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



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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
27 Aug 2020
Revision date
24 Nov 2022
BI trial number
1466-0001
Title of trial
Safety, tolerability, pharmacokinetics and pharmacodynamics of 
single rising subcutaneous doses of BI 3006337 in healthy male 
subjects (single-blind, partially randomised within dose groups, 
placebo-controlled, parallel (sequential) group design)
Coordinating 
Investigator
Trial site (s)
Multi-centre trial
Clinical phase
I
Trial rationale
BI 3006337 is a dual GLP-1/FGF21 receptor agonist designed for 
the treatment of nonalcoholic steatohepatitis (NASH). The 
complementary activities of GLP-1 and FGF21 on insulin 
resistance, obesity, hepatic fat metabolism, and fibrosis 
biomarkers provide the rationale to combine GLP-1 and FGF21 in 
one molecule with the expectation to improve multiple NASH-
associated pathologies.
Trial objectives
To investigate safety, tolerability and pharmacokinetics of single 
doses of BI 3006337 in healthy male subjects
Trial endpoints
Primary endpoint:
Percentage of subjects with drug-related adverse events (AEs)
after single dose of BI 3006337
Secondary endpoints:
AUC0-∞, Cmax, and tmax of BI 3006337
Trial design
Single-blind, partially randomised within dose groups, placebo-
controlled, parallel (sequential) group design

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Number of subjects 
total entered
92
each treatment
8 per dose group 1 - 10 (6 on BI 3006337 and 2 on placebo) 
12 per dose group 11 (9 on BI 3006337 and 3 on placebo) due to 
exploratory investigation of gastric emptying rate (paracetamol 
absorption test).
* 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 92, but is not to exceed 108.
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy, male subjects, age of 18 to 55 years (inclusive), body 
mass index (BMI) ≥20 to <32 kg/m2
Test product
BI 3006337 solution for injection 50 mg/mL 
dose
0.2 mg, 0.5 mg, 1 mg, 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, 50 mg, 
100 mg, 150 mg
mode of admin. SC
Reference product
Placebo of BI 3006337
dose
Not applicable
mode of admin. SC
Duration of 
treatment
Single dose
Statistical methods
Descriptive statistics will be calculated for all endpoints.

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16.
The Holter ECG devices will be brought back by the subjects the day after installation for analysis by the central ECG reader.
17.
Following BI 3006337 / placebo administration

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART (DG 1-10).................................................................................4
FLOW CHART (DG-11)....................................................................................6
TABLE OF CONTENTS ................................................................................ 11
ABBREVIATIONS.......................................................................................... 16
1.
INTRODUCTION ........................................................................... 19
1.1
MEDICAL BACKGROUND.............................................................................19
1.2
DRUG PROFILE................................................................................................20
1.2.1
Nonclinical pharmacology..................................................................................20
1.2.2
Toxicology............................................................................................................22
1.2.2.1
Genotoxicity..........................................................................................................22
1.2.2.2
Single dose toxicity...............................................................................................22
1.2.2.3
Repeated dose toxicity ..........................................................................................22
1.2.2.4
Special studies.......................................................................................................23
1.2.2.5
Reproductive and developmental toxicity.............................................................24
1.2.3
Nonclinical pharmacokinetics............................................................................24
1.2.5
Clinical experience in humans ...........................................................................25
1.2.6
Residual Effect Period ........................................................................................26
1.2.7
Drug product .......................................................................................................26
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................26
1.4
BENEFIT - RISK ASSESSMENT.....................................................................27
2.
TRIAL OBJECTIVES AND ENDPOINTS.................................. 31
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........31
2.1.1
Main objectives....................................................................................................31
2.1.2
Primary endpoint................................................................................................31
2.1.3
Secondary endpoints...........................................................................................31
2.2.2.1
Safety and tolerability...........................................................................................31
3.
DESCRIPTION OF DESIGN AND TRIAL 
POPULATION................................................................................. 33
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................33
3.1.1
Data Safety Monitoring Board – Operations and Safety Review...................34

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11.1
GLOBAL AMENDMENT 1 ..............................................................................84
11.2
GLOBAL AMENDMENT 2 ..............................................................................86
11.3
GLOBAL AMENDMENT 3 ..............................................................................88
11.4
GLOBAL AMENDMENT 4 ..............................................................................91
11.5
GLOBAL AMENDMENT 5 ..............................................................................91
11.6
GLOBAL AMENDMENT 6 ..............................................................................93
11.7
GLOBAL AMENDMENT 7 ..............................................................................94
11.8
GLOBAL AMENDMENT 8 ..............................................................................95
11.9
GLOBAL AMENDMENT 9 ..............................................................................96

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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 glucagon-like peptide 1 (GLP-1) and 
fibroblast growth factor 21 (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 that possesses glucose-lowering features by 
inducing insulin secretion and reducing the production of glucagon. It also suppresses 
appetite and retards gastric emptying.
GLP-1 receptor (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 (all 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 NAFLD 
activity score [R16-3177]. The fibroblast growth factor (FGF) family of hormones mediate 
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].

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1.2.2.5
Reproductive and developmental toxicity
Developmental and reproductive toxicity studies have not been conducted with BI 3006337.
1.2.3
Nonclinical pharmacokinetics
Two ELISA assays were designed to measure full length and therefore active components of 
the molecule (GLP-1 and FGF21). The pharmacokinetics (PKs) of BI 3006337 were dose 
linear after i.v. and s.c. dosing in mice, rats, cynomolgus monkeys and minipigs. The 
absorption rate constant (ka) and bioavailability (F) in preclinical 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 humans to 
peptides and amino acids. The molecular weight of BI 3006337 is 
, 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 exposure to active GLP-1 slightly higher than the exposure to 
active FGF21. Monkeys showed a PK profile for active GLP-1 substantially shorter than the 
profile for active FGF21. The cause of the discrepancies in the exposure between GLP-1 and 
FGF21 is unknown. 

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1.2.5
Clinical experience in humans
To date, humans have not been exposed to BI 3006337. This will be the first clinical trial in 
man. Experience with the single pharmacologically active components of BI 3006337 are 
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 (all 
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 hypoglycemia, even after prolonged 
fasting. Among the most common adverse effects for the GLP-1 class are nausea, vomiting, 
diarrhea, 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. Cardiac conduction disorders were described for GLP1R agonists in clinical trials as 
well as in the prescribing information for Saxenda® [R19-1407]. These were reported as first 
degree atrioventricular block, right bundle branch block, or left bundle branch block as well 
as QT-prolongation up to 10 ms. In clinical trials, there were more cases of pancreatitis 
among GLP1R-treated patients than among comparator-treated patients. If pancreatitis is 
suspected, GLP-1 agonists should be discontinued. They should be used with caution in 
patients with a history of pancreatitis. 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).
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 adverse events (AEs) in studies with FGF21 agonists were 
gastrointestinal (diarrhea and nausea), which were generally mild and did not require 
treatment. Effects of FGF21 agonists on HR or BP are conflicting, with studies from 
pegbelfermin, a PEGylated FGF21 agonist, showing no obvious changes, while a 2017 study 
of an intravenously administered, long-acting FGF21 analogue showed increases in BP and 
HR [R20-0507, R20-0509].

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1.2.6
Residual Effect Period
The Residual Effect Period (REP) of BI 3006337 in humans is not known to date. This is the 
period after the last dose with measurable drug levels and/or PD effects still likely to be 
present. Based on the PK half-life of about  days for the GLP-1 component and 6 days for 
the FGF21 component, it could be determined with about 30 days.
 This is the period after this dose with measurable drug
levels and/or PD effects still likely to be present.
In summary the overall residual effect period of 30 days was based on the longest IMP half-
life, in this case from the BI 3006337.
1.2.7
Drug product
For a more detailed description of the BI 3006337 profile, please refer to the current 
Investigator’s Brochure (IB) [c30782091].
1.3
RATIONALE FOR PERFORMING THE TRIAL
Healthy male subjects, aged 18-55 years will be recruited for this study. They are expected to 
provide a relatively stable physiological, biochemical and hormonal basis (steady state) for 
studying drug effects, they may not show disease-related variation and they will be selected 
not taking concomitant medication.
Within each dose group (DG), all actively treated individuals will receive the same 
BI 3006337 dose. The next higher dose will only be administered (to the next DG) if the 
treatment in the preceding DG was safe and showed acceptable tolerability.
BI 3006337 is a dual GLP-1/FGF21 receptor agonist showing in preclinical models, that 
BI 3006337 has superior efficacy to GLP1R analogues alone. Thus, these complementary 
activities on GLP-1 and FGF21 receptors have the potential to provide improved efficacy in 
metabolic disease states.
A high-unmet medical need is evident in this indication, since neither approved NASH-
targeted therapy nor effective disease modifying regimens are currently available. 
As a transition from preclinical investigations to clinical development, the present first-in-
man trial is designed to assess safety, tolerability, PK and PDs of BI 3006337 in healthy male 
volunteers. The present trial provides the basis for a continued ongoing clinical development 
of BI 3006337 in the indication NASH.
It is intended to investigate the following dose levels of BI 3006337 in this trial: 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. For this trial, s.c. 
doses in the range of 0.2 mg to 150 mg have been selected in order to assess the safety and
tolerability of BI 3006337 in healthy male subjects, and to investigate the PK of this novel 
dual GLP-1 and FGF21 receptor agonist. The background for this dose selection is described 
in the following paragraphs.
The predicted human dose for BI 3006337 is 
. The selected doses cover a safe 
starting dose in the sub-therapeutic range, the estimated therapeutic range and potentially 
supra-therapeutic doses within the levels that are determined by toxicological investigations.

