdrawn by means of either an indwelling venous catheter or by venipuncture with a metal
needle.
The plasma samples will be discarded after completion of the investigations but not later than 
2 years upon the final study report has been signed. The final instruction of blood sampling 
and processing will be written in a Laboratory Manual.
5.6.2
Acetaminophen absorption test
An acetaminophen absorption test will be performed on Day -1, Day 2, and Day 44 of Visit 2
for MD part only. The acetaminophen absorption test investigates the gastric emptying rate. 
For the test, commercially available liquid acetaminophen will be used (Acetaminophen
syrup, see Section 4.2.1.1.1 for details). Calonal Syrup 2% (concentration 20 mg/1 mL) to be 
used as 31 mL to make 620 mg acetaminophen will be administered orally to the trial 
participant, while in a sitting or standing position, under supervision of the investigating 
physician or an authorised designee. The acetaminophen syrup should be ingested within 3 
minutes. The so-called four-eye principle (two-person rule) should be applied for 
acetaminophen administration and – if applicable – its preparation if correct dosage cannot be 
ensured otherwise. Administration will be performed following an overnight fast, which is to 
start not later than 12 h before the scheduled acetaminophen dosing. For restrictions with 
regard to diet see Section 4.2.2.2. Subjects will be kept under close medical surveillance until 
after at least 10 h following acetaminophen administration. During the first 4 hours after 
acetaminophen intake, subjects will be confined to bed in a half-supine position unless supine 
positioning is required for trial-related measurements. At the predefined time points indicated 
in the Flow Chart before and after acetaminophen administration, blood samples for the 
determination of acetaminophen plasma concentrations will be collected. Refer to Section 
5.6.2.1 for details on blood collection and sample work-up and Section 5.6.2.2 for analytics.
5.6.2.1
Plasma sampling for acetaminophen absorption test
For quantification of acetaminophen plasma concentrations, 1 mL of blood will be taken from
an antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetic

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acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will
be withdrawn by means of either an indwelling venous catheter or by venepuncture with a
metal needle. Immediately after drawing the tubes will gently be inverted 5 - 10 times. The 
sample will be put on wet ice bath in an upright position until centrifugation.
The final instruction of blood sampling and processing will be written in a Laboratory 
Manual. 
At a minimum, the sample tube labels should list the following information: BI trial number,
subject number, visit, and planned sampling time. Further information such as matrix and
analyte may also be provided.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed to monitor subjects’ safety and to determine pharmacokinetic and biomarker
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 a s.c. 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. The biomarkers outlined in Section 5.4 are of 
exploratory nature.

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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.
Trial 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, and laboratory tests 
will be ± 30 min on Day -1 and for the first 72 h after trial drug administration, except for
urine safety laboratory tests, which can be obtained in the morning of the given day. Starting 
from 96 h post-trial drug administration, a deviation from the scheduled time for all the 
planned trial activities of ± 120 min is acceptable, except for urine safety laboratory tests, 
which can be obtained in the morning of the given day.
If several activities are scheduled at the same time point in the Flow Chart, ECG should be 
the first and meal the last activity. Furthermore, if several measurements including 
venepuncture are scheduled for the same time, venepuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on physiological 
parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the trial. For information 
regarding laboratory tests (including drug and virus screening), ECG, vital signs, and 
physical examination, refer to Sections 5.2.1 to 5.2.4. 
6.2.2
Treatment period
SRD part: Each subject will receive one dose of BI 3006337 or placebo at Visit 2.
MD part: Each subject will receive multiple weekly doses of BI 3006337 or placebo for 6 
weeks.

