Clinical trial NCT03195088
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2017-07-27; Completion date: 2017-11-14
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this trial is to investigate the safety and tolerability of single rising doses of BI 473494 in healthy male subjects.

The secondary objective is the exploration of PK including dose proportionality, and PD of BI 473494 after single dosing.

Detailed description:

Arms: arm 1: Healthy participants were administered a single dose of placebo matching BI 473494 solution via subcutaneous injection. arm 2: Healthy participants were administered a single dose of 35 micrograms (μg) BI 473494 solution via subcutaneous injection. arm 3: Healthy participants were administered a single dose of 75 micrograms (μg) BI 473494 solution via subcutaneous injection.
Interventions: intervention 1: BI 473494 intervention 2: Placebo
Intervention descriptions: intervention 1: Solution for injection intervention 2: Solution for injection

Protocol documents:
Prot_002.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c11760893-01
EudraCT No.:
BI Trial No.:
2016-003224-24
1400-0001
BI Investigational
Product:
BI 473494
Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of 
single rising subcutaneous doses of BI 473494 in healthy male 
subjects (single-blind, partially randomised, placebo-controlled 
parallel group design)
Lay Title:
This study in healthy men tests how different doses of BI 473494 are 
taken up in the body and how well BI 473494 is tolerated.
Clinical Phase:
I
Trial Clinical Monitor:
Phone: 
Fax: 
Principal Investigator:
Phone: 
Fax: 
Status:
Final Protocol
Version and Date:
Version: 1.0
Date: 02 May 2017
Page 1 of 87
Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 473494
Protocol date:
Trial number:
Revision date:
Not applicable
02 May 2017
1400-0001
Title of trial:
Safety, tolerability, pharmacokinetics and pharmacodynamics of single rising 
subcutaneous doses of BI 473494 in healthy male subjects (single-blind, partially 
randomised, placebo-controlled parallel group design)
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate safety, tolerability, pharmacokinetics (PK) incl. dose proportionality, 
and pharmacodynamics (PD) of BI 473494 following single rising doses 
Methodology:
Single-blind, partially randomised within dose groups, placebo-controlled, parallel-
group design
No. of subjects: 
total entered:
88*
each treatment:
8 per dose group (6 on active drug and 2 on placebo)
* Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned and 
approved highest dose will not be exceeded. Thus, the actual number of subjects entered may 
exceed 88, but will not exceed 104 subjects entered.
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 45 years (inclusive), body mass index (BMI) of 
20.0 to 29.9 kg/m2 (inclusive)
Test products:
BI 473494 solution for injection (1 mg/mL and 10 mg/mL)
dose:
35 µg - 75 µg - 150 µg - 300 µg - 550 µg - 1.0 mg - 1.6 mg - 2.6 mg - 4.0 mg - 6.0 mg
- 8.5 mg
mode of admin.:
Subcutaneous (SC) injection 
Comparator product:
Placebo (isotonic sodium chloride solution)
dose:
Not applicable
mode of admin.:
SC injection
Duration of treatment: Single dose


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 473494
Protocol date:
Trial number:
Revision date:
Not applicable
02 May 2017
1400-0001
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 473494 is the number [N (%)] 
of subjects with drug-related adverse events (AEs).
Further criteria of interest:

AEs including clinically relevant findings from the physical examination, safety 
laboratory tests, 12-lead electrocardiogram (ECG), vital signs (blood pressure 
[BP], pulse rate [PR]  
 
Criteria for
pharmacokinetics:
Secondary endpoints: AUC0-tz and Cmax of BI 473494
Criteria for 
pharmacodynamics:
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
Dose proportionality of BI 473494 will be explored using a regression model. A 95% 
confidence interval (CI) for the slope will be computed.


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FLOW CHART
Visit
Day
Planned time (relative to 
trial activities 17 [h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
BI 473494 in plasma 10, 11
PK urine
10,12,13
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-21 to 
-2
Screening (SCR)1
x
x
x
x
2
-1
-24:00
08:00
Ambulatory visit7
x7
x7
x7
x7
-12:30
18:30
Admission to trial site
x15
x
-12:00
19:00
Dinner
1
-0:452
06:15
Allocation to subject number
x
x
-0:10
06:50
0:00*
07:00
0:15
07:15
0:30
07:30
0:45
07:45
1:00
08:00
x
x
1:30
08:30
2:00
09:00
240 mL fluid intake
x
x
3:00
10:00
4:00
11:00
5:00
12:00
Lunch3, discharge from trial site5,19
x
x
6:00
13:00
8:00
15:00
9:00
16:00
Snack (voluntary)19
10:00
17:00
Discharge from trial site19
x
12:00
19:00
Dinner19
3
-1
-12:00
20:00
Admission to trial site19
x15
x
1
-1:002
07:00
 
x
x
x
x18
x
x
0:00*
08:00
SC injection of BI 473494 or 
placebo
▲
│
1:30
09:30
240 mL fluid intake, light 
breakfast3
│
│
3:00
11:00
4:00
12:00
240 mL fluid intake, lunch3
│
6:00
14:00
x
x
│
x9
x
x
8:00
16:00
Snack (voluntary)
│
9:00
17:00
11:00
19:00
Dinner
│
12:00
20:00
15:00
23:00
x
│


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Visit
Day
Planned time (relative to 
trial activities 17 [h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
BI 473494 in plasma 10, 11
PK urine
10,12,13
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
2
22:00
06:00
x
│
x
x
22:50
06:50
│
23:00
07:00
23:15
07:15
│
23:30
07:30
│
23:45
07:45
│
24:00
08:00
24:30
08:30
│
25:00
09:00
240 mL fluid intake3
│
x
x
26:00
10:00
│
x
27:00
11:00
│
28:00
12:00
Lunch3
x
│
x9
x
x
29:00
13:00
│
31:00
15:00
│
32:00
16:00
Snack (voluntary)
│
33:00
17:00
│
34:00
18:00
x
│
x9
x
x
35:00
19:00
Dinner
│
36:00
20:00
39:00
23:00
x
│
3
48:00
08:00
 
breakfast
x
x8
┼
│
x9
x
x
52:00
12:00
Lunch3
│
x
56:00
16:00
Snack (voluntary)
│
59:00
19:00
Dinner
│
60:00
20:00
x
│
x9
x
x
4
72:00
08:00
Breakfast (voluntary)3,
discharge from trial site
x
▼
x9
x
x
5
96:0014
08:00
Ambulatory visit
x
x9
x
x
6
120:0014
08:00
Ambulatory visit, 
x
x
x9
x
x
8
168:0014
08:00
Ambulatory visit
x
x9
x
x
11
240:0014
08:00
Ambulatory visit,
x
x9
x
15
336:0014
08:00
Ambulatory visit
x
x
x9
x
x
22
504:0014
08:00
Ambulatory visit, 
x
x
x9
x
x
29
672:0014
08:00
Ambulatory visit
x
x
x9
x
x
4
33 to 
40
End of trial (EOT) examination4
x
x
x
x
* Activities planned at 0:00 h on Day 1 of Visit 2 and Day 1 of Visit 3 may be separated by up to 4 days


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1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. 
2.
The time is approximate; the respective procedures are to be performed and completed 
 
 within 2 h prior to administration of BI 473494 or placebo in Visit 3. Allocation to treatment may be performed at
any time following enrolment but must be completed prior to 
3.
If several actions are indicated at the same time point, the intake of meals or liquids will be the last action.
4.
End of trial examination includes physical examination, body weight, vital signs, ECG, safety laboratory, recording of 
AEs and concomitant therapies.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to 
 
This safety lab will not include drug screening or alcohol 
breath test. The ambulatory visit can be omitted, if the screening examination is performed on Days -3 or -2. 
8.
In addition, two blood samples for stability testing will be taken at this point in DG 6 (1.0 mg), (refer to
Section 5.5.2.6).
9.
The ECG recording has to be performed as triple at this time point.
10. Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK data),
including addition of samples and visits as long as the total blood volume taken does not exceed 500 mL per subject. 
11.  Including blood sample for metabolite identification only in DG 6 (1.0 mg), (refer to Section 5.5.2.2).
12. A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the stated post-dose intervals (◄––│––│––►) 0-12, 12-24, 24-48 and 48-72h.
13. Urine sampling will be performed from DG 5 (550 µg) onwards.
14.  On Days 5-29, a deviation from the scheduled time of ± 70 min is acceptable for all the planned trial activities.
15.  Only urine drug screening and alcohol breath test will be done at this time point. On Day -1 in Visit 3, this safety 
laboratory is not needed when there is no discharge from trial site between Day 1 of Visit 2 and Day-1 of Visit 3.
17.  Planned time 
 relative to administration of BI 473494 or placebo in Visit 3.
18.  Three pre-dose triplicate ECGs within 60 minutes are to be recorded as baseline.
19.  Discharge in Visit 2, Day 1 is optional. Trial activities related to discharge will be adjusted accordingly.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 15
1.1
MEDICAL BACKGROUND............................................................................15
1.2
DRUG PROFILE...............................................................................................16
1.2.6
Clinical experience in humans.............................................................21
1.2.7
Drug product.........................................................................................21
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 22
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................22
2.2
TRIAL OBJECTIVES.......................................................................................25
2.3
BENEFIT - RISK ASSESSMENT ...................................................................25
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 29
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................29
3.1.1
Administrative structure of the trial...................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................31
3.3
SELECTION OF TRIAL POPULATION ......................................................32
3.3.1
Main diagnosis for study entry............................................................32
3.3.2
Inclusion criteria...................................................................................32
3.3.3
Exclusion criteria ..................................................................................33
3.3.4
Removal of subjects from therapy or assessments.............................34
3.3.4.1
Removal of individual subjects................................................34
3.3.4.2
Discontinuation of the trial by the sponsor..............................35
3.3.5
Replacement of subjects .......................................................................36
4.
TREATMENTS........................................................................................ 37
4.1
TREATMENTS TO BE ADMINISTERED....................................................37
4.1.1
Identity of BI investigational product and comparator product......37