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In the usual phase I settings, subjects stay in house in small groups for several days and there 
is a potential risk for spreading the Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2) across the subject group or site staff. Some trial procedures, e.g. collecting 
blood samples, recording of Electrocardiogram (ECG), 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 site detailing specific 
cautionary measures (e.g. hygiene rules, wearing of face masks and physical distance), which 
is filed in the ISF. The local requirements may be subject to change and the trial procedures 
will be adapted accordingly, if applicable.
Drug-related risks and safety measures
The test product BI 3006337 did not demonstrate any adverse effects on the core safety 
pharmacology function (central nervous, cardiovascular, respiratory, renal systems) evaluated 
as part of the 4-week GLP repeat dose toxicity study in monkeys. The effects on the 
gastrointestinal function including decreased food consumption, BW loss, and decreased BW
gain were observed in all animal species (mice, rats, monkeys) and are the expected 
pharmacological effects of BI 3006337, attributable to GLP-1 and FGF21 agonism. 
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 (DEXA and micro-CT or 
microscopic correlates. The nonclinical toxicology package did not indicate any adverse 
toxicities at doses providing high safety margins and the predicted exposures at the proposed 
dose levels in this Single-Rising Dose (SRD) trial in humans are far below those at the 
NOAELs achieved in the repeat dose toxicity studies. The risk of immunogenicity for 
BI 3006337 and its consequences in humans are currently unknown. BI 3006377 is judged to 
be a medium risk molecule with regard to the antigenicity risk assessment. Due to the s.c. 
administration local intolerabilities may occur. Subjects are exposed to risks of study 
procedures and risks related to the exposure to the trial medication.
Preclinical 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 Corona Virus Disease 2019 (COVID-19) pandemic. Based on the mechanism 
of action, BI 3006337 is not expected to promote malfunction of the immune system resulting 
in an increased risk of progression of COVID-19 infection.
It is unlikely that there will be an additional risk to overweight (Body Mass Index (BMI) 
<32.0 kg/m2), healthy subjects by the application of BI 3006337. These healthy subjects do 
not belong to the population at higher risk for severe illness from COVID-19 (e.g. older age, 
serious underlying medical conditions or obesity).
The following safety measures will be applied in this study in order to minimize the risk for 
healthy volunteers:
∀
Careful dose selection (refer to Section 1.3)
∀
Preliminary measurement of BI 3006337 serum concentrations and preliminary 
determination of PK parameters
∀
For precautionary reasons, drug plasma concentrations of healthy male volunteers in 
this trial should not exceed the mean Cmax of 395 μg/mL (BI 3006331 GLP-1 assay) 

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and 362 μg/mL (BI 3006331 FGF21 assay) or mean AUC0-168h of 52080 μg*h/mL 
(BI 3006331 GLP-1 assay) and 46340 μg*h/mL (BI 3006331 FGF21 assay)
∀
An extensive safety laboratory will be performed with special focus on full blood 
exam also including bone turnover biomarkers (see Flow Chart (DG 1-10) and Flow 
Chart (DG-11))
∀
For safety reasons, each DG of 8 subjects (6 on active, 2 on placebo) will be divided 
into two cohorts of 2 subjects each (cohort 1 and 2) and one cohort of 4 subjects 
(cohort 3). The drug administrations of these three cohorts will be separated by at 
least 72 hours (between 1st subject of each cohort) to cover the period of highest 
risk/peak effect
∀
A thorough ECG monitoring to cover the anticipated period of highest drug exposure 
and additional repeated single 12-lead ECGs over 336 hours following s.c. drug 
administration
∀
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 (DG 1-10) and Flow Chart (DG-11))
∀
The subjects will stay at the trial site for at least 72 hours after s.c. study drug 
administration at each dose level and will be monitored for vital signs and local
tolerability at injection site
∀
During in house-confinement the subjects will be under medical observation and
thoroughly monitored for both expected and unexpected AEs
∀
Only if the respective dose of BI 3006337 was safe and showed acceptable tolerability
and if no stopping criterion was met, the next higher dose will be given
∀
As reproductive toxicity studies have not yet been conducted, women will not be 
enrolled in this study.
∀
A risk management plan has been set up at the site detailing specific cautionary 
measures, e.g. hygiene rules, wearing of face masks and physical distance which is 
filed in the Investigator Site File (ISF). 
∀
In addition, a screening (SCR) of SARS-CoV-2 has been implemented to be 
performed as part of the safety assessments on Day -1 at visit 2. Subjects positive in 
the results for these virus are not eligible to the trial in accordance to exclusion 
criterion 29 and will be excluded from the trial. During the ambulatory visits, subjects
are allowed to enter the site only after it was confirmed that subjects 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 subjects´ 
safety; see also Section 5.2.6.1.4, AEs of special interest.
In summary, although not tested in humans to date, 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, healthy subjects will not be exposed to 
undue risks in relation to the important information expected from this trial as a basis for 
further clinical development of this compound. Healthy volunteers are not expected to have 

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any direct benefit from participation in this first in man clinical trial with BI 3006337, as is 
the usual case in such Phase I trials. The benefit/risk assessment for the administration of 
BI 3006337 to healthy subjects remains unaltered despite the COVID-19 pandemic. 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 healthy human volunteers.

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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 and PK of BI 3006337 
in healthy male subjects following s.c. administration of SRDs.
2.1.2
Primary endpoint
The primary endpoint for assessment of safety and tolerability of BI 3006337 is the 
percentage of subjects with drug-related AEs occurring between first administration of trial 
medication (BI 3006337 or placebo) and end of trial (EOT).
2.1.3
Secondary endpoints
The following PK parameters of BI 3006337 will be determined if feasible:
∀
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)
∀
tmax (time from dosing to the maximum measured concentration of the analyte in 
serum)
2.2.2.1
Safety and tolerability
Safety and tolerability of BI 3006337 will be assessed during the on-treatment period, i.e. 
occurring between first administration of trial medication (BI 3006337 or placebo) and EOT
based on:
∀
AEs (including clinically relevant findings from the physical examination)
∀
Safety laboratory tests
∀
12-lead ECG
∀
Continuous (24 h) ECG monitoring 
∀
Vital signs (Temperature, BP, pulse rate (PR))

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This SRD trial is designed as single-blind, partially randomised, and placebo-controlled
within sequential DGs parallel trial.
It is planned to include a total of 92 healthy male subjects in the trial. The subjects will be 
assigned to 10 groups consisting of 8 subjects per group and 1 group consisting of 12 
subjects. The groups will be dosed sequentially (see Table 3.1: 1). The investigator (after 
consultation with the sponsor) is allowed to alter the scheduled DGs (e.g., add low and/or 
intermediate DGs, as a maximum 2 DGs) on the basis of experience gained during the study 
(for instance, based on preliminary PK data), provided the planned and approved highest dose 
is not exceeded. Thus, the actual number of subjects entered may be more than 92 but is not 
to exceed 108. Such changes may be implemented via substantial Clinical Trial Protocol 
(CTP) Amendments.
Within  DG 1 - 10, 6 subjects will receive BI 3006337 and 2 will receive placebo. Only one 
dose is tested within each DG. For safety reasons, each DG will consist of 3 cohorts. The trial 
medication will be administered in the following order: 
∀
Cohort 1 (fixed order: ‘active – placebo’): 1 subject on active treatment and 1 subject 
on placebo (in total 2 subjects)
∀
Cohort 2 (fixed order: ‘active – active’): 2 subjects on active treatment 
(in total 2 subjects) 
∀
Cohort 3 (randomised): 3 subjects on active treatment and 1 subject on placebo 
(in total 4 subjects)
In cohort 1 both subjects will be dosed sequentially. Dosing of each subject in cohort 2 will 
be separated by a minimum of 10min (72 hours between last subject of cohort 1 and first 
subject of cohort 2, which is based on an anticipated time of approximately 39 h (FGF21) and 
42 h (GLP-1) to reach peak concentration of BI 3006337 and is expected to cover the period 
of highest risk/peak effect). The first 2 cohorts will be dosed in a single-blinded, fixed 
sequence fashion ‘active – placebo’ (cohort 1) and ‘active – active’ (cohort 2). First dosing in 
cohort 3 can only start after all subjects on the previous cohorts have completed 72 hours.
Dosing within cohort 3 will be separated by a minimum of 10 minutes.  Every effort should 
be made to recruit a complete DG with 8 subjects.  In case of dropouts prior to 
randomization, minimum data from 4 subjects on active drug need to be available for 
escalation to a higher dose.
Within DG-11, 9 subjects will receive BI 3006337 and 3 will receive placebo. The trial 
medication will be administered in the following order: 
∀
Cohort 1 (fixed order: ‘active – placebo’): 1 subject on active treatment and 1 subject 
on placebo (in total 2 subjects)
∀
Cohort 2 (fixed order: ‘active – active’): 2 subjects on active treatment 
(in total 2 subjects) 
∀
Cohort 3 (randomised): 6 subjects on active treatment and 2 subjects on placebo 
(in total 8 subjects)
The DGs to be evaluated are outlined in Table 3.1: 1 below.