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Trial medication will be administered as s.c. injection by the investigating physician (or 
authorised designee). Details on treatments and procedures of administration are described in 
Section 4.1.4.
In SRD part, trial participants will be kept under close medical surveillance for at least 72 h 
following s.c. administration of the trial medication. The subjects will then be allowed to 
leave the trial site at Day 4 after formal assessment and confirmation of their fitness by the 
investigator or 
 designee. On all other study days, the study will be performed in an 
ambulatory fashion.
In MD part, trial participants will be kept under close medical surveillance for at least 72 h 
following s.c. administration of the trial medication during hospitalisation and for at least 2 h 
following s.c. administration of the trial medication during the ambulatory visits. The trial 
participants will then be allowed to leave the trial site after formal assessment and 
confirmation of their fitness by the investigator or 
 designee.
For details on time points and procedures for collection of blood samples for PK analysis, 
ADA/Nab analysis, and analysis of acetaminophen PK, refer to the Flow Chart and Section
5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from the time of the subject’s written informed consent until the end of trial 
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2.
Subjects who discontinue after the treatment in SRD part and subjects who discontinue
treatment before the end of the planned treatment period in MD part should undergo the EOT
Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EOT
Visit for continued safety monitoring.
If a subject discontinues from the trial, the subject will be followed until the investigator or 
sub-investigator is convinced of the subject’s safety. If follow-up is not possible or comes to 
an end, follow-up should be formally completed after discussion with the sponsor. If a subject 
stop attending trial assessments, the investigator should assess the subject’s status as 
comprehensively as possible, and the well-being of the subject should be monitored. 
However, if the subject withdraws from the trial, it is the subject’s choice whether or not to 
participate in further assessments; he or she cannot be compelled.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in this trial.
Any confidence intervals computed are to be interpreted in the perspective of the exploratory 
character of the trial; i.e., confidence intervals are considered as interval estimates for effects.
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial 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 TS
who provide at least one 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.

ECG PK concentration set (ECGPCS): This subject set includes all subjects from the 
TS who provide at least one pair of a valid drug serum concentration and a 
corresponding (i.e., time-matched) ECG endpoint to be used in the exposure-response 
analyses. For placebo subjects, the serum 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 Report Planning Meeting (RPM) before 
database lock. The ECGPCS will be used for the exposure-response analyses.
Biomarker parameter analysis set (BMS): This set includes all subjects in the TS who 
provide at least one evaluable observation for at least one of the exploratory
biomarkers without protocol deviation relevant to the evaluation of biomarkers (as 
specified in the following subsection ‘Biomarkers’). Descriptive and model-based 
analysis of the biomarkers will be based on the BMS.
Descriptions of additional analysis sets may be provided in the TSAP.

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Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be suggested in the iPD specification file. IPDs will be identified no 
later than in the RPM, and the iPD categories will be updated as needed.
7.2.1.2
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 for drug BI 3006337 and 
acetaminophen will be calculated according to the relevant BI internal procedure. 
Serum/plasma concentration data and parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol deviation relevant to the evaluation of PK (to be decided no later than in the RPM) 
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.
Important 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
Serum/plasma concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

Missing samples/concentration data at important phases of PK disposition curve.
Serum/plasma concentration data and parameters of a subject which are flagged for exclusion 
will be reported with its individual values but will not be included in the statistical analyses.
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). 
7.2.1.3
Biomarkers
In general, biomarkers/PD endpoints of a subject will be included in the statistical analyses, if 
they are not flagged for exclusion due to a protocol deviation relevant to the evaluation 
thereof (to be decided no later than in the RPM) or due to non-evaluability (as revealed 
during data analysis, based on the criteria specified below).
Relevant protocol deviations may be as listed for PK in Section 7.2.1.2. Biomarker data 
and/or parameters of a subject may for example be considered as non-evaluable, if the time-
matched blood PK sample is considered as non-evaluable.

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Exclusion of a subject’s data will be documented in CTR. Biomarker 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.
7.2.2
Primary endpoint analyses
The primary endpoint as specified in Section 2.1.2 will be derived according to BI standards. 
The analysis will be based on the TS and will be descriptive in nature.
7.2.3
Secondary endpoint analyses
Primary analyses
The secondary endpoints (refer to Section 2.1.3) will be analysed descriptively. Analyses will 
be performed for the parent drug.
Further exploratory analyses
In the SRD part, dose proportionality will be explored via graphical checks and if applicable 
via the power model stated below. The analysis will be performed for the PK endpoints 
AUC0-∞and Cmax as specified in Section 2.1.3.
The power model describes the functional relationship between the dose level and PK 
endpoint on the log scale via
 = log (xkm) = μ + b ∙log (Dk) + ekm ,
where 
ykm
logarithm of response (PK parameter) measured on subject m receiving dose k,
μ
the overall mean,
β
slope parameter of linear regression line,
D
level of dose k, k=1,…,3,
ekm
the random error associated with the mth subject who was administered dose k 
(e~(0, ) iid).
The slope parameter β together with its two-sided 90% confidence interval will be estimated. 
Additionally, the r-fold change  !" together with its 90% CI will be derived.
As some small doses at the beginning and/or some doses at the upper end might not 
contribute to the linear relationship between dose and PK, dose proportionality over the entire 
dose range investigated might not be shown. In that case an attempt will be made to identify a 
subrange of at least 3 consecutive doses where dose proportionality can be concluded.