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4.1.3
Method of assigning subjects to treatment groups ............................38
4.1.4
Selection of doses in the trial................................................................39
4.1.5
Drug assignment and administration of doses for each subject .......39
4.1.6
Blinding and procedures for unblinding ............................................40
4.1.6.1
Blinding....................................................................................40
4.1.6.2
Procedures for emergency unblinding .....................................41
4.1.7
Packaging, labelling, and re-supply ....................................................41
4.1.7.1
BI 473494.................................................................................41
4.1.8
Storage conditions.................................................................................42
4.1.9
Drug accountability ..............................................................................42
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................43
4.2.1
Other treatments and emergency procedures....................................43
4.2.2
Restrictions............................................................................................44
4.2.2.1
Restrictions regarding concomitant treatment .........................44
4.2.2.2
Restrictions on diet and life style.............................................44
4.3
TREATMENT COMPLIANCE.......................................................................45
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 46
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................46
5.1.1
Endpoints of efficacy.............................................................................46
5.1.2
Assessment of efficacy...........................................................................46
5.2
SAFETY..............................................................................................................46
5.2.1
Endpoints of safety................................................................................46
5.2.2
Assessment of adverse events...............................................................46
5.2.2.1
Definitions of adverse events...................................................46
5.2.2.2
Adverse event collection and reporting ...................................49
5.2.3
Assessment of safety laboratory parameters......................................51
5.2.4
Electrocardiogram................................................................................54
5.2.4.1
12-lead resting ECG.................................................................54
5.2.5
Assessment of other safety parameters...............................................56
5.2.5.1
Vital signs ................................................................................56
5.2.5.2
Medical examinations..............................................................56
5.3
OTHER...............................................................................................................56
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................56
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................57
5.5.1
Pharmacokinetic endpoints..................................................................57
5.5.1.1
Secondary endpoints................................................................57


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5.5.2
Methods of sample collection...............................................................58
5.5.2.1
Plasma sampling for pharmacokinetic analysis of BI 473494.58
5.5.2.2
Plasma sampling for metabolism analysis ...............................59
5.5.2.4
Urine sampling for pharmacokinetic analysis..........................60
5.5.2.5
Urine sampling for metabolism analysis..................................61
5.5.2.6
Additional blood sample for stability-testing ..........................62
5.5.3
Analytical determinations ....................................................................63
5.5.3.1
Analytical determination of BI 473494 plasma concentration 63
5.5.3.2
Analytical determination of BI 473494 urine concentration ...63
5.7
PHARMACODYNAMICS................................................................................64
5.7.4
Methods of sample collection...............................................................66
5.7.4.1
Plasma glucose.........................................................................66
5.7.4.2
Plasma insulin..........................................................................67
5.7.5
Analytical determinations ....................................................................68
5.7.5.1
Analytical determination of plasma glucose and insulin.........68
6.
INVESTIGATIONAL PLAN.................................................................. 70
6.1
VISIT SCHEDULE............................................................................................70
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................70
6.2.1
Visit 1 - Screening period .....................................................................70
6.2.2
Visit 2 – Baseline period .......................................................................71
6.2.3
Visit 3 – Treatment period ...................................................................71
6.2.4
Visit 4 - End of trial period ..................................................................71
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 73
7.1
STATISTICAL DESIGN – MODEL ...............................................................73
7.1.1
Objectives...............................................................................................73
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................73
7.3
PLANNED ANALYSES....................................................................................73
7.3.1
Primary analyses...................................................................................73
7.3.2
Secondary analyses ...............................................................................73
7.3.3
Safety analyses.......................................................................................75
7.3.4
Preliminary PK analyses......................................................................76


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7.3.5
Pharmacokinetic analyses ....................................................................76
7.4
HANDLING OF MISSING DATA ..................................................................78
7.4.1
Safety......................................................................................................78
7.4.2
Plasma/urine drug concentration - time profiles ...............................78
7.4.3
Pharmacokinetic parameters...............................................................78
7.5
RANDOMISATION ..........................................................................................78
7.6
DETERMINATION OF SAMPLE SIZE ........................................................79
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 80
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................80
8.2
DATA QUALITY ASSURANCE .....................................................................80
8.3
RECORDS..........................................................................................................81
8.3.1
Source documents .................................................................................81
8.3.2
Direct access to source data and documents.......................................81
8.3.3
Storage period of records.....................................................................81
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................81
8.5
STATEMENT OF CONFIDENTIALITY.......................................................81
8.6
COMPLETION OF TRIAL..............................................................................82
9.
REFERENCES......................................................................................... 83
9.1
PUBLISHED REFERENCES...........................................................................83
9.2
UNPUBLISHED REFERENCES.....................................................................85
10. APPENDICES .......................................................................................... 86
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 87


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ABBREVIATIONS
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse events of special interest
Aet1-t2
Amount of analyte eliminated in urine over the time interval t1 to t2
AMP
Auxiliary Medicinal Product
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BW
Body weight
CA
Competent authority
CALCR
Calcitonin receptor
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CML
Clinical Monitor Local


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CRA
Clinical Research Associate
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CTSU
Clinical Trial Supplies Unit
CYP
Cytochrome P450
DG
Dose group
DI
Disposition index
DILI
Drug induced liver injury
EC50
Half-maximal effective concentration
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EMA
European Medicines Agency
EOT
End of trial
F
Absolute bioavailability factor
FDA
Food and Drug Administration
FE
Fluoride EDTA
FIH
First in human
GCP
Good clinical practice
GLP
Good laboratory practice
HbA1c
Glycosylated Haemoglobin A1c (N-(1-Deoxy)Fructosyl-Haemoglobin)
HED
Human equivalent dose
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IPVs
Important protocol violations
IRB
Institutional Review Board
ISF
Investigator site file


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LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MedDRA
Medical Dictionary for Regulatory Activities
NOA
Not analysed
NOAEL
No observed adverse effect level
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PE
Polyethylene
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
qw
Once weekly
REP
Residual effect period
SAE
Serious adverse event
SC
Subcutaneous
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SRD
Single-rising dose
T2D
Diabetes mellitus type 2
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
Ter in die, three times daily
TMF
Trial master file
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma


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TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WOCBP
Women of child-bearing potential
ZDF rat
Zucker Diabetic Fatty rat


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
The prevalence of diabetes is increasing at an alarming rate. Approximately 95% of these
cases are accounted for type 2 diabetes (T2D). Factors contributing to this increased
prevalence are obesity, physical inactivity, and an increasingly aging population. In the US,
diabetes is the leading cause of blindness, end stage renal disease and lower extremity
amputations. Further, the overall risk of cardiovascular disease is more than doubled, and life
expectancy is reduced by an average of 7 years. An HbA1c <7% set forth by the American
Diabetes Association to reduce the risk of diabetes complications is achieved in only about
50-60 % of T2D patients in western countries and hasn´t improved further in recent years. As
almost 90% of T2D patients are overweight or obese, and obesity further worsens glycemic
control and diabetic complications, a major fear for patients is to gain even more weight on 
anti-hyperglycemic medication like insulin, thiazolidinediones and sulfonylureas. In addition,
the risk of hypoglycaemia in patients treated with sulfonylureas or insulin is a major fear for
these patients [c14085574].
Obesity with and without T2D is also a highly prevalent disease. Obesity is associated with a 
variety of medical conditions, including all components of the metabolic syndrome, cardio-
vascular, pulmonary, gastrointestinal, endocrine, joint as well as psychosocial disorders. 
Although some of these conditions can be treated by currently available medications, others 
are very difficult to treat and pose a significant challenge to caregivers. In general and 
according to regulatory guidelines, medical treatment for weight loss is recommended for 
obese patients with a body mass index (BMI) > 30 kg/m2 as well as overweight patients with 
a BMI > 27 kg/m2 and at least one weight-associated co-morbidity [c14085574].
Amylin is a peptide hormone which is co-secreted with insulin from pancreatic islet cells and 
influences postprandial glucose excursions as well as food portion size and food preferences. 
While insulin replacement therapy is a hallmark of diabetes treatment in patients with 
dysfunctional -cells, i.e. patients deficient in both insulin and amylin, the restoration of both 
hormones may allow a more thorough control of glucose homeostasis [R17-0949].
The short-acting amylin analogue pramlintide (Symlin®), which has been approved by the 
FDA in 2005, induced anti-diabetic efficacy in humans and has been evaluated for the 
treatment of obesity in several clinical trials. In a meta-analysis of eight randomized clinical 
trials in patients with T2D receiving insulin, a 16-52 week treatment with pramlintide (120-
150 μg b.i.d-t.i.d), showed a significant HbA1c reduction of about -0.3 % versus control. 
Furthermore, the combined analysis of weight loss in diabetic and non-diabetic obese patient 


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showed a modest body weight reduction of about -2.3 kg [R14-1973]. Supportive evidence 
for the achievement of a higher efficacy comes from a Phase 2 dose-range clinical trial in 
non-diabetic obese patients. In an extension period treatment using 360 μg b.i.d pramlintide, 
a placebo corrected body weight loss of 7.2 kg (6.8%) after 12 month was achieved 
[R17-0597]. With the lower dose of 120 μg t.i.d., 40% of patients vs. 12% for placebo 
achieved >10% weight loss [c14085574]. 
1.2
DRUG PROFILE


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1.2.6
Clinical experience in humans
This is a First-in-Man (FIM) study. Clinical data are not available up to date. For further 
details see “Investigator’s Brochure” [c14085574].
A short-acting amylin agonist, pramlintide (Symlin®), was approved by the FDA in 2005 for 
subcutaneous administration in patients with diabetes type 1 or 2 who show unfavourable 
glycaemic control despite optimal insulin treatment. The most common side effects of this 
short-acting amylin agonist are nausea, vomiting, anorexia and headache. These events seem 
to be dose-dependent, easy to monitor, reversible and manageable in clinical trials. 
Hypoglycaemic events as described particularly in patients with type 1 diabetes when 
pramlintide was co-administered with insulin are not expected in this trial where healthy male 
subjects will receive a single dose of BI 473494 [R17-0994].
1.2.7
Drug product
Please refer to Section 4.1. For a more detailed description of BI 473494’s profile please refer 
to the current Investigator’s Brochure [c14085574].