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Table 3.1: 1
Planned dose groups
Dose Group
1
2
3
4
5
6
7
8
9
10
11
Dose (mg)
0.2
0.5
1
2
4
8
15
30
50
100
150
Number of 
subjects
8
8
8
8
8
8
8
8
8
8
12
Subjects 
receiving 
placebo
2
2
2
2
2
2
2
2
2
2
3
Subjects 
receiving 
BI 3006337
6
6
6
6
6
6
6
6
6
6
9
The groups will be dosed consecutively in ascending order, and a time interval of at least 72 
hours will be maintained between the last drug administration to subjects in the previous DG
and the first drug administration to subjects in the subsequent DG. The decision to proceed to 
the next DG will be based upon the safety and tolerability of the preceding DGs. The next 
DG will only be treated if no safety concerns have arisen in the preceding DGs (i.e. no dose-
limiting events occurred), and if none of the pre-specified trial-specific stopping criteria have 
been met (refer to Section 3.3.4.2). In addition to safety and tolerability as well as PK
parameters, the trial will be performed to investigate PDs like metabolic parameters and BW.
3.1.1
Data Safety Monitoring Board – Operations and Safety Review
A documented Safety Review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested anytime for any reasonable cause by the 
Principal Investigator (or an authorised deputy) or the Sponsor of the study, e.g. because of 
any unforeseen AEs, etc. Dose escalation will only be permitted if no safety concerns exist in 
the opinion of the Principal Investigator (or an authorised deputy), the Clinical Trial Leader 
(CTL) (or an authorised deputy) and a medical expert representative from the therapeutic
area. Changes to the planned dosing schedule (i.e. addition of new DGs that are not 
predefined) will be implemented through a substantial amendment. In summary, the 
implementation of Data Safety Monitoring Board and safety monitoring measures as 
described in current protocol are considered adequate to ensure subject safety in this phase I 
trial.
Every effort should be done to recruit complete DG 1-10 with 8 subjects and DG-11 with 12 
subjects. In case of dropouts prior to randomization, for DG 1-10 a minimum data from 4 
subjects on active drug need to be available for escalation to a higher dose. For DG-11 data 
from all subjects on active drug need to be available. For the minimum dataset with regards 
to preliminary PK data, see Section 7.4. The minimum data set for review consists of the 
following:
∀
AEs in the current and preceding DGs up to at least 72 h post dosing, including 
clinically relevant findings from ancillary safety testing listed below (Note: AEs may 
be ongoing at the time of Safety Reviews and AE information may be subject to 
change prior to Database Lock)

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∀
Results from 12-lead ECG and continuous ECG monitoring in the current and 
preceding DGs up to at least 72 h post dosing
∀
Vital signs in the current and preceding DGs up to at least 72 h post dosing
∀
Clinical laboratory tests in the current and preceding DGs up to at least 72 h post 
dosing
∀
Assessment of local tolerability
∀
Preliminary PK data as described in Section 7.4
∀
Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy), the CTL (or an authorised deputy) and a medical expert representative 
from the therapeutic area after in-depth analysis of all available safety data, especially 
Serious Adverse Events (SAEs) (if occurred), AEs, and out-of-range laboratory results (if 
considered clinically significant). For the purpose of safety evaluation and decision taking at 
completion of each dose level in this trial, the Principal Investigator will provide 
 assessment 
based on 
 direct clinical experience in the use of the investigational compound; because 
decisions in this phase I dose escalation trial are taken based on safety observations of the 
participant subject cohorts, the view of the investigator on individual subjects is considered 
essential for the overall safety assessment. In addition and depending on the results and 
findings, suitable experts from the sponsor (e.g. trial statistician) or external institutions may 
be consulted on an as needed basis. In these cases expert recommendations will be 
documented in the minutes of the Safety Review and considered for the decision making. 
Dose escalation will only be permitted if no safety concerns exist. Decision of the Drug 
Safety Monitoring Board must be unanimously. 
Safety Reviews can be conducted face-to-face or by video/telephone conference. The CTL is 
responsible for the organisation and minutes of the reviews. Minutes will be signed off by the 
Principal Investigator (or an authorised deputy) and CTL (or an authorised deputy) and will 
be filed in the ISF and Trial Master File (TMF).
An overview of all relevant trial activities is provided in the Flow Chart (DG 1-10) and Flow 
Chart (DG-11). For visit schedules and details of trial procedures at selected visits, refer to 
Sections 6.1 and 6.2, respectively.
3.1.2
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a CTL, responsible for coordinating all required activities, in order to
∀
manage the trial in accordance with applicable regulations and internal Standard 
Operating Procedures (SOPs),
∀
direct the clinical trial team in the preparation, conduct, and reporting of the trial
∀
ensure appropriate training and information of local Clinical Trial Manager, Clinical
Research Associates (CRAs), and the participating trial site.
The BI investigational product BI 3006337 (test product) and the placebo (reference product) 
will be provided by the
 
The trial will be conducted on two sites: 
and 
under the supervision of the 

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3.3
SELECTION OF TRIAL POPULATION
It is planned that 92 healthy male subjects will enter the study. The actual number of subjects 
entered may exceed the total of 92 if additional intermediate doses are tested (see Section 3.1)
but will not exceed108 subjects entered. Subjects will be recruited from the volunteers' pool 
of the trial site.
The trial involves overweight subjects because overweight or even obesity is a risk factor for 
the development of NAFLD and NASH, which is an indication the current study medication 
is developed for. In addition, medications with a GLP-1-component are better tolerated by 
subjects with higher BW.
Only male subjects will be included in the trial because no data on reproductive toxicology 
are available at this time. With respect to the embryo-fetal risk coming from the treatment of 
male subjects with BI 3006337, where it is theoretically possible that relevant exposure to
BI 3006337 may be achieved in women of childbearing potential (WOCBP) from exposure to
seminal fluid, male contraception (condom or abstinence) should be used in order to avoid
exposure of an existing embryo/fetus [R16-0373] (see Section 3.3.3, exclusion criterion 24).
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 study will be performed in healthy subjects.
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 (Temperature, 
BP, PR), 12-lead ECG, neurological examination, and clinical laboratory tests 
(2)
Age of ≥18 to ≤55 years at SCR
(3)
BMI of ≥20.0 to <32.0 kg/m2 at SCR
(4)
A minimum absolute BW of 70 kg at SCR
(5)
Male subjects who meet any of the following criteria from the administration of trial 
medication until 30 days after administration of trial medication:
∀Use of adequate contraception, e.g. any of the following methods (of female 
partners) plus condom or sexually abstinence (if lifestyle-related): implants, 
injectables, vaginal contraceptives, intrauterine device, oral contraception (failure 
rate <1%). In case of use of oral contraception women should have been stable on 
the same pill for a minimum of 3 months before taking study treatment.
∀Surgically sterilised/vasectomised (including hysterectomy with or without 
bilateral salpingectomy or bilateral oophorectomy of female partner. In case of 
salpingectomy or oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment).

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∀Postmenopausal female partner, defined as at least 1 year of spontaneous 
amenorrhea.
(6)
Signed and dated written informed consent prior to admission to the study, in 
accordance with Good Clinical Practice (GCP) and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
(1)
Female gender
(2)
Any finding in the medical examination (including BP, PR or ECG) or neurological 
examination deviating from normal and assessed as clinically relevant by the 
investigator
(3)
3 times repeated measurements of systolic BP outside the range of 90 to 150 mmHg, 
diastolic BP outside the range of 50 to 90 mmHg, or PR outside the range of 40 to 100 
bpm. In case of documented white coat hypertension the decision for eligibility is left to 
the investigator. 
(4)
Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance, in particular, hepatic parameters ALT (1.25xULN), AST
(1.25xULN) and T-BIL (1.5xULN) or renal parameters (creatinine 1.25xULN) 
exceeding the Upper Limit of Normal (ULN) as specified: after 2 times repeated 
measurements
(5)
Any evidence of a concomitant disease assessed as clinically relevant by the 
investigator
(6)
Clinically relevant gastrointestinal, hepatic, renal, respiratory, cardiovascular, 
metabolic, immunological or hormonal disorders
(7)
Diseases of the central nervous system (including but not limited to any kind of 
seizures or stroke), and other relevant neurological or psychiatric disorders
(8)
History of relevant orthostatic hypotension, fainting spells, or blackouts
(9)
Chronic or relevant acute infections, including positive tests for Hep B antigen/ Hep C 
antibodies, HIV-1/2 antibodies and SARS-CoV-2
(10) History of relevant allergy or hypersensitivity (including allergy to the trial medication
or its excipients) 
(11) Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
(12) Participation in another trial where an investigational drug has been administered 
within 30 days prior to planned administration of trial medication, or current 
participation in another trial involving administration of investigational drug
(13) Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
(14) Inability to refrain from smoking on specified trial days
(15) Alcohol intake (from signing of ICF to EOT)