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7.2.5
Safety analyses
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 
RPM).
Treatments will be compared in a descriptive way. The placebo group in the safety evaluation 
will consist of all subjects treated with placebo for SRD and MD part respectively, regardless 
of the dose group in which they were treated. The test treatment groups will be compared to 
the placebo group in a descriptive way. Tabulations of frequencies/proportions will be used 

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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 time of the measurement 
or on the recorded time of AE onset (concept of treatment-emergent AEs). Therefore, 
measurements performed, or AEs recorded prior to first intake of trial medication will be 
assigned to the screening period, those between the first trial medication intake and end of 
REP (see Section 1.2.5) 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 unblinding the trial 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. 
The ECG variables QT, 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 with regard to QT/QTc interval, HR, PR interval and QRS duration. These 
endpoints and their analyses will be described in the TSAP.
Results regarding the C-SSRS will only be listed.
7.2.6
Other analysis
The relationship between plasma concentrations and ECG endpoints will be investigated in 
an exploratory manner. Further details will be specified in the TSAP.
7.2.7
Interim analyses
No formal interim analysis is planned.
A preliminary, exploratory analysis of the PK parameters (e.g., AUC0-tz, AUC0-∞and Cmax of 
substance) may be performed based on all evaluable data prior to data base lock. This may be 

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necessary, e.g., in case the information is needed to inform other activities during the 
development of substance such as concomitant treatment restrictions in other studies. In 
contrast to the final PK calculations, the preliminary, exploratory analysis will be based on 
planned sampling times rather than on actual times, regardless of whether actual times were 
within the time windows or not. Therefore, minor deviations of preliminary and final results 
may occur. Results will be provided as individual values and geometric means as well as the 
adjusted gMean ratios determined according to the planned primary analysis. The 
preliminary, exploratory results will be distributed to the trial team. No formal preliminary 
PK report will be written. 
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.
7.3.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedure. 
PK parameters that cannot be reasonably calculated based on the available drug
concentration-time data will not be imputed.
7.3.3
Biomarkers/pharmacodynamics
Handling of missing data of PD endpoints will be performed according to the relevant BI 
internal procedure. Imputation rules will be described in the TSAP.
7.4
RANDOMISATION
Subjects will be randomised in a 3:1 ratio (test treatment to placebo) within each dose group.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation scheme 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 scheme will contain additional blocks to allow for subject replacement 
(refer to Section 3.3.5).
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 36 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 8 subjects per dose group in SRD part (6 on active 
treatment, and 2 on placebo) and 12 subjects per dose group in MD part (9 on active 
treatment, and 3 on placebo) is commonly used in single-rising and multiple dose studies of 
the present type and is in general considered as sufficient for the exploratory evaluation of 
single dose safety and pharmacokinetics.

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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 and none of the stopping criteria apply. Thus, 
the actual number of subjects entered may exceed 36, but will not exceed 48 subjects entered.

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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 Japanese 
GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 1997) and 
other relevant regulations. Investigators and site staff must adhere to these principles.
Deviation from the protocol, the principles of ICH GCP or applicable regulations will be 
treated as ‘protocol deviation.’
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. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a general rule, no trial results should be published prior to finalisation 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 investigator or delegate must give a full explanation to trial subjects based on the subject 
information form. A language understandable to the subject should be chosen and technical 
terms and expressions avoided, if possible.
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. 

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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.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, 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.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number,
and social security number) have properly been removed or redacted to ensure subject
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g., re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

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
Subject identification: gender, 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.
8.3.2
Direct access to source data and documents
The investigator/institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g., FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.