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Following favorable preclinical investigations of the long-acting amylin agonist BI 473494, 
this first-in-human (FIH) trial will be performed to investigate safety, tolerability, 
pharmacokinetics and pharmacodynamics of BI 473494 in healthy male volunteers to provide
the basis for further clinical development in the indications obesity and T2D.
Healthy male volunteers aged 18 - 45 years will be recruited for this trial. They provide a 
relatively stable physiological, biochemical and hormonal basis (steady state) for studying 
drug effects, they show no disease-related variation and are not taking concomitant 
medication. Within each dose group, all actively treated subjects will receive the same dose 
of BI 473494. The next higher dose will only be administered if the treatment in the 
preceding dose group was safe and showed acceptable tolerability as assessed during the 
study as well as in a documented safety review prior to dose escalation.
Dose selection
It is planned to investigate the following dose levels of BI 473494 in this trial: 35 µg, 75 µg,
150 µg, 300 µg, 550 µg, 1.0 mg, 1.6 mg, 2.6 mg, 4.0 mg, 6.0 mg and 8.5 mg. The rationale 
for this dose selection is described in the following paragraphs.
1.
Selection of starting dose
No safety or efficacy data for BI 473494 in humans are available. The rationale for the 
starting dose is based on nonclinical toxicology, safety pharmacology and pharmacokinetic 
data.
According to the US FDA Guidance for Industry ‘Estimating the Maximum Safe Starting 
Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers’ [R06-1037], the 
Cynomolgus monkey was considered the most appropriate species for calculating the safe 
starting dose of BI 473494. This species shows a comparable pharmacodynamic response to 
activation of amylin and calcitonin receptors. The derived pharmacokinetic parameters (e.g. 
Cmax, AUC0-168, plasma protein binding) were very similar to the predicted human 
parameters.


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Using allometric scaling according to the above mentioned FDA Guidance,
 
divided by a conversion factor for body surface area of 3.1 (monkey), results 
in a human equivalent dose (HED) of 129 µg/kg/week. Applying a default safety factor of 10, 
a resulting safe starting dose of 12.9 µg/kg is derived, resulting in 774 µg for an individual 
with 60 kg body weight. This dose is in the range of the estimated human therapeutic dose. 
However, significant pharmacological effects (body weight loss and thymus involution/ 
atrophy, reduction of plasma calcium and magnesium) were seen in Cynomolgus monkeys at
the low dose of 20 µg/kg/week. The corresponding HED is 6.45 µg/kg/week and the resulting 
dose for a 60 kg individual is 387 µg. After applying a default safety factor of 10 the safe 
starting dose is 38.7 µg (rounded to 35 µg). 
An identical safe starting dose including a safety factor of 10 would be calculated if the 
lowest dose inducing effects which might be interpreted as cases of hypocalcemic tetany in 
rats (i.e. at ~40 µg/kg) would be used as a starting point for the calculation of the HED.
Therefore, to avoid significant pharmacodynamic effects with the first dose, the 
recommended safe starting is 35 µg. 
 
 For details, see Section 5.3.8 of the Investigator’s 
Brochure [c14085574].
 
 
Since the observed PD effects have been shown 
to be dose-dependent [c14085574] and a sufficient safety margin has been applied, no 
inacceptable effects would be expected at the starting dose.
2.
Maximum dose 
As stated above, a weekly dose of about 800 µg may be required to achieve therapeutic 
systemic exposure of BI 473494 in patients with T2D. An even higher dose/exposure might 
be required for the treatment of obesity. Higher doses might still be well tolerated while 
providing a larger magnitude of therapeutic effects. Furthermore, testing of doses higher than 
800 µg is reasonable to account for bioavailability or in vivo pharmacological potency being 
lower than expected. Additionally, higher than therapeutic doses are typically explored in 
FIH studies to provide a safety margin for subsequent studies (e.g. studies with multiple 
dosing and accumulation, drug-drug interaction studies, studies in patients with impaired 
excretion function, etc.) or for accidental IV injection with higher bioavailability, where 
substantial increases in exposure (AUC and/or Cmax) may be seen.
For this clinical trial, 8.5 mg has been selected as the maximum dose, a dose that is expected 
to be high enough to obtain exposures in the therapeutic range, even if the bioavailability is 
significantly lower than the expected 60% (see Section 1.2.5). 


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However, for the case that exposure is higher than anticipated (e.g. due to bioavailability 
higher than expected or non-linear kinetics) and to account for uncertainties in the 
determination of NOAEL in the preclinical species, 
These exposure limits provide sufficient safety 
margins to the highest exposure at steady state tested in Cynomolgus monkeys where strong 
pharmacodynamics effects (Body weight loss and thymus involution/atrophy, strong 
reduction of calcium and magnesium, decrease in body temperature and increase in QTcR)
were seen 
. They also 
provide sufficient safety margins to the highest exposure at steady state tested in rats where 
effects on bone marrow, thymus and spleen were seen. The effects in rats are considered to 
occur secondary to weight loss and were only partially reversible after 4 weeks recovery
No such effects are expected after single 
dose in humans since weight loss is considered to be minor if at all after single dose 
administration in the FIH study.
To prevent that an exposure beyond this threshold will be reached in the human study, 
preliminary PK data of preceding dose groups will be provided to confirm exposure is in the 
range of predicted values and to estimate the expected exposure of the next dose group (see 
Section 7.3.4).
 
3.
Dose escalation
In order to cover the anticipated dose range with due caution, a stepwise and moderate dose 
increase up to a maximum dose of 8.5 mg has been selected for this trial. Dose escalation will 
not exceed a factor of 2.1 and the escalation factor will be as shallow as 1.5 to 1.4 for the 
higher dose range. This dose escalation is expected to be adequate and safe, particularly when 
the preclinical dose/concentration-toxicity relationships are taken into consideration.
Finally, preliminary (interim) PK data will be provided in order to further support the safe 
conduct of the trial (see Section 7.3.4).


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2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the safety and tolerability of single rising 
doses of BI 473494 administered subcutaneously in healthy male subjects.
The secondary objective is the exploration of PK including dose proportionality,
of 
BI 473494 after single dosing. 
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of a new long-
acting subcutaneous drug which might improve therapy for obesity with or without T2D. The
subjects are exposed to the risks of the study procedures and the risks related to the exposure 
to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to veinpuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
Drug-related risks and safety measures
Since the nature of the target and the mode of action of BI 473494 are well understood - a 
short-acting compound from the same class (amylin agonist) has been marketed for over a 
decade - and the animal models used are believed to be predictive for the effects in humans, 
BI 473494 is not seen as a high risk compound. The pharmacological effects of BI 473494 
are dose-dependent and no evidence for prolonged effects or effects other than those expected 
by the pharmacological activity of the compound have been observed. Following repetitive 
dosing, plasma exposures
 
 are supported by preclinical safety data in Cynomolgus monkey
and rats, respectively.


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To ascertain the safety and minimize the risk for healthy volunteers, several safety measures 
and investigations will be implemented in this trial:

Only healthy volunteers will be included according to the in- and exclusion criteria.

Careful dose selection as described in Section 2.1. The start dose is selected with due 
caution and has ample safety margins with respect to both, NOAEL in the most 
sensitive species and pharmacodynamic effects. Dose escalation will be shallow as 
outlined in Section 2.1. Finally, dose selection was based on a sound preclinical 
package including 6 weeks toxicological studies.

Preliminary measurement of BI 473494 plasma concentrations and preliminary 
determination of PK parameters (AUC, Cmax,, see Section 7.3.4). For the sake of 
caution, drug plasma concentrations of healthy male volunteers in this trial
 
will be
considered as a preliminary threshold (see Section 2.1). Further dose escalation 
beyond these thresholds would only be allowed after a safety interim analysis and 
filing and approval of a substantial CTP amendment. 


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
An extensive safety laboratory will be performed with special focus on full blood
exam (see time points in the Flow Chart).

For safety reasons, each dose group of 8 subjects (6 on active, 2 on placebo) will be 
divided into 3 cohorts. The 1st and 2nd cohort will each comprise 2 subjects, the 3rd
cohort will be a group of 4 subjects. Investigational drug administrations in these 
three cohorts will be separated by at least 72 hours (between 1st subject of each 
cohort), which is based on an anticipated median tmax of BI 473494 of 16-20 h (as 
derived from the median tmax of semaglutide in humans [R17-0493]) and median tmax
of 32-40 h (as derived from the 6 weeks toxicology study in Cynomolgus monkeys 
[n00253475]) and is expected to cover the period of highest risk and peak 
pharmacodynamic effects. The first 2 cohorts will be dosed in a single blind, fixed 
sequence mode ‘active – placebo’ (1st cohort) and ‘active – active’ (2nd cohort). This 
design ensures that there is a time interval of at least 72 hours between first and 
second active dose of each dose level. This is expected to be sufficient to detect 
relevant acute effects of BI 473494. If BI 473494 was safe and well tolerated during 
the first administration, the remaining subjects of the respective dose level could be 
dosed as close as 10 minutes apart.

A thorough ECG monitoring to cover the anticipated period of highest drug exposure 
with triple 12-lead ECGs over 29 Days following SC drug administration. Dose
escalation would be stopped as soon as at least 2 subjects at one dose level showed 
relevant QT prolongation (see Section 3.3.4.2 for details).

Vital signs, body weight, aural body temperature will be assessed at time points given
in the Flow Chart.

Although the risk of hypoglycaemic events is considered to be low for BI 473494 
based on its mode of action 
blood glucose will be monitored
 
 after administration of investigational trial medication (see Flow 
Chart).

Although the risk of hypocalcemic events is considered low in healthy humans, 
 
 and clinical signs of hypocalcemia will be closely monitored and dose 
escalation would be stopped if any of the pre-specified trial-specific stopping criteria 
were met as outlined in Section 3.3.4.2.  

Participants will stay at the trial site for at least 72 h after SC investigational drug 
administration at each dose level.
 
 
this is expected to cover the 
period of highest risk and peak pharmacodynamic effect.

During in-house confinement subjects will be under medical observation and closely 
monitored for both expected and unexpected adverse events.


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
Only if the respective dose of BI 473494 was safe and showed acceptable tolerability 
and if no stopping criterion was met (refer to Section 3.3.4.2), the next higher dose
will be given no earlier than 20 days later (referring to the 1st subject of each dose 
group).