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(16) Drug abuse or positive drug at SCR and visit 2 (D-2)
(17) Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
(18) Intention to perform excessive physical activities within 5 days prior to the 
administration of trial medication or during the trial
(19) Inability to comply with the dietary regimen of the trial site
(20) A marked prolongation of QT/QTcF interval (such as QTcF intervals that are 3 times 
repeatedly greater than 450 ms) or any other relevant ECG finding at SCR
(21) A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
(22) Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, 
the subject has a condition that would not allow safe participation in the study, or 
excessive dietary behaviour
In addition, the following trial-specific exclusion criteria apply:
(23) Male subjects with sperm donation from the administration of trial medication until 30 
days after administration of trial medication
(24) Personal or family history of medullary thyroid carcinoma or history of multiple 
endocrine neoplasia syndrome type 2
(25) 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
(26) Findings from SCR Holter ECG of HR judged to be clinically relevant by the 
investigator or the cardiologist of the ECG core lab
(27) GLP-1-agonist or FGF21-agonist treatment in the last 6 months prior to SCR
(28) A positive Polymerase chain reaction (PCR) test for SARS-CoV-2 on visit 2 at day -2
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication (BI 3006337 or placebo), the data of this subject will not be entered in the 
case report form (CRF) and will not be reported in the Clinical Trial Report (CTR). If a 
subject is removed from or withdraws from the trial after the first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF; in addition, the data will be included in the CRF and will be reported in the CTR.
At the time of discontinuation, a complete EOT examination will be performed, if possible, 
and the information will be recorded in the CRF. If the discontinuation occurs before the end 

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of the REP (see Section 1.2.4), the discontinued subject should if possible be questioned for 
AEs and concomitant therapies at or after the end of the REP in order to ensure collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject.
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
(1)
The subject withdraws consent for trial treatment or trial participation, without the need 
to justify the decision
(2)
Findings from continuous ECG (or the 12 lead ECGs) judged to be clinically relevant 
by the investigator
(3)
The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future
(4)
The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
(5)
The subject is no longer able to participate for medical reasons (such as surgery, AEs, 
or diseases)
(6)
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
(7)
The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of T-
BIL ≥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
(8)
The patient experiences an infection with SARS-CoV-2 (as confirmed by PCR Test)
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in Flow Chart (DG 1-10) and Flow Chart (DG-11) and Section 6.2.3.
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.

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3.3.4.3
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial at any time for any of the following reasons:
(1)
Failure to meet expected enrolment goals overall or at a particular trial site
(2)
New toxicological findings, SAEs, or any safety information invalidating the earlier 
positive benefit-risk assessment. More specifically, the dose escalation will be 
terminated if more than 50% of the subjects at one dose level show unexpected drug-
related and clinically relevant AEs of moderate or severe intensity, or if at least one 
drug-related SAE is reported.
(3)
The dose escalation will be terminated if unexpected severe non-SAEs considered as 
drug-related by the investigator in 2 subjects of the same DG (8 subjects) occure.
(4)
Violation of GCP, or the CTP by a trial site or investigator, or the contract with BI 
impairing the appropriate conduct of the trial.
(5)
The sponsor decides to discontinue the further development of the investigational 
product.
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 a subject is considered as non-evaluable for the minimum data set (see Section 3.1.1), 
enrolment of a new subject to the current cohort will be considered in order to support the 
benefit-risk assessment and to achieve the required number of evaluable subjects before dose-
escalation. Required evaluable subjects per cohort and dosing group are defined in Section 
3.1.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products BI 3006337 (test product) & placebo (reference product) have
been manufactured by BI Pharma GmbH & Co. KG. BI 3006337 solution for injection is a 
sterile, buffered, isotonic, preservative-free, clear and slightly brown liquid solution at pH of 
 BI 3006337 solution for injection is formulated at a protein concentration of 50 mg/mL 
of active pharmaceutical ingredient (API) and contains the excipients L-Histidine-HCl, 
Trometamol, Trehalose, Polysorbate 20 and water for injection. The placebo and the solvent 
for dilution of BI 3006337 composites of the same components without API.
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
Route of administration:
s.c.
Duration of use:
Single dose
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
Route of administration:
s.c.
Duration of use:
Single dose
Placebo of BI 3006337 solution for injection also serves as solvent for dilution of 
BI 3006337.
4.1.2
Identity of non-investigational medicinal product
Not applicable.
4.1.3
Selection of doses in the trial
For this trial, s.c. doses in the range of 0.2 mg to 150 mg have been selected in order to assess 
the safety and tolerability of BI 3006337 in healthy male volunteers, and to investigate the 
PK of this novel dual GLP-1 and FGF21 receptor agonist. The selected doses cover a safe 
starting dose in the sub-therapeutic range, the estimated therapeutic range and potentially 
supra-therapeutic doses within the levels determined by toxicological investigations (see 
Section 1.2).

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4.1.4
Method of assigning subjects to treatment groups
Prior to the SCR visit, subjects will be contacted and informed about the planned visit dates. 
The subjects willing to participate will be recruited to DGs (3 cohorts per DG) according to 
their temporal availability. As soon as enough subjects have been allocated to one of the 
planned dose cohorts (3 cohorts per DG), the following subjects will be allocated to one of 
the other dose cohorts. Therefore, the allocation of subjects to dose cohorts is not influenced 
by trial personnel, but only by the subjects’ temporal availability. As the study includes 
healthy subjects from a homogenous population, relevant imbalances between the DGs are 
not expected.
In Cohorts 3 of each DG, subjects will be randomly assigned to treatments (active or placebo) 
prior to the first administration of trial medication, while treatments in Cohorts 1 and 2 will 
be assigned in a fixed order for safety reasons, as described in Section 3.1.
For the purpose of random assignment, the randomization list will be provided to the Clinical 
Trail Leader in advance. Numbers of the randomization list will be allocated to subjects by 
the method ‘first come - first served’ according to Flow Chart (DG 1-10) and Flow Chart 
(DG-11). The sites will receive the randomization number from the Clinical Trial Leader to 
assign the subjects to the treatment according to the randomization list. Once a subject 
number has been assigned, it cannot be reassigned to any other subject.
The randomization procedure is described in Section 7.6.
4.1.5
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.5: 1 below. The dose volume for 
placebo corresponds to dose volume of the respective dose level.
Table 4.1.5: 1
BI 3006337 and placebo treatments, s.c. administration
Dose
group
Substance
Pharmaceutical form
Unit strength
Total dose
1
BI 3006337
Solution for injection
50 mg/mL
0.2 mg
2
BI 3006337
Solution for injection
50 mg/mL
0.5 mg
3
BI 3006337
Solution for injection
50 mg/mL
1 mg
4
BI 3006337
Solution for injection
50 mg/mL
2 mg
5
BI 3006337
Solution for injection
50 mg/mL
4 mg
6
BI 3006337
Solution for injection
50 mg/mL
8 mg
7
BI 3006337
Solution for injection
50 mg/mL
15 mg
8
BI 3006337
Solution for injection
50 mg/mL
30 mg
9
BI 3006337
Solution for injection
50 mg/mL
50 mg
10
BI 3006337
Solution for injection
50 mg/mL
100 mg
11
BI 3006337
Solution for injection
50 mg/ml
150 mg
1-11
Placebo*
Solution for injection
--
--
* Subjects receiving placebo are equally distributed across dose groups 

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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 the Medication Handling Instruction provided by the sponsor. The 
investigator can decide at any time to discontinue dosing in case of intolerability or safety 
concerns.
On Day 1 of Visit 2 (time-point 0:00), 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®, 
, 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 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.
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 (DG 1-10) and Flow Chart (DG-11). For restrictions with regard to diet see 
Section 4.2.2.2.
Subjects will be kept under close medical surveillance until 72 h after drug administration.
Thereafter, the trial will be performed in an ambulatory fashion.
4.1.6
Blinding and procedures for unblinding
4.1.6.1
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.
A single–blind design is considered acceptable because the potential bias in this type of study 
seems to be low and according to study procedures it is assured that the investigator's 
knowledge of the next treatment does not influence the decision to enter a subject.
All trial data will be handled open label. This means that trial functions of the sponsor are 
unblinded (including clinical monitor, data manager, statistician, bioanalyst, 
pharmacokineticist, pharmacometrician, drug metabolism scientist as well as dedicated 
personnel of the trial site). This is considered acceptable because the potential for bias seems 
to be low and does not outweigh practical considerations.