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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage have to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage 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 (e.g., biomarker proposal, analysis plan and 
report) ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the 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 the whole trial 
(‘Last Subject Completed’).
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.

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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.
When the trial is completed, the investigator should inform the head of the trial site in writing 
of the completion of the trial, and the head of the trial site should promptly inform the IRB 
and sponsor in writing of the completion.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at 
, 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. The investigators will have access to the 
BI web portal Clinergize to access documents provided by the sponsor.
BI has appointed a CT Leader, responsible for coordinating all required trial activities, in 
order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of local Clinical Trial Managers
(CT Managers), Clinical Research Associates (CRAs), 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.
Analyses of BI 3006337 concentrations in plasma will be performed at the
The analyses of acetaminophen 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 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
P13-02280
Torres DM, Williams CD, Harrison SA. Features, diagnosis, and 
treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 
2012; 10(8); 837-858.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
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promotes bone loss by potentiating the effects of peroxisome proliferator-
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Xu P, Zhang Y, Liu Y, et al. Fibroblast growth factor 21 attenuates 
hepatic fibrogenesis through TGF-beta/smad2/3 and NF-kappaB signaling 
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steatosis, increases energy expenditure, and improves insulin sensitivity 
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action in the brain increases energy expenditure and insulin sensitivity in 
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(BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in 
patients with non-alcoholic steatohepatitis: a randomised, double-blind, 
placebo-controlled, Phase IIa trial. Lancet 2018; 392; 2705-2717.
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metabolic regulator. J Clin Invest; 115(6), p. 1627-1635; 2005.
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Kim AM, Somayaji VR, Dong JQ, et al. Once-weekly administration of a 
long-acting fibroblast growth factor 21 analogue modulates lipids, bone 
turnover markers, blood pressure and body weight differently in obese 
people with hypertriglyceridaemia and in non-human primates. Diabetes 
Obes Metab 2017; 19; 1762-1772.
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Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled trial of 
subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med 
2021;384(12):1113-1124.
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(U.S. prescribing information, revised: 06/2021). Website: 
accessdata.fda.gov/drugsatfda_docs/label/2021/215256 s000lbl.pdf 
(access date: 2021-08-27); 2021.
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E Temple B_de Tillman EJ Rolph TP Cheng A Yale K. Efruxifermin in 
non-alcoholic steatohepatitis: a randomized, double-blind, placebo-
controlled, Phase IIa trial. Nature Med; 27, p. 1262 1271; 2021.
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information, revised: 12/2021). Website: novo-pi.com/saxenda.pdf 
(access date: 2022-05-19); 2021.
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prescribing information, revised: 12/2021). Website: novo-
pi.com/victoza.pdf (access date: 2022-05-19); 2021.

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release, conditions or restrictions regarding supply and use, other 
conditions and requirements of the marketing authorisation, conditions or 
restrictions with regard to the safe and effective use of the medicinal 
product, labelling and package leaflet, scientific conclusions and grounds 
for the variation to the terms of the marketing authorisation(s), last 
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Trulicity (dulaglutide) injection, for subcutaneous use (Eli Lilly) (U.S. 
prescribing information, revised: 12/2021). Website: 
pi.lilly.com/us/trulicity-uspi.pdf (access date: 2022-05-19); 2021.
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(U.S. prescribing information, revised: 03/2022). Website: novo-
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Harrison SA Ruane PJ Freilich B Neff G Patil R Behling C et al. A 
randomized, double-blind, placebo-controlled Phase iIa trial of 
efruxifermin for patients with compensated NASH cirrhosis. JHEP Rep; 
2022.
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Harrison SA. Efruxifermin (EFX) in nonalcoholic steatohepatitis with
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Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjar MS, Krarup N, 
et al. Semaglutide 2.4 mg once weekly in patients with non-alcoholic 
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trial. Lancet Gastroenterol Hepatol; 2023; 8(6); 511-522.
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9.2
UNPUBLISHED REFERENCES
c30782091
BI 3006337 Investigator’s Brochure. Current version.
c39685874
, et al. Clinical Trial Report for 1466-0001. In 
preparation.