A documented Safety Review will be performed prior to each dose escalation (see 
Section 3.1)

As reproductive toxicity studies have not yet been conducted, women of child-bearing 
potential will not be included in this study.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety, see also Section 5.2.2.1.
In summary, the information gained from this trial will provide the basis for further clinical 
development of the long-acting amylin analogue BI 473494 which is expected to become a 
valuable therapeutic option for patients with obesity and T2D. BI 473494 has a favourable 
benefit-risk-assessment which allows safe testing in humans. Based on a thorough preclinical 
data package as well as knowledge gained from more than 10 years of experience with the 
short-acting amylin analogue pramlintide, as well as the implemented safety measures 
described above, healthy subjects will not be exposed to unacceptable risk in relation to the 
important information expected from this trial. Healthy volunteers are not expected to have 
any direct benefit from participation in the first-in-human trial with BI 473494, as is usually 
the case in such phase I trials. Considering the medical need regarding the treatment of 
obesity and T2D, the Sponsor considers that the benefit outweighs the potential risks and 
justifies exposure of healthy human volunteers.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This single-rising dose trial is designed as single-blind, partially randomised, and placebo-
controlled within parallel dose groups.
A total of 88 healthy male subjects is planned to participate in the trial, according to 11 
sequential groups comprising 8 subjects per group. However, 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 88, but will not exceed 
104 subjects entered. Such changes may be implemented via non-substantial CTP 
amendment.
Within each dose group, 6 subjects will receive the active drug and 2 will receive placebo.
Only one dose is tested within each dose group. Each dose group will consist of 3 cohorts 
which will be treated subsequently for safety reasons.
The dose groups to be evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups
Dose Group
1
2
3
4
5
6
7
8
9
10
11
Dose 
35 
µg
75 
µg
150 
µg
300 
µg
550 
µg
1.0 
mg
1.6 
mg
2.6
mg
4.0
mg
6.0
mg
8.5
mg
Number of subjects
8
8
8
8
8
8
8
8
8
8
8
Subjects receiving 
placebo
2
2
2
2
2
2
2
2
2
2
2
Subjects receiving 
active drug
6
6
6
6
6
6
6
6
6
6
6
Subject number 
The dose groups will be investigated consecutively in ascending order of doses, maintaining a 
time interval of at least 7 days between the last drug administration in the previous dose 
group and the first drug administration of the subsequent dose group.
 
The decision to proceed to the next dose group will 
be based upon the safety, tolerability and on pharmacokinetic data of the preceding dose 
groups. The next dose will only be given if, in the opinion of the Investigator, no safety 
concerns arose in the preceding dose group (i.e. no dose-limiting events occurred) and if none 
of the pre-specified trial-specific stopping criteria were met (refer to Section 3.3.4.2).
A documented Safety Review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested anytime for any reasonable cause by the 
Principal Investigator (or an authorised deputy) or the Sponsor of the study, e.g. because of 


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any unforeseen adverse events, etc. Dose escalation will only be permitted if no safety 
concerns exist in the opinion of the Principal Investigator (or an authorised deputy) and the 
Trial Clinical Monitor (or an authorised deputy).
The minimum data set for review consists of the following data (for the current dose group 
safety data of at least 3 days following BI 473494 or placebo administration in at least 
6 subjects should be considered):

AEs in the current and preceding dose groups, including clinically relevant findings 
from ancillary safety testing listed below (note: AEs may be ongoing at the time of 
Safety Reviews and AE information may be subject to change prior to Database Lock)

Results from 12-lead ECG in the current and preceding dose groups.

Vital signs 
 in the current and preceding dose groups

Clinical laboratory tests in the current and preceding dose groups


Preliminary PK data as per Section 7.3.4. 

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) and the Trial Clinical Monitor (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs and out-of-range 
laboratory results (if considered clinically significant). Safety Reviews can be conducted 
face-to-face or by video/telephone conference. The Trial Clinical Monitor is responsible for 
organization and minutes of the reviews. Minutes will be signed off by the Principal 
Investigator (or an authorised deputy) and filed in the ISF and TMF.
The Investigator (after consultation with the Sponsor) is allowed to alter the scheduled dose 
levels (e.g. add low and/or intermediate dose levels) provided the planned and approved 
highest dose is not exceeded and to prolong in-house confinement on the basis of experience 
gained during the study. In the case of additional dose levels, the total number of subjects in 
this trial might increase. The Investigator and/or the Sponsor should stop dose escalation in 
case the safety evaluation leads to concerns that would not allow higher dosing.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.


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The BI investigational product BI 473494 will be provided by the Clinical Trial Supplies Unit 
(CTSU), BI Pharma GmbH & Co. KG, Biberach, Germany. The comparator product 
(isotonic sodium chloride solution, Braun, as placebo)
 
The trial will be conducted at 
 
, under the supervision of the Principal Investigator. 
Safety laboratory tests will be performed by the local laboratory of the trial site 
The analyses of BI 473494 concentrations in plasma and urine will be performed at the 
Department of Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, 
Biberach, Germany.
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management will be done by BI according to BI SOPs. Statistical tasks and 
programming will be performed by 
 
according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For single-rising dose trials, the design described in Section 3.1 is viewed favourable under
the provision not to expose the subjects involved to undue risks since the main study 
objective is to investigate safety and tolerability of BI 473494. To minimize risk for subjects, 
administration of ascending doses will be applied in a sequential manner with no overlap 
between dose groups for at least 7 Days after dosing of last cohort in each dose group. 
Moreover, the first four subjects in each dose group will be treated in fixed-sequence 
(1. Active, 2. Placebo, 3. Active, 4. Active). With the rising dose design, single-blind 
conditions regarding the subject’s treatment (active or placebo) are maintained within each 
dose group. However, the current dose level will be known to subjects and investigators. 


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The disadvantage of this trial design is a possible observer bias with regard to the dose-
depending effects as well as time effects, but it has the virtue of minimizing subject risk by 
sequentially studying ascending doses. As time-effects are expected to be small relative to the 
differences between the doses in the broad range investigated, unbiased comparisons between 
treatments can still be expected.
It is standard in trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety and tolerability. Each dose group consists of 8 subjects with 6 on 
active treatment, and 2 on placebo. The placebo control group includes all subjects of all dose 
groups treated with placebo. 6 subjects per active treatment group are in general considered 
as sufficient for the exploratory evaluation of pharmacokinetics. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 88 healthy male subjects will enter the study. The actual number of subjects 
entered may exceed the total of 88 if additional intermediate doses will be tested (see Section 
3.1) but will not exceed 104 subjects entered. Subjects will be recruited from the volunteers' 
pool of the trial site. 
Only male subjects will be included into the study because hitherto no data on reproductive
toxicology are available. With respect to the embryo-fetal risk derived from the treatment of 
male subjects with BI 473494, where it is theoretically possible that relevant exposure to 
BI 473494 may be achieved in women of child-bearing potential (WOCBP) from exposure to 
seminal fluid, male contraception (condom or sexual abstinence) should be used in order to 
avoid exposure of an existing embryo/fetus [R16-0373] (see Section 3.3.3, exclusion 
criterion 23).
A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry 
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 45 years (incl.)
3. BMI of 20.0 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation


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


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22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criteria apply:
23. Male subjects with WOCBP partner who are unwilling to use male contraception 
(condom or sexual abstinence) from administration of investigational trial medication 
until 30 days after administration of investigational trial medication
24.
25. Known maltose intolerance / maltose malabsorption 
 
 
26. Laboratory values outside the reference range for ALT, AST, total bilirubin, fasting 
plasma glucose or HbA1c.
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events (AEs), or diseases)
4. An AE or clinically significant laboratory change or abnormality occurred that the 
Investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension or hypertension or clinically relevant changes in ECG 
requiring intervention.
5. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of 
investigational trial medication
, the data of this subject will not be entered in the 


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case report form (CRF) or trial database and will not be reported in the clinical trial report 
(CTR). If a subject is removed from or withdraws from the trial after first administration of 
investigational trial medication
, this will be documented and the reason for 
discontinuation must be recorded in the CRF. In this case, the data will be included in the 
CRF/trial database and will be reported in the CTR. At the time of discontinuation a complete 
end of trial examination will be performed if possible and the information will be recorded in 
the CRFs. These discontinuations will be discussed in the CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP, or the contract with BI by a trial site or investigator, 
disturbing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
5. Dose escalation will be stopped as soon as at least 2 subjects at one dose level on active 
drug showed relevant individual QT prolongation, i.e. a QTc increase of greater 60 ms 
from baseline in connection with absolute QT or QTc greater than 500 ms, which has 
been confirmed by a repeat ECG recording (e.g. follow-up ECG)
6. Dose escalation will be stopped based on preliminary PK results (plasma, see 
Section 7.3.4) as soon as measured (in at least one subject) or 
 (upper limit of acceptable exposure in this 
trial, see Section 2.1). Further dose progression would be allowed only after a safety 
interim analysis and filing and approval of a pertinent protocol amendment.
7. Drug administration within a dose group and further dose escalation will be stopped if 3
or more of the subjects on active drug at the current dose level experienced vomiting of at 
least moderate intensity (see Section 5.2.2.1 for definition of AE intensity)
8. Drug administration within a dose group and further dose escalation will be stopped if 2
or more of the subjects on active at one dose level experienced severe vomiting (see 
Section 5.2.2.1 for definition of AE intensity)
9.


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3.3.5
Replacement of subjects
In case that there are less than 4 subjects on active per dose level who complete the trial, the 
Trial Clinical Monitor together with the Trial Pharmacokineticist and the Trial Statistician are 
to decide if and how many subjects will be replaced. A replacement subject will be assigned a 
unique study subject number, and will be assigned to the same treatment as the subject he 
replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The BI investigational product has been manufactured by BI Pharma GmbH & Co. KG. 
BI 473494 is administered as chloride salt and doses will be calculated as free peptide. The 
comparator product is commercially available.
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test product for doses up to 1.0 mg are:
Substance:
BI 473494
Pharmaceutical formulation: Solution for injection 
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
1 mg/mL (1 mL per vial)
Route of administration:
SC injection
Duration of use:
Single dose 
The characteristics of the test product for doses above 1.0 mg are:
Substance:
BI 473494
Pharmaceutical formulation: Solution for injection 
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
10 mg/mL (1 mL per vial)
Route of administration:
SC injection
Duration of use:
Single dose
The characteristics of the comparator product (placebo) for all dose groups are:
Name:
Isotone Natriumchloridlösung 0.9 % Braun Injektionslösung
Substance:
Placebo containing sodium chloride 0.9 %
Pharmaceutical formulation: Solution for intravenous and SC injection
Source:
B. Braun Melsungen AG, Germany
Unit strength:
0.9 %, 10 mL ampoule 
Route of administration:
SC injection
Duration of use:
Single dose


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4.1.3
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups 
according to their temporal availability. As soon as enough subjects have been allocated to
one of the planned dose cohorts (3 cohorts per dose group), the following subjects will be 
allocated to one of the other dose cohorts. Therefore, the allocation of subjects to dose 
cohorts is not influenced by trial personnel, but only by the subjects’ temporal availability. As 
the study includes healthy subjects from a homogenous population, relevant imbalances 
between the dose groups are not expected.
The randomisation list with study subject numbers and allocated treatments will be provided
to the trial site in advance. The allocation of subjects to study subject numbers will be 
performed in Visit 2 prior to the first administration of trial medication. For this purpose, the 
subjects will be allocated to a study subject number by the method ‘first come first served’. 
Once a subject number has been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.5.