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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.
Subjects will be instructed not to perform any tasks or physical activity that may influence
the 24-hour ECG Holter recordings of HR in Visits 1 and 2.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured serum 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 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. At the EOT examination, it will include review of vital signs, 12-lead ECG, 
laboratory tests, a physical examination including determination of BW 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 (HR is considered to be equal to PR) will be 
measured by a BP monitor at the times indicated in Flow Chart (DG 1-10) and Flow Chart 
(DG-11), after subjects have rested for at least 5 min in a supine position. All recordings 
should be made using the same type of BP recording instrument on the same arm, if possible.
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 Flow Chart (DG 1-10) and Flow Chart (DG-11) after the 
subjects have fasted for at least 10 h for blood lab safety samples. For retests, at the discretion 
of the investigator or designee, overnight fasting is not required. The parameters that will be 
determined are listed in Table 5.2.3: 1 and 5.2.3: 2. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.

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Table 5.2.3: 1
Routine laboratory tests
Functional lab 
group
Test name
A
B
C
D
E
F
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
Reticulocytes, absol.
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
Glycosylated haemoglobin A1c (HbA1c)
X
X
X
X
X
X
X
X
X
X
X
X
X
--
X
X
X
X
X
X
--
--
--
--
--
--
--
--
X
X
X
X
X
X
--
X
X
X
X
X
X
--
Automatic WBC 
differential 
(relative and 
absolute)
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
X
X
X
X
X
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 
Prothrombin time – (INR)
X
X
X
X
X
X
--
--
X
X
X
X
Enzymes
AST (Aspartate transaminase) /GOT, SGOT 
ALT (Alanine transaminase) /GPT, SGPT
Alkaline Phosphatase (ALP)
Gamma-Glutamyl Transferase (GGT)
Creatine Kinase (CK)
Creatine Kinase Isoenzyme MB [only if CK is 
elevated] 
Insulin
Lactate Dehydrogenase
Lipase
Amylase
X
X
X
X
X
X
--
X
X
X
X
X
X
X
X
X
--
X
X
X
X
X
X
X
X
X
--
X
X
X
--
--
--
--
--
--
X
--
--
--
X
X
X
X
X
X
--
X
X
X
X
X
X
X
X
X
--
X
X
X
Hormones
Thyroid Stimulating Hormone (TSH)
X
--
--
--
--
--
Substrates
Glucose (Plasma or Serum)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
C-Peptide
Protein, Total
C-Reactive Protein (Quant)
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
--
X
X
X
X
X
X
X
X
X
--
X
X
--
--
--
X
X
X
X
--
X
X
X
X
X
X
--
--
--
X
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
X
X
X
X
--
X
X
X
X
X
Electrolytes
Calcium
Sodium
Potassium
Inorganic phosphate
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
X
X
X
X

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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Drug screening (serum)
Alcohol
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody 
To encourage compliance with alcoholic restrictions, a breath or urine alcohol test (e.g. 
Alcotest® 65107410 or 55106810, 
) will be performed prior to each 
treatment period, and may be repeated at any time during the study at the discretion of an 
investigator or designee. The results will not be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and Table 5.2.3: 2 will be performed at:
In Belgium the drug SCR and D-2 tests will be performed at the trial site using Triage Tox 
Drug Screen 94600 from 
 or comparable test systems. SARS-CoV-2 virus 
PCR test will be performed either by 
or the trial site.
Laboratory data will be transmitted electronically from the laboratory to the trial site.

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5.2.4
Electrocardiogram
5.2.4.1
12-lead resting Electrocardiogram
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 Flow Chart (DG 1-10) and Flow Chart (DG-11).
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 or a similar 
procedure to allow reproducible placement throughout the study.
To achieve a stable HR at rest and to assure high quality recordings, the site personnel will be 
instructed to assure a relaxed and quiet environment, so that all subjects are at complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled
for the same time (except for blood drawing from an intravenous cannula that is already in 
place) to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in Flow Chart (DG 1-10) and Flow Chart (DG-11).
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database.
Storing
All ECGs will be stored electronically at the ECG core lab for a minimum of 10 years.
Data transfer
All ECGs will be transferred electronically to the central ECG lab
, 
 for evaluation.
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).
Evaluation
a) Central ECG lab
Central ECG lab evaluation will be performed post-study for the first of each triplicate 
ECGs per time point on Days 1, 2, 3, 4, 5, 6, 8, 11, 15.

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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.
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 automatic interval measurements no lead will be provided.
For blinding arrangements see Section 4.1.5. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular subject should be evaluated by 
a single reader. For quality assurance and control of the measurements, all ECGs of a 
subject will be subsequently reviewed by the ECG technician supervisor or his/her 
designee to assess the overall variance of the measured intervals and, to detect 
accidental switching of leads and/or false subject assignments of the ECGs. After 
quality control, the fiducial point markings will be reviewed by the cardiologist 
assigned to the study.
Evaluation of ECGs will comply with the ICH E14 guidance document and 
supplements [R07-4722, R16-0366] as well as the FDA requirements for annotated 
digital ECGs [R09-4830].
b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of 
cardiac safety during the study, the QT and 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.
Abnormal findings, irrespective of whether they originate from central or local evaluation,
will be reported as AEs (during the trial) or baseline conditions (at SCR) 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 be asked to see a medical specialist to receive the appropriate 
medical treatment. 
5.2.4.2
Continuous Holter ECG recording
HR will be continuously recorded by means of 2-channel Holter ECGs for at least 24 hours in 
Visit 1 (SCR examination), in Visit 2 on Day -1 (for baseline assessment) and Visit 2 on 
Days 1, 2 and 3 (following drug administration) during the recording intervals indicated in 
Flow Chart (DG 1-10) and Flow Chart (DG-11) using 5-lead ECG Holter recorders (e.g. 

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CardioMem® CM-3000, 
). All recordings will be 
performed with five leads to create a two-channel ECG output.
The Holter devices and procedures and the evaluation of all Holter data will be managed by
an ECG core lab 
). The ECG Holter recording and
transmission procedures will be explained in detail in a study specific ‘ECG Holter manual’
which will be given to the trial site and stored in ISF. All recorded Holter data will be
electronically transferred to the core lab using a program supplied by the lab.
Each Holter recording will also be assessed by a board-certified cardiologist. The 
interpretation of Holter ECGs will include an overall assessment and a classification of each 
finding (normal, abnormal clinically relevant, abnormal clinically not relevant, not 
assessable). Abnormalities detected during centralised Holter ECG evaluation will be entered 
as AEs if assessed as clinically relevant based on the investigator’s judgment.
If the maximum serum concentrations of BI 3006337 reveal a significantly different tmax than
anticipated, the timing of the Holter HR recording in Visit 2 can be altered for the succeeding 
DGs.
For blinding arrangements see Section 4.1.5.
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 (DG 1-10) and Flow Chart (DG-11), 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.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
∀
Worsening of the underlying disease or of other pre-existing 
∀
Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator

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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 SAE is defined as any AE which fulfils at least one of the following criteria:
∀
Results in death 
∀
Is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 
∀
Requires inpatient hospitalisation
∀
Requires prolongation of existing hospitalisation
∀
Results in persistent or significant disability or incapacity 
∀
Is a congenital anomaly/birth defect 
∀
Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse
5.2.6.1.3
Adverse Events considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in Section 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI has set up a list of further AEs, which, by their nature, can always be considered to be 
‘serious’ even though they may not have met the criteria of an SAE as defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
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.
The following are considered as AESIs:
∀
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

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∀
An elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of T-BIL
≥2-fold ULN measured in the same blood sample, and/or
∀
Aminotransferase (ALT and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF. In 
case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, T-BIL) available, the Investigator should make sure that these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following except for 
vomiting:
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
As nausea, vomiting and diarrhea have been shown to be associated with pharmacological 
doses of GLP1R agonists, the intensity of such AEs is defined as follows for this clinical 
trial:
Nausea:
Mild: 
Early satiety and bloating, able to maintain caloric intake on regular diet
Moderate: 
Able to maintain nutrition with dietary and lifestyle modifications; may need 
pharmacologic intervention
Severe: 
Prolonged inadequate oral caloric or fluid intake; severe or medically 
significant but not immediately life-threatening; hospitalization (different from 
trial site) indicated
Vomiting:
Mild: 
Increase of < 3 episodes in 24 hours (individual episodes separated by at least 
30 min)
Moderate: 
3 to 5 episodes in 24 hours (individual episodes separated by at least 30 min)
Severe:
≥6 episodes in 24 hours (individual episodes separated by at least 30 min); 
severe or medically significant but not immediately life-threatening; requiring
i.v. fluids, or is resistant to antiemetic treatment, hospitalization (different
from trial site) indicated
Diarrhea:
Mild: 
Increase of <4 stools in 24 hours over baseline
Moderate: 
Increase of 4 - 6 stools in 24 hours over baseline
Severe: 
Increase of ≥7 stools in 24 hours over baseline; severe or medically significant
but not immediately life-threatening; requiring i.v. fluids, or is resistant to 
antidiarrheal treatment, hospitalization (different from trial site) indicated

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5.2.6.1.6
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the drug 
∀
The event is known to be caused by or attributed to the drug class
∀
A plausible time to onset of the event relative to the time of drug exposure
∀
Evidence that the event is reproducible when the drug is re-introduced
∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)
∀
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
∀
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger
∀
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
Adverse event collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in Flow Chart (DG 1-10) and Flow Chart (DG-11). Assessment will be made 

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using non-specific questions such as ‘How do you feel?’. Specific questions will be asked 
wherever necessary in order to more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
∀
From signing the informed consent onwards until an individual subject’s EOT: 
∀
All AEs (serious and non-serious) and all AESIs.
∀
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 
SCR failures prior to administration of any trial medication. In these cases, the 
subjects’ data must be collected at trial site but will not be entered in the CRF or 
trial database and will not be reported in the CTR.
∀
After the individual subject’s EOT:
∀
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and related SAEs and related AESIs 
of which the investigator may become aware of by any means of communication, 
e.g. phone call. Those AEs should, however, not be reported in the CRF.
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 via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
5.2.6.2.3
Information required
All (S)AEs, including those persisting after the individual subject’s EOT, must be followed 
up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no further 
information can be obtained.
5.2.6.2.4
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.