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10.
APPENDIX
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)
10.1.1
Columbia-Suicide Severity Rating Scale (C-SSRS) Screening

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10.1.2
Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit

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11.
DESCRIPTION OF GLOBAL AMENDMENT
11.1
GLOBAL AMENDMENT 1
Date of amendment
15 Feb 2024
BI Trial number
1466-0003
BI Investigational Medicinal 
Product(s)
BI 3006337
Title of protocol
Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of single rising subcutaneous 
doses and multiple subcutaneous doses over 6 
weeks of BI 3006337 in healthy male Japanese 
subjects (single-blind, randomised within dose 
groups, placebo-controlled, parallel group design)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
PROTOCOL SYNOPSIS
Description of change
Title of trial
Safety, tolerability, pharmacokinetics, and
pharmacodynamics of single rising subcutaneous
doses and multiple subcutaneous doses over 6 weeks
of BI 3006337 in healthy male Japanese subjects
(single-blind, randomised within dose groups,
placebo-controlled, parallel group design)
Rationale for change
Correction and clarification
Section to be changed
PROTOCOL SYNOPSIS
Description of change
Trial site
Rationale for change
Correction and clarification
Section to be changed
FLOWCHART
SRD part: DG1 – DG3
Description of change
Some planned times shown XX.XX format were
changed to XX:XX format to be consistent with
other planned times
Rationale for change
Correction and clarification

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Section to be changed
FLOWCHART
SRD part: DG1 – DG3
Description of change
Planned time of Day 2 of Visit 2 
From: 23:50
Change to: 22:50 
Rationale for change
Correction and clarification
Section to be changed
FLOWCHART
MD part: DG4
Description of change
Header of the flowchart
From: Serum biomarkers13
Change to: Blood biomarkers13
Rationale for change
Correction and clarification
Section to be changed
FLOWCHART
MD part: DG4
Description of change
Planned time of Day 2 of Visit 2
From: 23:30
Change to: 23:45
Rationale for change
Correction and clarification
Section to be changed
FLOWCHART
MD part: DG4
Description of change
Timing of discharge from trial site
From: 
Planned time of 47:00 on Day 3 of Visit 2
Change to:
Planned time of 72:00 on Day 4 of Visit 2
From: 
Planned time of 1055:00 on Day 45 of Visit 2
Change to: 
Planned time of 1080:00 on Day 46 of Visit 2
Rationale for change
To enhance the safety monitoring
Section to be changed
FLOWCHART
MD part: DG4
Description of change
The following events were newly added:
Lunch at planned time of 51:00 on Day 3 of Visit 2
and 1059:00 on Day 45 of Visit 2

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Snack (voluntary) at planned time of 55:00 on Day 
3 of Visit 2 and 1063:00 on Day 45 of Visit 2
Dinner at planned time of 58:00 on Day 3 of Visit 2
and 1066:00 on Day 45 of Visit 2
Breakfast (voluntary)10 at planned time of 72:00 on 
Day 4 of Visit 2 and 1080:00 on Day 46 of Visit 2
Rationale for change
Updated in accordance with the changes in timing 
of discharge from trial site
Section to be changed
FLOWCHART
MD part: DG4
Description of change
Footnote No. 14
Only bloodplasma/serum samples for biobanking 
will be collected at EOT visit
Rationale for change
Correction and clarification
Section to be changed
ABBREVIATIONS AND DEFINITIONS
Description of change
The following terminology was newly added:
Gastrointestinal (GI)
Rationale for change
Clarification
Section to be changed
ABBREVIATIONS AND DEFINITIONS
Description of change
%AUC tz-∞: Percentage of AUC tz0-∞obtained by
extrapolation
PCR: Polymerase chain reaction
VzF,ss: Apparent volume of distribution during the
terminal phase after extravascular administration
Rationale for change
Correction and clarification
Section to be changed
Section 1.4.2
Description of change
Although a trend of BI 30063367 related increase in 
the heart rate was detected, it was considered non-
adverse based on the lack of apparent dose-related 
relationship and associated effects on other ECG 
parameters.
Rationale for change
Correction and clarification
Section to be changed
Description of change