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4.1.4
Selection of doses in the trial
For this trial, subcutaneous doses of BI 473494 in the range of 35 µg to 8.5 mg have been 
selected in order to assess safety and tolerability in healthy male volunteers, and to 
investigate pharmacokinetics of BI 473494. The doses selected cover a safe starting dose in 
the sub-therapeutic range, the therapeutic dose as well as supra-therapeutic dose below levels 
established by toxicological investigations and including a safety margin (see Sections 1.2
and 2.3).
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 the dose volume of the respective dose level.
Table 4.1.5: 1
BI 473494 and placebo treatments, SC administration
Dose
group
Substance
Pharmaceutical form
Unit strength
Dose volume per 
administration (single dose)
Total dose
1
BI 473494
Solution for injection
1 mg/mL
35 µl = 0.035 mL
35 µg
2
BI 473494
Solution for injection
1 mg/mL
75 µl = 0.075 mL
75 µg
3
BI 473494
Solution for injection
1 mg/mL
150 µl = 0.15 mL
150 µg
4
BI 473494
Solution for injection
1 mg/mL
300 µl = 0.3 mL
300 µg
5
BI 473494
Solution for injection
1 mg/mL
550 µl = 0.55 mL
550 µg
6
BI 473494
Solution for injection
1 mg/mL
1000 µl = 1.0 mL
1.0 mg
7
BI 473494
Solution for injection
10 mg/mL
160 µl = 0.16 mL
1.6 mg
8
BI 473494
Solution for injection
10 mg/mL
260 µl = 0.26 mL
2.6 mg
9
BI 473494
Solution for injection
10 mg/mL
400 µl = 0.4 mL
4.0 mg
10
BI 473494
Solution for injection
10 mg/mL
600 µl = 0.6 mL
6.0 mg
11
BI 473494
Solution for injection
10 mg/mL
850 µl = 0.85 mL
8.5 mg
1-11
Placebo*
Solution for injection
--
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups 
The syringes containing the SC solutions for administration (BI 473494 or placebo) will be 
prepared by pharmacists, qualified pharmacy staff members or qualified medical study 
personnel at the trial site under the responsibility of the Investigator. The Investigator can 
decide at any time to stop dosing or (after consultation with the Sponsor) to decrease the dose
escalation by adding intermediate doses in case of intolerability or safety concerns.
The trial medication BI 473494 or placebo will be administered to subjects on Day 1 of Visit 
3 (at time-point 0:00) by SC injection into a lifted skin fold of the abdominal wall by the 
investigating physician or an authorised designee while subject lies in semi-upright position. 
Skin is sanitized prior to injection. Size of syringes used for administration is dependent on 
administered volume (e.g. BD Micro-Fine™ + Demi 0.3 mL with 8 mm needle attached or 


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1 mL Inject®-F/Inject®, B. Braun Melsungen, Germany with hypodermic needles for SC 
injection (30G x 12 mm or 30G x 13 mm). For lower volumes using BD Micro-Fine™ + 
Demi syringes and higher volumes using 1 mL Inject®-F/Inject® syringes, the injection 
needle has to be placed at a 90 degree or 45 degree angle, respectively. Injection of trial 
medication into the skin fold has to be performed over at least 15 seconds. For volumes 
higher than 1.0 mL, dose will be split into two injections. Following SC injection, the subject 
should remain in a semi-upright position for at least 30 minutes. Injection site will be marked 
by a pen.
The so-called four-eye principle (two-person rule) should be applied for administration of 
trial medication and – if applicable – its preparation, if correct dosage cannot be ensured 
otherwise.
Administration of BI 473494 or placebo will be performed by the Investigator or an 
authorized designee following an overnight fast, which is to start no later than 10 h before the 
scheduled dosing. Water may be consumed ad libitum except for 1 hour before and 1.5 hours 
after drug administration. Standardised meals will be served as outlined in the Flow Chart. 
For restrictions with regard to diet see Section 4.2.2.2.
Subjects will be kept under close medical surveillance until 72 h following investigational 
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 treatments administered will be blinded to subjects only (singe-blind). With the rising 
dose design, single-blind conditions regarding the subjects’ treatment (active or placebo) are 
maintained within each dose group, however the current dose level will be known to subjects 
and investigators.
The database of this trial will be handled in an open-label fashion, because no bias with 
regard to data cleaning of safety measures is expected. This is considered acceptable because 
the potential for bias seems to be low and does not outweigh practical considerations.
The Bioanalyst of the analytical laboratory, the Trial Pharmacokineticist and the Trial 
Pharmacometrician may receive the randomisation codes prior to official unblinding to 
perform preliminary PK analyses. He or she will treat the codes confidentially. 
In addition, the Drug Metabolism Scientist may receive the randomisation codes prior to 
official unblinding to perform metabolites in safety testing analysis (MIST). He or she will 
confirm in writing that the codes will be treated confidentially.
Within the ECG laboratory, the staff involved with interval measurements and assessments 
will be blinded with respect to the treatment within each dose level and also with regard to
the recording date and time as well as time the points of the ECGs. The interval 
measurements for a given subject will be performed in a random and blinded sequence by a 
single technician. No more than two different blinded readers will evaluate the ECGs of the 
study.


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4.1.6.2
Procedures for emergency unblinding
As this trial will be conducted single-blinded, the treatment information will be known. 
Therefore, no emergency envelopes will be provided.
4.1.7
Packaging, labelling, and re-supply
4.1.7.1
BI 473494
Vials containing BI 473494 will be provided by the Department of Pharmaceutical 
Development of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. Smaller boxes within the
clinical trial supply containers will be labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Batch number
Vials will be labelled with the reduced requirements.
The telephone number of the Sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms.
Examples of the labels will be available in the ISF.
Considering the short shelf life of BI 473494 solution for injection, it is planned to send the 
trial medication to the site in several fractions.   


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4.1.8
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
Local Clinical Monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.9
Drug accountability
The pharmacist or pharmaceutical assistant will receive the investigational drugs delivered by 
the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the Sponsor and the 
head of the trial site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon 
written authorisation by the Clinical Monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The pharmacist or pharmaceutical assistant must maintain records of the product’s delivery to 
the trial site, the inventory at the site, the use by each subject, and the disposal of unused 
products. 


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These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
pharmacist or pharmaceutical assistant will maintain records that document adequately that 
the subjects were provided the doses specified by the CTP, and that reconcile all 
investigational products received from the Sponsor. At the time of disposal, the pharmacist or 
pharmaceutical assistant must verify that no remaining supplies are in the Investigator’s 
possession.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
No additional treatment is planned. However, in case of adverse events in need of treatment, 
the Investigator can authorise symptomatic therapy. In those cases, subjects will be treated as 
necessary and, if required, kept under supervision at the trial site or transferred to a hospital 
until all medical evaluation results have returned to an acceptable level.
There are no special emergency procedures to be followed. Most frequent AEs which were 
observed with the short actin amylin agonist pramlintide are nausea, vomiting, anorexia and 
headache and these are expected to possibly occur with increasing doses of BI 473494. In 
case of prolonged or severe vomiting, the Investigator will monitor serum electrolytes, if 
deemed necessary in addition to safety monitoring. If nausea or vomiting is not amenable to 
conservative management, anti-emetics (e.g. dimenhydrinate, ondansetron and domperidon)
may be administered at the Investigator’s discretion.
Symptoms of mild to moderate hypoglycemia or blood glucose levels below 49 mg/dL in 
bedside test can be treated by ingestion of carbohydrates (e.g. stepwise in defined amounts of 
10 g). Typical clinical signs of mild or moderate hypoglycemia include cold sweats, cool pale 
skin, nervousness or tremor, anxious feeling, unusual tiredness or weakness, confusion, 
difficulty in concentration, drowsiness, excessive hunger, temporary vision changes, 
headache, nausea, and palpitations. Severe hypoglycemia may lead to unconsciousness. 
Subjects experiencing hypoglycemia should remain confined until the symptoms have 
improved and resolved, blood glucose is within or above the normal range and the 
investigating investigator deems the subject safe for discharge.
Hypoglycemic events will be recorded as AEs if symptomatic, or if plasma glucose levels
(safety laboratory) are below 54 mg/dL or blood glucose levels (bedside test) are below 
49 mg/dL.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed.
 
 
All concomitant or rescue therapies will be recorded 
(including time of intake on study days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart.
In the 4 hours following SC administration of the investigational trial medication (BI 473494 
or placebo) until lunch at least the amounts of fluid given in the Flow Chart must be 
consumed. Subjects will be fasted for 1.5 h following SC administration of BI 473494 or 
placebo. 
Furthermore, no food is allowed within at least
fluid intake is restricted to the 
liquid administered 
 and an additional 240 mL of water served at 
2 h after start (mandatory for all subjects). 
During days of urine collection, total fluid intake should be at least 1.5 litres and should not 
exceed 3.5 litres. 
Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products including St. John's wort (Hypericum perforatum) are not permitted starting 
4 days before 
 until the end of trial examination.
Alcoholic beverages must not be consumed from 4 days before 
 until 
completion of assessments of Day 8 in Visit 3. Thereafter, up to 20 g alcohol per day 
corresponding to 0.5 L of beer or 0.2 L of white wine per day are allowed. Red wine is not 
allowed until after the end-of-trial examination.
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 5 h after 
and from 10 h before 
until 8 h after administration of investigational trial medication (BI 473494 or placebo). 
Excessive physical activity (such as competitive sport) should be avoided starting 4 days 
before 
 until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.