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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.
5.2.6.2.5
Hypoglycemia
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.
5.2.6.2.6
Neurological examination
A neurological examination will be performed at the time points specified in Flow Chart (DG
1-10) and Flow Chart (DG-11). The neurological assessment includes:
∀
General level of arousal (vigilance)
∀
Orientation
∀
Eye movement
∀
Pupil size and pupil reactivity
∀
Deep tendon reflexes
∀
Assessment of muscle strength
∀
Tremor
∀
Point-to-point movements
∀
Romberg test
∀
Gait
∀
Sensitivity
Documentation, Assessment and Reporting
Results will be documented in source data at the clinical trial site and assessed for clinical
relevance by an investigator, deputy investigator or sub-investigator. Clinically relevant
findings of the neurological examination will be reported as baseline conditions (at screening) 
and/or collected and reported as (S)AEs (during the trial, deviation/worsening from baseline). 
Case narratives may be written, if necessary.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Date and clock times of drug administration and PK sampling will be recorded in the CRFs.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. as a result of preliminary PK data), including addition of 

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samples and visits, as long as the total blood volume taken per subject does not exceed 
375 mL for DG 1-10 and 500 mL for DG-11. Such changes would be implemented via non-
substantial CTP Amendments.
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 3006337 concentrations in serum, 6.0 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 (DG 1-10) and Flow Chart (DG-11). Blood will be 
withdrawn by means of either an indwelling venous catheter or by venepuncture with a metal 
needle. The tube should be inverted 6 times (without shaking) and left upright at room 
temperature and undisturbed for 30 to 60 minutes to allow the sample to thoroughly clot.
The blood samples will be centrifuged for approximately 10-15 minutes at approximately 
1500 g to 2000 g and at room temperature. Three serum aliquots will be obtained and stored 
in polypropylene (PP) tubes. The first aliquot should contain at least 0.5 mL of serum. The 
remainder of the serum will be divided over aliquot 2 and 3. The process from end of 
centrifugation until transfer of serum aliqouts into the freezer should be completed within 30 
minutes. The time each aliquot was placed in the freezer will be documented. Until transfer 
on dry ice to the analytical laboratory, the aliquots will be stored upright at approximately -
70°C or below at the trial site. The second and third aliquots will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the serum samples will be stored at approximately -70°C or below
until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. Further information such as matrix, analyte and aliquot number may 
also be provided. The final instruction of blood sampling and processing will be written in a 
Laboratory Manual. 
After completion of the trial, the samples may be used for further methodological 
investigations (e.g. for stability testing). However, only data related to the analyte (including 
ADA, if applicable) will be generated by these additional investigations. The study samples 
will be discarded after completion of the additional investigations, but not later than 5 years 
after the CTR is archived.

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5.5
BIOBANKING
Not applicable.

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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 SCR and the EOT examination are provided in Flow Chart (DG
1-10) and Flow Chart (DG-11).
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 of Visit 2 are to be performed and completed within a 1 h- or 2 h- or 
3h period, respectively, prior to the trial drug administration (including blank values for PK 
and PD/biomarkers).
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 30 min for the first 72 h after trial drug. For the 24 h Holter ECG the maximum 
deviation will be ± 60 min for the first 72 h after trial drug. 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. 
Subjects are allowed to have a shower moment in the morning on Day 1, 2 and 3 of max 15 
minutes.
If several activities are scheduled at the same time point in Flow Chart (DG 1-10) and Flow 
Chart (DG-11), ECG should be the first and meal the last activity. Furthermore, if several 
measurements including venipuncture are scheduled for the same time, venipuncture should 
be the last of the measurements due to its inconvenience to the subject and possible influence 
on physiological parameters.
For planned individual serum concentration sampling times refer to Flow Chart (DG 1-10)
and Flow Chart (DG-11). 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 PK
parameters.
If a subject misses an appointment (e.g. ambulatory visit), it will be rescheduled if possible.
A time window of ± one day would be acceptable. The relevance of measurements outside 
the permitted time windows will be assessed no later than at the Report Planning Meeting
(RPM).
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Visit 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 study. For information 
regarding laboratory tests (including drug and virus SCR), ECG, 24 h Holter ECG, vital
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
6.2.2
Visit 2 - Baseline period
On Day -2, the subjects will be admitted to the trial site, a drug SCR and alcohol urine or breath 
test will be done at this time point. Additionally, a PCR test on Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2) will be performed. On Day -1, the examination of 

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laboratory parameters, ECG, vital signs for the generation of baseline values as well as Holter 
monitoring of HR take place. Subjects are instructed not to perform any tasks or physical 
activity that may influence the 24-hour ECG Holter recordings of HR. 
In the morning of Day 1 (i.e. the day with administration of BI 3006337 or placebo), subjects 
will undergo the examination of laboratory parameters, ECG, vital signs and start of Holter 
monitoring of HR for each subject prior to administration of BI 3006337 or placebo.
6.2.3
Visit 2 - Treatment period
Each subject will receive one dose of trial medication (BI 3006337 or placebo) on Day 1 of 
Visit 2 according to a randomized allocation.
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.
Study 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.
For details on time points and procedures for collection of serum samples for PK analysis, 
refer to Flow Chart (DG 1-10) and Flow Chart (DG-11) and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in Flow Chart (DG 1-10) and Flow Chart (DG-11). For details on times 
of all other trial procedures, refer to Flow Chart (DG 1-10) and Flow Chart (DG-11). AEs and 
concomitant therapy will be assessed continuously from SCR until the EOT examination.
6.2.4
Visit 3 - End of trial period
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the EOT period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue before the end of the planned treatment period should undergo the
EOT Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EOT Visit must be followed 
until they have resolved, have been sufficiently characterized, or no further information can 
be obtained.

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7.3.4
Safety analyses
Safety will be assessed as defined by the endpoints listed in Section 2.1.2 and 2.2.2 based on 
the TS. Safety analyses will be descriptive in nature and will be based on BI standards, refer 
to "Analysis and presentation of AE data from Clinical Trials" (BI-KMED-BDS-HTG-0041) 
and "Display and Analysis of Laboratory Data" (BI-KMED-BDS-HTG-0042). 
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, regardless of the DG 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 for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyse continuous 
(quantitative) data.

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7.4
INTERIM ANALYSES
No formal interim analysis is planned.
A preliminary analysis of PK parameters (AUC0-∞,Cmax and tmax of BI 3006337) as well as
nausea/vomiting and HR provided as individual values and appropriate summary measures, 
will be performed for 
∀
Dose levels 1, 2 and 3 before proceeding to dose level 7, and subsequently dose level 
8 and 9
∀
Dose levels 4, 5, 6 before proceeding to dose level 10
In contrast to the final PK
 calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows. Therefore, minor deviations may occur between preliminary and final results. 
The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without subject identification information. The 
preliminary results will be distributed to the investigator and the trial team. 
Depending on the results of available preliminary PK
 analyses and the tolerability and 
safety of the compound, changes to the dosing schedule (e.g., additional intermediate doses),
and additional PK
 preliminary analysis may be performed if requested by the Clinical
Trial Lead, the investigator or Trial Clinical pharmacokineticist. Preliminary PK
 results 
will not be reported in the CTR.
No inferential statistical interim analysis is planned. However, after completion of each DG
the investigator (or his or her deputy) is allowed to postpone further dose progression until a 
preliminary analysis of the data has been performed.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMIZATION
Each DG will be divided into three cohorts. The subjects of the first 2 cohorts (2 subjects per 
cohort) will not be randomized to maintain a treatment sequence of active-placebo (Cohort 1) 
and active-active (Cohort 2) due to safety reasons. In the third cohort of each dose level 
(4 subjects) the subjects will be randomized to active or placebo treatment using a 3:1 
allocation ratio (test treatment to placebo).
The sponsor will arrange for the randomization as well as packaging and labelling of trial 
medication. The randomization list will be generated using a validated system that uses a 

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pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable. The block size will be documented in the CTR. 
The randomization list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 92 subjects in this trial. The planned sample size is not based 
on a power calculation. The first 10 DGs have a sample size of 8 subjects. The size of 8 
subjects per DG (6 on active treatment, and 2 on placebo) is commonly used in SRD studies 
of the present type and is in general considered as sufficient for the exploratory evaluation of 
single dose safety and PK [R95-0013]. DG-11 has a sample size of 12 subjects due to 
.
Additional subjects may be entered to allow testing of 2 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 randomized 
subjects may exceed 92, but no more than 108 subjects are expected in this study.