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Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 3.1
Description of change
Minimum safety data set required for each dose 
escalation was changed from at least 48 hours to 72 
hours following the IMP administration.
Rationale for change
To enhance the safety monitoring
Section to be changed
Section 4.1.4
Description of change
In SRD part, subjects will be kept under close 
medical surveillance until at least 72 h after drug 
administration.
In MD part, subjects will be kept under close 
medical surveillance until at least 7247 h after drug 
administration during hospitalisation and until at 
least 2 h after drug administration at the ambulatory 
visits. Hypersensitivity reactions should be treated 
according to medical standards (see Section 4.2.1).
Rationale for change
To enhance the safety monitoring
Section to be changed
Section 4.2.1
Description of change
Except for acetaminophen administration to 
perform the acetaminophen absorption test (see 
Section 4.2.1.1.1) and glucose administration to 
perform the OGTT (see Section 4.2.1.1.2) , no 
additional treatment is planned. However, in case of 
AEs in need of treatment, the investigator can 
authorize symptomatic therapy. In those cases, trial 
participants will be treated as necessary and, if 
required, kept under supervision at the trial site or 
transferred to a hospital until all medical evaluation 
results have returned to an acceptable level.
Prolonged or severe gastrointestinal (GI) events
Rationale for change
Correction and clarification

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Section to be changed
Section 5.2.3
Description of change
Drug screening and COVID-19 Antigen Rapid Test
(Nasopharyngeal Swab)SARS CoV-2 PCR test will 
be performed at SCR and before each admission to 
the site (Day -2 of Visit 2 for SRD part and Day -2 
of Visit 2 and Day 43 of Visit 2 for MD part).
Table 5.2.3:3 Exclusionary laboratory tests
COVID-19 infection: COVID-19 Antigen Rapid 
Test (Nasopharyngeal Swab) SARS CoV-2 PCR
test (nasal swab)
Rationale for change
Correction and clarification
Section to be changed
Section 5.4.1
Description of change

Markers for bone formation: 

Procollagen Type 1 N-terminal Propeptide
(P1NP) 

Bone-specific Alkaline Phosphatase (BALP) 

Osteocalcin (OC)

Markers for bone resorption: 

Carboxy-terminal Collagen Crosslinks  
(CTX-1)
Rationale for change
Correction and clarification
Section to be changed
Section 5.5.1
Description of change
Approximately 8.5 mL blood will be drawn for 
DNA, 410 mL for plasma and 8.5 mL serum 
banking purposes.
Rationale for change
Blood volume updated
Section to be changed
Section 5.6.1
Description of change
At the predefined time points before and after 
glucose intake indicated in the Flow Chart, blood 
samples for the determination of plasma glucose 
and insulin, and C-peptide will be collected.
Rationale for change
Correction and clarification
Section to be changed
Section 5.6.2.1
Description of change
For quantification of acetaminophen plasma 
concentrations, 1 mL of blood will be taken from an 
antecubital or forearm vein into a K2-EDTA 
(ditripotassium ethylenediaminetetraacetic acid)-
anticoagulant blood drawing tube at the times 
indicated in the Flow Chart.
Rationale for change
Correction and clarification

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Section to be changed
Section 6.2.2
Description of change
In MD part, trial participants will be kept under 
close medical surveillance for at least 7247 h 
following s.c. administration of the trial medication 
during hospitalisation and for at least 2 h following 
s.c. administration of the trial medication during the 
ambulatory visits. The trial participants will then be 
allowed to leave the trial site after formal 
assessment and confirmation of their fitness by the 
investigator or 
 designee.
Rationale for change
To enhance the safety monitoring

 
 
 
 
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clinical-trial-protocol-version-02
Safety, tolerability, pharmacokinetics, and pharmacodynamics of single rising
subcutaneous doses and multiple subcutaneous doses over 6 weeks of BI 3006337 in
healthy male Japanese subjects (single-blind, randomised within dose groups,
placebo-controlled, parallel group design)
Author-Clinical Trial Leader
19 Feb 2024 02:47 CET
Author-Trial Statistician
19 Feb 2024 08:22 CET
Approval-Clinical Program 
19 Feb 2024 08:44 CET
Verification-Paper Signature
Completion
20 Feb 2024 02:10 CET

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