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4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of investigational and non-investigational medicinal products and urinary excretion of 
BI 473494 will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 473494 is the number [N (%)] of 
subjects with drug-related adverse events.
Further criteria of interest:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate,
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death, 


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
is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect, or 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse.
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.2.2, subsections ‘AE collection’ and ‘AE reporting to Sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
The following are considered as AESIs in this trial:

Hepatic injury: A hepatic injury is defined by the following alterations of hepatic 
laboratory parameters: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN


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These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure these parameters are analysed, if necessary in an unscheduled blood test. 
Should the results meet the criteria of hepatic injury alert, the procedures described in 
the DILI checklist should be followed.
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 vomiting has been shown to be associated with pharmacological doses of the short acting 
amylin agonist pramlintide, the intensity of vomiting is defined as follows for this clinical 
trial:
Moderate: 
3 to 5 episodes in 24 hours (individual episodes separated by at least 5 min)
Severe:
≥ 6 episodes in 24 hours (individual episodes separated by at least 5 min) or 
requiring intravenous fluids, or vomiting that persists despite of anti-emetic 
treatment
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).


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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. 
5.2.2.2
Adverse event collection and reporting
AEs collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A careful written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, and intensity of the event as 
well as any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs.
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 


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o
The investigator does not need to actively monitor the subject for AEs but 
should only report related SAEs and related AESIs of which the Investigator 
may become aware of by any means of communication, e.g. phone call. Those 
AEs should, however, not be reported in the CRF.
The REP for BI 473494, when measurable drug levels or PD effects are still likely to be 
present after the last administration, is not known for this first-in-human trial. Therefore, all 
AEs reported until the end of trial examination (last per protocol contact) will be considered 
on treatment; please see Section 7.3.3.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form, if applicable. The Investigator should determine the causal 
relationship to the trial medication and any possible interactions between the trial medication
The following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions 


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
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no further 
information can be obtained.
Hypoglycaemia
Hypoglycaemic events will be recorded as AEs if symptomatic, or if plasma glucose levels 
are below 54 mg/dL (in safety laboratory) or blood glucose levels are below 49 mg/dL (in 
bedside test).
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required on Days 22 and 29 for hematologic parameters
and at the discretion of the Investigator or designee for retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 


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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 (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
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 differential WBC 
(relative and absolute)
Neutrophils, eosinophils, basophils, 
monocytes, lymphocytes
X
X
X
---
X
X
Coagulation
Activated partial thromboplastin time 
(aPTT)
Prothrombin time (Quick’s test and INR)
X
X
---
---
X
X
---
---
---
---
X
X
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gammaglutamyl transferase (GGT)
Glutamate dehydrogenase (GLDH)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
---
---
X
X
---
X
X
X
X
X
X
X
X
X
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
X
X
X
X
X
X
X
X
X
X
Substrates
Plasma glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
Albumin
C-Reactive Protein (CRP) 
Urea in serum
Total cholesterol 
Triglycerides
X
X
X
X
X
X
X
X
X 
X
X 
X 
X 
X 
X
---
X
---
---
---
X 
X 
X 
X 
X
X
X 
X 
X
---
X 
---
---
---
X 
X
---
---
---
---
---
---
---
---
---
---
---
---
---
---
X 
X 
X 
X 
X
X
X 
X 
X 
X
Electrolytes
Calcium
Sodium
Potassium
Magnesium
Chloride
Inorganic phosphate
X
X
X
X
X 
X
X
X
X
X 
X
X
X
X
X
X 
X
X
X
X
X
X 
X
X
---
---
---
---
---
---
X
X
X
X 
X
X
A: Parameters to be determined at Visit 1 (screening examination)
B: Parameters to be determined at Visit 2 on Day -1 (for time point, refer to Flow Chart)
C: Parameters to be determined at Visit 3 on Days 1 (at -1:00), 3, 6, 15 (for time points, refer to Flow Chart)
D: Parameters to be determined at Visit 3 on Day 1 (at 6:00 and at 12:00) and Day 2
E: Parameters to be determined at Visit 3 on Day 22 and 29
F: Parameters to be determined at Visit 4 (end of trial examination)


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
Test name 
A
B
C
D
E
F
Hormones
Thyroid stimulating hormone (TSH)
X
---
---
---
---
---
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
X
X
X
X
X
X
X
X
X
Urine sediment
(microscopic examination 
if erythrocytes, leukocytes 
nitrite or protein are 
abnormal in urine)
Only positive findings will be reported 
(e.g. presence of sediment bacteria, casts in 
sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
X
X
X
---
---
X
A: Parameters to be determined at Visit 1 (screening examination)
B: Parameters to be determined at Visit 2 on Day -1 (for time point, refer to Flow Chart)
C: Parameters to be determined at Visit 3 on Days 1 (at -1:00), 3, 6, 15 (for time points, refer to Flow Chart)
D: Parameters to be determined at Visit 3 on Day 1 (at 6:00 and at 12:00) and Day 2
E: Parameters to be determined at Visit 3 on Day 22 and 29
F: Parameters to be determined at Visit 4 (end of trial examination)
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 (i.e. pathological or 
atypical cells) or in the urinalysis, respectively.
A bedside glucose test will be performed for safety reasons at the time points indicated in the 
Flow Chart using Accu-Chek® Aviva (Roche Diagnostics). For quantification of blood 
glucose one drop (50 µl) of blood taken from the intravenous cannula or an arm vein will be 
sufficient. The results will be listed in the trial report but will not enter statistical analysis.
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and at beginning of Visits 2 and 3 (if subjects 
are discharged from trial site between Visit 2 and 3).


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody/p24-antigen (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed prior to baseline period in Visit 2 (and 
prior to treatment period in Visit 3, in case there is a discharge between Visit 2 and 3), and 
may be repeated at any time during the study at the discretion of an investigator or designee. 
The results will not be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at Medizinisches 
Versorgungszentrum Dr. Klein, Dr. Schmitt & Partner, Kaiserslautern, Germany with the 
exception of the urinalysis stix and drug screening tests. These tests will be performed at the 
trial site using Combur 9 Test (Roche Diagnostics, GmbH, Mannheim, Germany) and 
AccuSign® DOA 10 test (Diagnostik Nord GmbH, Schwerin, Germany).
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the time points given in the Flow Chart.
In order to achieve a stable heart rate at rest and to assure high quality recordings at 
comparable resting phases, all ECGs will be recorded for a 10-sec duration after the subjects 
have rested for at least 5 min in a supine position. The site personnel will be instructed to 
assure a relaxed and quiet environment so that all subjects are at complete rest during the 
recordings. ECG assessment will always precede all other study procedures of the same time 
point to avoid impact of sampling on the ECG quality.
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). 


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Precise electrode placement will be marked with an indelible mark on the skin to allow 
reproducible placement throughout the study.
ECGs will be recorded as single ECGs or as triple ECGs (three single ECGs recorded within 
180 sec) as indicated in the Flow Chart. Three triple ECGs will be recorded at baseline as 
indicated in the Flow Chart.
All locally printed ECGs will be evaluated by the Investigator or a designee.
ECGs may be repeated for quality reasons (like alternating current artefacts, muscle 
movements, electrode dislocation). For time points with triple ECGs, all three single ECGs 
will be repeated. For the repeats due to quality reasons, only the repeated ECG recordings 
will be sent to the central ECG lab, whereas the initially recorded ECGs will be discarded. 
Additional (unscheduled) ECGs may be collected by the Investigator for safety reasons. 
These ECGs are assigned to the prior scheduled time point. Unscheduled ECGs will not be 
included into the statistical analysis of interval lengths. 
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of cardiac 
safety during the study, the QT and QTcB values generated by the ECG machines or their 
manual corrections by the investigators will be used. In doubtful cases, ECGs may be sent 
upfront for centralised evaluation (see below). In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the Investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
A post-study centralised evaluation of the 12-lead ECGs recorded on Days 1 to 29 in Visit 3 
will be performed by an independent ECG laboratory. This analysis will include the 
determination of cardiac axis as well as the intervals RR, PR, QRS and QT measured semi-
automatically. Only the first of the three replicate ECGs at a single time point or at baseline
will be evaluated. The remaining second and third replicate ECG will be stored for additional 
analysis if required, e.g. by authorities at a later time point.
For each QT interval, the RR interval preceding the QT will be measured to calculate the 
respective frequency corrected QTc intervals ‘QTcF’ according to Fridericia’s formula 
(QTcF = QT / RR1/3) and ‘QTcB’ according to Bazett’s formula (QTcB = QT / RR1/2). The 
QTcF correction will be used for evaluation and reporting. Abnormalities detected during 
centralised ECG evaluation will not necessarily qualify as AE. All interval measurements in 
one subject will be performed on the same lead. The intervals will be measured from four 
cardiac cycles (beats) in lead II. If lead II shows a flat T wave or is not measurable for any 
reason, lead V5 will be used, or if that lead is not measurable, then lead I will be used. The 
lead actually used will be reported in the CTR.
For blinding arrangements see Section 4.1.6.
Assessed ECGs will comply with the ICH E14 guidance document and supplements 
[R05-2311, R13-0801, R13-4095] as well as the FDA requirements for annotated digital 
ECGs [R09-4830].


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5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a
blood pressure device (Dinamap, GE Medical Systems, Freiburg, Germany) at the times 
indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine position. 
All recordings should be made using the same type of blood pressure recording instrument on 
the same arm if possible.
5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 
laboratory tests, and a physical examination. At the end of trial examination, it will include 
review of vital signs, 12-lead ECG, laboratory tests, and a physical examination with 
determination of weight.
5.3
OTHER
Not applicable.
5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic 
 
 parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that
might occur as a result of administration of trial medication. The safety assessments are 
standard, are accepted for evaluation of safety and tolerability of a subcutaneously 
administered drug, and are widely used in clinical trials. The pharmacokinetic parameters and 
measurements outlined in Section 5.5 are generally used assessments of drug exposure. 
 