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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 GCP, 
relevant BI SOPs, the EU regulation 536/2014, and other relevant regulations. Investigators 
and site staff must adhere to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of International Conference of Harmonization - Good Clinical Practice (ICH-
GCP).
The BI 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 archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the responsible IRB/Independent Ethics Committee (IEC) and CA according to 
national and international regulations. The same applies for the implementation of changes 
introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.

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8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB/IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
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:
∀
Subject identification: sex, year of birth (in accordance with local laws and 
regulations)
∀
Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)
∀
Dates of subject’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
AEs and outcome events (onset date [mandatory], and end date [if available])
∀
SAEs (onset date [mandatory], and end date [if available])

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∀
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 sponsor will monitor the conduct of the trial by regular on-site monitoring visits and 
inhouse data quality review. The frequency of site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
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 CRA, 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(s) must retain the source and essential documents (including ISF) according to 
the 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.
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 patient data in accordance with the principles 6 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:

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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, biobanking and 
future use of biological samples and clinical data, in particular
∀
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials
∀
An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place
∀
A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage
∀
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
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.

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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.
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER) (2005).
R09-1400
European Medicines Agency (EMEA). ICH topic M3 (R2) non-clinical 
safety studies for the conduct of human clinical trials and marketing 
authorization for pharmaceuticals: step 4: note for guidance on non-clinical 
safety studies for the conduct of human clinical trials and marketing 
authorization for pharmaceuticals (June 2009, CPMP/ICH/286/95). 
http://www.emea.europa.eu; 2009.
R09-4830 
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R12-0027
European Medicines Agency (EMA). Committee for medicinal products for 
human use (CHMP): ICH guideline S6 (R1) - preclinical safety evaluation 
of biotechnology-derived pharmaceuticals: step 5 (June 2011,
EMA/CHMP/ICH/731268/1998).
http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guide
line/2009/ 09/WC500002828.pdf (access date: 10 January 2012); London: 
European Medicines Agency (EMA); 2011.
R15-6057
Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital 
Stat Rep 2013; 61(4); 1-117.
R15-5365
Weston CJ, Shepherd EL, Claridge LC, Rantakari P, Curbishley SM, 
Tomlinson JW, et.al. Vascular adhesion protein-1 promotes liver 
inflammation and drives hepatic fibrosis. J Clin Invest 2015; 125(2); 501-
520.
R15-6070
Dharel N, Fuchs M. Nonalcoholic fatty liver disease - a major public health 
challenge for the 21st century. JSM Gastroenterol Hepatol 2014; 2(2); 
1018.
R16-0366
E14 Implementation Working Group. ICH E14 guideline: the clinical 
evaluation of QT/QTc interval prolongation and proarrhythmic potential for 
non-antiarrhythmic drugs: questions & answers (R3) (current version dated 
10 December 2015).
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/E
fficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2016); 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (2015).

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c30782091
BI 3006337 Investigator’s Brochure. Current version.
n00275086
Effect of 8 weeks of treatment with YH25724 on metabolic parameters, 
hepatic pathology and NAFLD Activity Score including Fibrosis Stage in 
male DIO-NASH mice.
n00275087
Efficacy study of YH25724 in thioacetamide (TAA)-included liver fibrosis 
model in Wistar rats.
n00275088
YH25724: Estimation of in vitro potencies of YH25724 binding to 
glucagon-like peptide 1 receptor (GLP-1R) of different species.
n00275089
Binding kinetics of YH25724 to human, mouse and rat beta-Klotho.
n00275090
Comparison of GLP-1 activity of YH25724 and dulaglutide in human and 
mouse GLP-1R overexpressed cell line.
n00276740
A 2-Week Repeated Dose Subcutaneous Dose Range Finding Toxicity 
Study and Toxicokinetic Study of BI 3006337 in ICR Mice. Report in 
finalization.
n00276741
Two-Week Repeated Subcutaneous Injection Toxicity and Toxicokinetic 
Study of BI 3006337 in Sprague-Dawley Rats. Report in finalization.
n00276743
Two-Week Repeated Subcutaneous Injection Toxicity and Toxicokinetic 
Study of BI 3006337 in Sprague-Dawley Rats. Report in finalization.
n00276744
BI 3006337: 2-week Subcutaneous Injection Dose Range Finding Toxicity 
Study in Cynomolgus Monkeys. Report in finalization.
n00276745
Toxicity Study by Daily Subcutaneous Injections to Sprague-Dawley Rats 
for 4 Weeks Followed by a 4 Week Recovery Period.
n00276746
Toxicity Study by Daily Subcutaneous Injection to Cynomolgus Monkeys 
for 4 Weeks Followed by a 4-Week Recovery Period.

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10.
APPENDICES
Not applicable.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1 
Date of amendment
28 Jan 2021
EudraCT number
EU number
2020-002600-38
BI Trial number
1466-0001
BI Investigational Medicinal 
Product(s)
BI 3006337
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising subcutaneous 
doses of BI 3006337 in overweight healthy male 
subjects (single-blind, partially randomised within 
dose groups, placebo-controlled, parallel 
(sequential) 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
Flow Chart, Section 1.4, Section 3.1, Table 5.2.3.1, 
Section 5.2.4.2
Description of change
Observation time for each subject was prolonged to 
72h. Time interval between each subject in cohort 
1, 2 and the first subject of cohort 3 was prolonged 
to 72h.
Rationale for change
HA request
Section to be changed
Section 3.1
Description of change
Dosing of cohort 3 of each dosing group will start if 
the data from all subjects of the first 2 cohorts are 
available and reviewed.
Rationale for change
HA request
Section to be changed
Section 3.1
Description of change
Data from all subjects from one dosing groups need 
to be available prior escalation to the next higher 
dose.
Rationale for change
HA request
Section to be changed
Section 3.3.5
Description of change
Subjects will not be replaced on study. If a subject 
is considered as non-evaluable for the minimum 
data set, enrolment of a new subject to the current 
cohort will be considered in order to support the 
benefit-risk assessment for dose escalation.

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Rationale for change
HA request
Section to be changed
Section 3.1
Description of change
Misleading wording regarding time interval 
between dosing groups was corrected.
Rationale for change
HA request
Section to be changed
Flow Chart, Footnote 17
Description of change
Close monitoring measures at post-dose, 1h after 
dosing and 2 h after dosing were implemented.
Rationale for change
HA request
Section to be changed
Flow Chart, Footnote 2, Footnote 7, Footnote 14, 
Footnote 18, numbering of Footnotes, Table of 
content, Section 1.2, Section 1.2.6, Section 1.2.7, 
Section 1.3, Section 1.4, Section 2.2.2.3, Section 
3.1, Section 3.1.2, Section 3.3.3, Section 3.3.4, 
Section 4.1, Section 4.1.1, Section 4.1.3, Section 
4.1.7.2, Section 4.2.1, Section 4.2.2.2, Section 
5.4.2, Section 5.4.3.1, Section 5.4.4.2, Section 6.1, 
Section 6.2.2, Section 7.3, Section 7.3.3.2, Section 
7.3.4, Section 7.4
Description of change
Removal of the paracetamol test from the protocol.
Rationale for change
HA request
Section to be changed
Flow Chart
Description of change
Consistence in the protocol regarding 1.5h fasting 
after dosing BI3006337
Rationale for change
HA request
Section to be changed
Section 4.1.5
Description of change
Detailed description of rescue procedure and 
personnel in case of an emergency situation during 
and after drug administration.
Rationale for change
HA request
Section to be changed
Section 3.1, Section 3.1.1, Section 4.1.5
Description of change
Clarification that the implementation of new dosing 
groups, that are not predefined in the protocol, are 
considered substantial.
Rationale for change
HA request
Section to be changed
Table of content, Section 3.1.1
Description of change
Clarification regarding the Data Safety Monitoring 
Board
Rationale for change
HA request
Section to be changed
Clinical trial protocol synopsis, Section 1.3, Section 
4.1.3, Table 3.1.1, Table 4.1.5.1
Description of change
Definition of new lower DGs
Rationale for change
Maximize safety for subjects
Section to be changed
Flow Chart, Section 1.4, Section 5.3.1, Section 
5.4.2
Description of change
Decreasing maximum total volume of blood 
withdrawn to 350ml