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5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the CRFs by the medical personnel. The actual sampling times will be used for determination 
of pharmacokinetic parameters.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK data) including addition of samples and 
visits as long as the total blood volume taken per subject does not exceed 500 mL. Such 
changes would be implemented via non-substantial CTP Amendments.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters will be determined for BI 473494 if feasible:
5.5.1.1
Secondary endpoints

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis of BI 473494
For quantification of BI 473494 plasma concentrations, 2.7 mL of blood will be taken from 
an antecubital or forearm vein into a K3-EDTA (tripotassium ethylenediaminetetraacetic 
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by veinpuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 
2000 x g to 4000 x g and at 4 to 8 °C. Two plasma aliquots will be obtained and stored in 
polypropylene tubes. The first aliquot should contain at least 0.6 mL plasma. The second 
aliquot may contain 0.6 mL plasma or less. The process from blood collection until transfer 
of plasma aliquots into the freezer should be completed within 90 min with interim storage of 
blood samples and aliquots in an ice/water bath or on crushed ice. For each aliquot the time 
when the sample was placed in the freezer will be documented. Until transfer on dry ice to 
the analytical laboratory, the aliquots will be stored upright at about -20°C or below at the 
trial site. The second aliquot will be transferred to the analytical laboratory after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory the 
plasma samples will be stored at about -20°C or below until analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, planned sampling time and “PK-1” or “PK-2”. Further information 
such as matrix and analyte may also be provided. 
Plasma samples for PK analyses will be shipped to: 
Boehringer Ingelheim Pharma GmbH & Co. KG
Drug Metabolism and Pharmacokinetics Germany
G144
Birkendorfer Straße 65
88397 Biberach a.d. Riss, Germany


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After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) will be
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years upon the final study 
report has been signed.
5.5.2.2
Plasma sampling for metabolism analysis
Additional K3-EDTA plasma samples for the identification of drug metabolites will be 
investigated in the 1.0 mg dose group. Based on the knowledge gained during the trial
conduct, e.g. from preliminary PK results, the dose group may be changed to a different one. 
The change will be implemented via a non-substantial CTP Amendment.
The blood samples will be drawn in parallel to PK samples on Day 1 to 29 (see Flow Chart). 
At each of these time points, 2.7 mL blood will be needed for metabolite analysis. The blood 
samples will be processed in the same way as the PK samples described in Section 5.5.2.1. 
Two plasma aliquots will be obtained and stored in polypropylene cryotubes. The first aliquot 
(labelled as ‘MIST-1’) should contain at least 0.5 mL of plasma. The remaining plasma will 
be in the second aliquot (labelled as ‘MIST-2’). The process from blood collection to transfer 
of plasma aliquots into the freezer should be completed within 90 min, with interim storage 
of blood samples on crushed ice between blood collection and centrifugation. Until transfer 
on dry ice to the metabolism laboratory, the aliquots will be stored at the trial site. Samples 
will be positioned upright and will be frozen at approximately -70°C. The second aliquot will 
be shipped to the metabolism laboratory after the metabolism scientist has acknowledged safe 
arrival of the first aliquot. At the metabolism laboratory, the plasma samples will be stored at 
about -70°C until analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, planned sampling time and ‘MIST-1’ or ‘MIST-2’. Further information 
such as matrix and analyte may also be provided. 
Plasma samples dedicated to metabolism investigation are transferred to:
Boehringer Ingelheim Pharma GmbH & Co. KG
Drug Metabolism and Pharmacokinetics Germany
G144
Birkendorfer Straße 65
88397 Biberach a.d. Riss, Germany
Only data related to the parent compound and its metabolites will be acquired. Evaluation of 
the drug metabolism will be reported separately but not included in the CTR of this trial. The 
study samples will be discarded after completion of the experiments but no later than 5 years 
after the final study report has been signed.


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5.5.2.4
Urine sampling for pharmacokinetic analysis
Urine for PK analysis will be collected starting from DG 5 (550 µg) in the defined intervals
(see Flow Chart).
A blank urine sample will be collected before administration of trial medication (within the 
2 h before drug dosing on Day 1 in Visit 3) and two aliquots of at least 0.6 mL will be 
retained to check for analytical interference.
All urine voided during the sampling intervals indicated in the Flow Chart will be collected in 
2 L polyethylene (PE) containers and stored in the refrigerator. Subjects are told to empty 


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their bladders at the end of each sampling interval. In order to facilitate urine sampling, 
subjects will be advised to drink at least 100 mL water before the end of each urine sampling 
interval.
Due to the known adsorption of the drug to the container wall and possible instability, 
additives (details to be defined between clinical site, Trial Clinical Monitor and Trial 
Bioanalyst) will need to be added to each 2 L PE collection container prior to the start of
urine sampling. The weight of the empty container will be determined, additives will be 
added, and the weight of the container at the end of each sampling interval will be 
determined. Throughout the collection interval the sampling container will be stored in a 
refrigerator at about 2 – 8°C and protected from light.
Within 1 hour after the end of the collection interval two aliquots containing at least 0.6 mL
will be taken from the homogenized urine fraction, transferred into polypropylene tubes and 
stored for bioanalytical measurement in a freezer at approximately -20°C or below. In case 
more than one collection container is used in a sampling interval, the contents of all 
containers have to be mixed before aliquots are prepared. Mixing should be done by 
transferring the entire content of all collection containers into a single PE/PP or glass 
container, and stirring the mixed fractions for about 1 min (manually or using a stir bar or 
other stirring device out of PE, PP, Teflon or glass). Generally the collection container should 
be shaken upon addition of every urine fraction to ensure proper mixing of additives and 
urine.
At minimum, the sample tube labels should list at least the following information: BI trial 
number, subject number, visit, planned collection time (interval start/stop) and ‘PK-1’ or 
‘PK-2’. Further information such as matrix and analyte may also be provided. 
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at 
about -20°C or below at the trial site. The second aliquot will be transferred after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory the 
plasma samples will be stored at about -20°C or below until analysis. 
Urine samples for PK analyses are transferred to:
Boehringer Ingelheim Pharma GmbH & Co. KG
Drug Metabolism and Pharmacokinetics Germany
G144
Birkendorfer Straße 65
88397 Biberach a.d. Riss, Germany
After completion of the trial the urine samples may be used for further methodological
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) will be generated by these additional investigations. 
The study samples will be discarded after completion of the additional investigations but no 
later than 5 years upon the final study report has been signed.
5.5.2.5
Urine sampling for metabolism analysis
Urine samples will be collected for PK analyses in defined intervals starting from DG 5
onwards as described in Section 5.5.2.4 (see also Flow Chart). For metabolic profiling the 
urine samples will be processed in the same way as the PK samples described in Section 


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5.5.2.4. A blank urine sample will be collected before administration of trial medication 
(within the 2 h before drug dosing on Day 1 in Visit 3). From homogenized urine samples 
collected during the interval 48:00 – 72:00 post administration, aliquots for metabolic 
profiling will be derived. Two aliquots of 50 mL from both pre-dose (blank urine) and from 
the 48:00-72:00 post-dose interval will be taken, transferred into polypropylene tubes and 
stored for bioanalytical measurement in a freezer at approximately -20°C or below.
At minimum, the sample tube labels should list at least the following information: BI trial 
number, subject number, visit, planned collection time (interval start/stop) and ‘MetID1’ and
‘MetID2’. Further information such as matrix and analyte may also be provided.
Urine samples for metabolic profiling are transferred to:
Boehringer Ingelheim Pharma GmbH & Co. KG
Drug Metabolism and Pharmacokinetics Germany
G144
Birkendorfer Straße 65
88397 Biberach a.d. Riss, Germany
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at 
about -20°C or below at the trial site. The second aliquot will be transferred after the 
bioanalyst has acknowledged safe arrival of the first aliquot.
Only data related to the parent compound and its metabolites will be acquired. Evaluation of 
the drug metabolism will be reported separately but will not be included in the CTR of this 
trial. The study samples will be discarded after completion of the experiments but no later 
than 5 years after the final study report has been signed.
5.5.2.6
Additional blood sample for stability-testing
In order to assess the stability of the analyte in whole blood, one additional blood sample will 
be taken from all subjects of DG 6 (i.e. the 1.0 mg dose group). Based on the knowledge
gained during the trial conduct, e.g. from preliminary PK results, the chosen timing or dose 
group may be changed to a different one. The change will be implemented via a non-
substantial CTP Amendment.
Approximately 2.4 mL blood will be taken from an antecubital or forearm vein using two 
1.2 mL K3-EDTA-blood drawing tubes at the time indicated in the Flow Chart (immediately 
after the drawing of a regular blood PK sample, which is to say that no additional venous 
puncture will be necessary).
From each K3-EDTA tube, one aliquot will be generated:

One aliquot (‘stability reference’) will be centrifuged within 10 min after collection. 
Centrifugation will last for about 10 min (at about 2000 x g to 4000 x g and 4 to 8°C), 
plasma will be separated and transferred into a freezer immediately

The second aliquot (‘stability test’) will be stored for about 4 h at room temperature 
and ambient light conditions (documentation of storage time necessary) and will then 
be centrifuged and stored according to the first sample. 


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At a minimum, the aliquots should be labelled with the following information: BI trial 
number, administered drug, subject number, planned sampling time, ‘stability reference’ or 
‘stability test’.
Until transfer to the analytical laboratory, both aliquots will be stored at about -20 °C or 
below at the trial site. Both aliquots will be provided to the responsible bioanalyst together 
with the information about sample handling (i.e. storage time of ‘test sample’ at room 
temperature). After receipt, the aliquots will be stored at the bioanalytical laboratory at about 
-20°C or below until analysis.
Plasma samples for stability analyses will be shipped to: 
Boehringer Ingelheim Pharma GmbH & Co. KG
Drug Metabolism and Pharmacokinetics Germany
G144
Birkendorfer Straße 65
88397 Biberach a.d. Riss, Germany
The results of the analysis of these samples will not be reported within this clinical trial but 
will be used for bioanalytical assay validation and therefore included in the corresponding 
method validation report. The remaining sample volume will be discarded upon completion 
of the method validation report at the latest.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 473494 plasma concentration
BI 473494 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will
be available prior to the start of sample analysis. As described in Section 4.1.6, the bioanalyst 
will be unblinded during sample analysis.
5.5.3.2
Analytical determination of BI 473494 urine concentration
BI 473494 concentrations in urine will be determined by a validated LC-MS/MS assay. All 
details of the analytical method will be available prior to the start of sample analysis. It 
should be noted that due to potential adsorption and stability issues the assay may use 
extended acceptance criteria. Insofar it may not meet all requirements of the FDA and EMA 
guidances on bioanalytical method validation for a fully validated method [R01-0476; 
R12-0309]. Details will be given in the corresponding analytical report. As described in 
Section 4.1.6, the bioanalyst will be unblinded during sample analysis.