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Rationale for change
Due to removal of the paracetamol test and for 
consistency with the subject informed consent form
11.2
GLOBAL AMENDMENT 2 
Date of amendment
28 Jan 2021
EudraCT number
EU number
2020-002600-38
BI Trial number
1466-0001
BI Investigational Medicinal 
Product(s)
BI 3006337
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising subcutaneous 
doses of BI 3006337 in overweight healthy male 
subjects (single-blind, partially randomised within 
dose groups, placebo-controlled, parallel 
(sequential) 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
Flow Chart
Description of change
Space of time from Dinner (day-1) until drug 
administration
Rationale for change
Typing error
Section to be changed
Section 3.3.3
Description of change
Space of time in the EC19 description regarding the 
excessive physical activities prior to the 
administration of trial medication.
Rationale for change
Error in the earlier Version regarding the space of 
time.
Section to be changed
Section 5.2.3
Description of change
Drug SCR tests will be performed only at SCR
Rationale for change
Inconsistency in the earlier version between Flow 
Chart and Section 5.2.3
Section to be changed
Flow Chart, Section 2.2.2.3, Section 3.1.2
Description of change
Serum samples for adiponectin and bone biomarker 
assessments.
Rationale for change
Error in the earlier Version regarding measurements 
of adiponectin and bone biomarker.
Section to be changed
Section 5.3.2.1, Section 5.3.2.2
Description of change
Update of storage conditions for blood samples
Rationale for change
Error in the earlier Version

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Section to be changed
Section 1.4
Description of change
Implementation of a SARS-CoV-2 risk mitigation 
strategy
Rationale for change
Maximize safety for subjects
Section to be changed
Section 3.1
Description of change
DG
Rationale for change
Typing error in earlier Version
Section to be changed
Section 3.3.2
Description of change
Estradiol assessment (FISH) was removed from IC 
5
Rationale for change
Inconsistency between CTP and ICF
Section to be changed
Section 3.3.3
Description of change
Clarification of repetitive measurements in EC3, 
EC4 and EC21
Rationale for change
Misleading wording
Section to be changed
Section 3.3.4.1
Description of change
Clarification of subject removal due to ECGs 
findings (2)
Rationale for change
Error in the earlier Version regarding ECGs 
findings
Section to be changed
Flow Chart, Section1.4
Description of change
Screening process timeframe from day -24 until day 
-5
Rationale for change
Inconsistency within the earlier protocol version
Section to be changed
Flow Chart, 5.2.4.1
Description of change
Implement 12 lead ECG on day 11
Rationale for change
Error in the earlier Version regarding repeated 12-
lead ECGs over 336 hours following SC drug 
administration  
Section to be changed
Section 4.2.1
Description of change
Refer to Section 5.2.6.2.5 regarding Hypoglycemic 
events
Rationale for change
For clarification purpose
Section to be changed
Section 7.3.4
Description of change
Refer to Section 1.2.6 for declaration to which 
period recorded data will assigned.
Rationale for change
For clarification purpose
Section to be changed
Section 3.1
Description of change
Simultaneous dosing for one subject on active and 
one on placebo in cohort 1 of each DG
Rationale for change
For clarification purpose

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Description of change
Update excl. criteria 10 regarding alcohol abuse
Rationale for change
To avoid alcohol abuse
Section to be changed
Section 3.3.3, Section 5.2.4.1
Description of change
Specify the QT/QTcF interval
Rationale for change
For clarification purpose
Section to be changed
Section 3.3.3
Description of change
Specifiy the forbiddance of sperm donation
Rationale for change
Maximize safety to avoid accidental pregnancy
Section to be changed
Section 3.3.4
Description of change
Misleading wording
Rationale for change
Error in the earlier Version
Section to be changed
Section 4.1.5
Description of change
IMP administration in supine position
Rationale for change
Administrative reasons
Section to be changed
Section 4.1.5, Section 5.2.5.1
Description of change
Specify the mark of the injection site
Rationale for change
Due to local process
Section to be changed
Section 4.1.5
Description of change
Specify fasting after IMP administration
Rationale for change
For clarification purpose
Section to be changed
Section 4.1.5
Description of change
Remove the emergency process from the former 
CRO
Rationale for change
For administrative reasons
Section to be changed
Section 4.2.1
Description of change
Implement SARS-CoV-2 vaccination
Rationale for change
For administrative reasons
Section to be changed
Section 4.2.2.2
Description of change
Update the alcohol prohibition
Rationale for change
Avoid alcohol abuse
Section to be changed
Section 5.2.2
Description of change
Update the device for BP monitoring
Rationale for change
Administrative reasons
Section to be changed
Section 5.2.3
Description of change
Reference values will be provided by the CRO
Rationale for change
Administrative reasons
Section to be changed
Section 5.2.3
Description of change
Update the devices for Glucose monitoring, breath
alcohol test, drug test and SARS CoV-2 test.
Rationale for change
Administrative reasons
Section to be changed
Section 5.2.4.1
Description of change
Update the device for the twelve-lead resting ECG
Rationale for change
Administrative reasons
Section to be changed
Section 5.3.2.1
Description of change
Update the process of blood sampling for 
pharmacokinetic analysis
Rationale for change
For clarification purpose

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11.6
GLOBAL AMENDMENT 6
Date of amendment
07 Dec 2021
EudraCT number
EU number
2020-002600-38
BI Trial number
1466-0001
BI Investigational Medicinal 
Product(s)
BI 3006337
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising subcutaneous 
doses of BI 3006337 in healthy male subjects 
(single-blind, partially randomised within dose 
groups, placebo-controlled, parallel (sequential) 
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
Title page
Description of change
Remove overweight status of eligible subjects
Rationale for change
Extend BMI range from ≥20 to <32 kg/m2
Section to be changed
Clinical trial protocol synopsis
Description of change
Remove overweight status of eligible subjects, 
extend body mass index (BMI) ≥20 to <32 kg/m2
Rationale for change
Extend BMI range for a broader study population to
assess safety, tolerability, PK
Section to be changed
Flow Chart
Description of change
Implement a breakfast on Visit 2, day -1
Rationale for change
Administrative reasons
Section to be changed
Table of Content
Description of change
Update 4.1.8.
Rationale for change
Formatting error in earlier Version
Section to be changed
Section 1.3, Section 1.4, Section 2.1.1, Section 3.1, 
Section 3.3, Section 3.3.1, Section 4.1.3
Description of change
Remove overweight status of eligible subjects  
Rationale for change
Extend BMI range from ≥20 to <32 kg/m2
Section to be changed
Section 3.1.2
Description of change
Update new address of 
Rationale for change
Typing error in earlier Version
Section to be changed
Section 3.2.2
Description of change
Extend body mass index (BMI) ≥20 to <32 kg/m2
Rationale for change
Extend BMI range for a broader study population to 
assess safety, tolerability, PK and 

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Section to be changed
Section 3.3.3
Description of change
Increase BP range from 90 to 150 mmHg and left
the decision of eligibility to the investigator in case 
of documented white coat hypertension.
Rationale for change
BMI > 25 kg/m2 is usually associated with a higher 
blood pressure
Section to be changed
Section 4.1.7.1
Description of change
Update Section 4.1.7.1
Rationale for change
Formatting error in earlier Version
Section to be changed
Table 1.2.4:1
Description of change
Editorial reason
Rationale for change
Typing error in earlier version.
Section to be changed
Section 3.3.3
Description of change
Reduce the time of participation in another trial 
where an investigational drug has been 
administered to 30 days prior to planned 
administration of trial medication
Rational of change
Alignment to standard recruitment for healthy 
volunteers
11.7
GLOBAL AMENDMENT 7
Date of amendment
18 Jul 2022
EudraCT number
EU number
2020-002600-38
BI Trial number
1466-0001
BI Investigational Medicinal 
Product(s)
BI 3006337
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising subcutaneous
doses of BI 3006337 in healthy male subjects 
(single-blind, partially randomised within dose 
groups, placebo-controlled, parallel (sequential) 
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
Section 3.3.2
Description of change
Decrease the minimum absolute BW from 75 kg to 
70 kg at SCR
Rationale for change
Align the body weight to the BMI range from ≥20 
to <32 kg/m2

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11.8
GLOBAL AMENDMENT 8
Date of amendment
05 Sep 2022
EudraCT number
EU number
2020-002600-38
BI Trial number
1466-0001
BI Investigational Medicinal 
Product(s)
BI 3006337
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising subcutaneous 
doses of BI 3006337 in healthy male subjects 
(single-blind, partially randomised within dose 
groups, placebo-controlled, parallel (sequential) 
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
Title Page
Description of change
assigned as coordinating 
investigator
Rationale for change
Open an additional site in 
)
Section to be changed
Clinical Trial Protocol, Synopsis
Description of change
Trial Sites
Rationale for change
Multi-Centre Trial
Section to be changed
Flow Chart
Description of change
Extend screening period to 28 days (day-33 – day -
5)
Rationale for change
To obtain more time for proper screening of 
potential subjects
Section to be changed
Flow chart (footnote 5)
Description of change
Perform breath or urine test to avoid alcohol abuse
Rationale for change
To be more flexible to test alcohol abuse
Section to be changed
Flow Chart, Section 1.4, Section 5.3.1, Section 
5.4.2
Description of change
Increase the total blood volume from 350ml to 
375ml taken per subject
Rationale for change
Calculation error in earlier version
Section to be changed
Flow chart (footnote 15)
Description of change
Perform additional PCR test if locally necessary
Rationale for change
To increase safety of subjects and trial personnel
Section to be changed
Section 3.1

 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
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Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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