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5.7
PHARMACODYNAMICS


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5.7.4
Methods of sample collection
5.7.4.1
Plasma glucose
For determination of plasma glucose, blood samples of 2.7 mL will be drawn from an 
antecubital or forearm vein into Potassium-Fluoride Sodium-EDTA (tripotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tubes (FE tubes) at times 
indicated in the Flow Chart. Blood will be withdrawn by means of either an indwelling
venous catheter or by veinpuncture with a metal needle.
The FE blood samples will be centrifuged for about 10 min at about 2000 x g to 4000 x g at
4 to 8°C. Two plasma aliquots will be obtained and stored in polypropylene tubes. The first 
aliquot should contain at least 0.5 mL plasma. The second aliquot should contain 0.5 mL 


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plasma or less. Loss of glucose should be minimized by placing the blood tube in crushed ice
after blood collection and separating the plasma from the cells within 30 min. The process 
from blood collection until transfer of plasma aliquots into the freezer should be completed 
within 90 min, with interim storage of blood samples on crushed ice between blood collection 
and centrifugation. For each aliquot the time when the sample was placed in the freezer will 
be documented. Until transfer on dry ice to the analytical laboratory, the aliquots will be 
stored upright at about -20°C or below at the trial site. The second aliquot will be transferred 
to the analytical laboratory after the bioanalyst has acknowledged safe arrival of the first 
aliquot. At the analytical laboratory the plasma samples will be stored at about -20°C or 
below until analysis.
At a minimum, the sample tube labels should list the following information: BI trial number,
subject number, visit, planned sampling time, and ‘aliquot 1’ or ‘aliquot 2’. Further 
information such as matrix and analyte may also be provided.
Plasma samples for glucose analyses will be shipped to: 
5.7.4.2
Plasma insulin 
For quantification of insulin in plasma, 4.9 mL of blood will be collected from an antecubital 
or forearm vein into an K3-EDTA (ethylenediaminetetraacetic acid)-anticoagulant blood 
drawing tube at the times indicated in the Flow Chart. Blood will be withdrawn by means of 
either an indwelling venous catheter or by veinpuncture with a metal needle.
The K3-EDTA-anticoagulated blood samples will be centrifuged for about 10 min at 2000 x g
to 4000 x g at 4 to 8°C. Two plasma aliquots will be obtained and stored in polypropylene
tubes containing at least 1.0 mL plasma. The process from blood collection until transfer of 
plasma aliquots into the freezer should be completed within 90 min, with interim storage of 
blood samples on crushed ice between blood collection and centrifugation. For each aliquot 
the time when the sample was placed in the freezer will be documented. Until transfer on dry 
ice to the analytical laboratory, the aliquots will be stored upright at about -20°C or below at 
the trial site. The second aliquot will be transferred to the analytical laboratory after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory the 
plasma samples will be stored at about -20°C or below until analysis.
At a minimum, the sample tube labels should list the following information: BI trial number,
subject number, visit, planned sampling time, and ‘aliquot 1’ or ‘aliquot 2’. Further 
information such as matrix and analyte may also be provided.
Plasma samples for insulin analyses will be shipped to: 


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5.7.5
Analytical determinations
5.7.5.1
Analytical determination of plasma glucose and insulin
Glucose and insulin will be measured in plasma at 
 
 or another central laboratory appointed by BI.
After completion of the study the samples may be used for further exploratory biomarker 
investigations. The study samples will be discarded after completion of any additional 
investigations but no later than 5 years after the CTR has been signed.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ 
trial medication 
administration on Days 1 of Visits 2 or 3 are to be performed and completed within a 2 h-
period prior to the trial drug administration (including blank values for PK 
Starting from 96 h post administration a deviation from the scheduled time for PK sampling 
ECG
of ± 70 min is acceptable. However, ECGs should always 
be time-matched with blood PK sampling.
The acceptable deviation from the scheduled time for vital signs and laboratory tests will be 
± 30 min for the first 72 h after trial drug administration. Starting from 96 h post 
administration a deviation from the scheduled time for vital signs and laboratory tests of ± 70
min is acceptable.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including veinpuncture are scheduled for the same time, veinpuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned individual plasma concentration sampling times and urine collection intervals
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for determination of 
pharmacokinetic parameter.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Visit 1 - Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.


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6.2.2
Visit 2 – Baseline period
 
 For details on test procedures please refer to Section 5.7.
 at baseline have to be performed within 4 days prior 
to administration of the investigational trial medication BI 473494 or placebo. 
Within 3 days before Day 1 of Visit 2 (but no later than Day -1), subjects will visit the trial 
site in the morning in an ambulatory fashion for assessment of safety laboratory parameters. 
In the evening of Day -1, subjects will be admitted to the trial site for overnight stay, and 
drug screening and alcohol breath test will be performed. Subjects will remain under close 
medical surveillance for at least 12 h before and 5 h after 
 
Dependent on logistical planning, the subjects will then be 
allowed to leave the trial site on Day 1 after formal assessment and confirmation of their
fitness by the Investigator or a designee or stay in-house if administration of BI drug is 
planned for the following day.
6.2.3
Visit 3 – Treatment period
In case subjects were discharged from trial site in Visit 2, subjects will be admitted to the trial 
site in the evening of Day -1 in Visit 3 for in-house confinement and drug screening and 
alcohol breath test will be performed. If subjects were not discharged on Day 1 of Visit 2, no 
further drug screening and alcohol breath test needs to be performed.
Subjects will remain under close medical surveillance for at least 11 h before and 72 h 
following application of the investigational trial medication BI 473494 or placebo on Day 1 
of Visit 3. Trial medication will be administered as SC injection by the investigating 
physician. Details on treatments and procedures of administration are described in 
Section 4.1.5.
 
Subjects will then be allowed to leave the trial site on Day 4 after formal assessment and 
confirmation of their fitness by the Investigator or a designee. On all other subsequent study 
days, the study will be performed in an ambulatory fashion.
For details on time points and procedures for collection of plasma and urine samples for PK
analysis, refer to Flow Chart and Section 5.5.2. 
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.4
Visit 4 - End of trial period 
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.


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


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the safety and tolerability of BI 473494 by 
using descriptive statistics for all endpoints comparing active dose groups to placebo. The 
primary endpoint is defined in Section 5.2.1. Inferential statistics is not planned (as explained 
in Section 7.2).
The secondary objective is the exploration of the PK 
 of BI 473494. Endpoints as 
specified in Sections 5.5.1 and 5.7.1 will be analysed by descriptive statistics. Secondary 
endpoints as defined in Section 5.5.1.1, as well as AUC0-168 and AUC0-∞, will be subjected to 
analysis of dose proportionality by use of the power model.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of different dose groups of BI 473494 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will 
be described in their entirety and evaluated by descriptive statistical methods.
Confidence intervals will be computed and will have to be interpreted in the perspective of 
the exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.3
PLANNED ANALYSES
All individual data will be listed.
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.
7.3.1
Primary analyses
Analysis of safety and tolerability is described in Section 7.3.3.
7.3.2
Secondary analyses
The secondary parameters (refer to Section 5.5.1) will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472). 


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Pharmacokinetic parameters of a subject will be included in the analysis unless the subject 
has an important protocol violation relevant for the evaluation. Whether a protocol violation 
is important will be decided no later than in the Report Planning Meeting. 
Reasons for exclusion of single pharmacokinetic parameters may be:

The subject experiences emesis at or before two times median tmax. Median tmax is to 
be determined for the test product excluding the subjects experiencing emesis.

The subject experiences emesis at any time during the labelled dosing interval.

Time deviations

Use of restricted medications 
The subject set for the evaluation of PK endpoints (PKS) will include all treated subjects that 
provide at least one observation for at least one secondary endpoint without important 
protocol violations with respect to the statistical evaluation of PK endpoints. It will be 
decided in the Report Planning Meeting which subjects are to be included in the PKS.
Excluded subjects will be listed with their individual plasma concentrations and individual 
pharmacokinetic parameters, however, will not be included in descriptive statistics for plasma 
concentrations, pharmacokinetic parameters or other statistical assessment.
Assessment of dose proportionality
Dose proportionality will be assessed using the pharmacokinetic endpoints as specified in 
Section 5.5.1.1. 
The basic model for the investigation of dose proportionality will be a power model that 
describes the functional relationship between the dose and PK endpoints.
The model consists of a regression model applied to log-transformed data. The corresponding 
ANCOVA model includes the logarithm of the dose as a covariate. 
Together with 
and 
, taking natural logarithms converts this model 
to a linear form as follows:
where
logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where i = 1, 2, …, 11, j = 1, 2, …, 6;

intercept parameter;
slope parameter;
logarithm of dose i;
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
This equation can be fit as a linear regression model.
ij
i
ij
ε
)
X
exp(
)
exp(Y







)
exp(


)
exp(
ε
ij
ij



ij
i
ij
ε
X
β
α
Y




ij
Y
β
i
X
ij
ε


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Based on the estimate for slope parameter (β), a 2-sided 95% CI for the slope will be 
computed. Perfect dose proportionality would correspond to a slope of 1. The assumption of a 
linear relationship between the log-transformed pharmacokinetic endpoint and the log-
transformed dose will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed.
Graphical displays
To support the analyses of dose proportionality, graphical representations of the data might 
be created. These might include (but are not limited to) individual time-courses of trough 
plasma concentrations and the (geometric) mean plasma concentration time profiles.
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is, 
all subjects who received at least one dose of study drug), will be included in the safety 
analysis. Safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. The active treatment groups will be compared to the placebo group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
The analyses will be done by ‘treatment at onset’.
Measurements (such as ECG, vital signs,
or laboratory parameters) or AEs 
will be assigned to treatments (see Section 4.1) based on the actual treatment at the planned 
time of the measurement or on the recorded time of AE onset (concept of treatment emergent 
AEs). Therefore, measurements planned or AEs recorded prior to first intake of trial 
medication will be assigned to 'screening', those between first trial medication intake until the 
end of trial visit will be assigned to the treatment period, and those after the end of trial 
examination will be assigned to ‘post-study’. These assignments including the corresponding 
time intervals will be defined in detail in the TSAP.
Additionally, further treatment intervals (analysing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening and post-study intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.2.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.


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Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.
A centralised evaluation of all 12-lead ECGs recordings (see Section 5.2.4) will be the basis 
for the derivation of further ECG parameters based on the ECG variables QT, HR, QTcF, 
QTcB, PR, QRS, and RR. The baseline value of an ECG variable is defined as the mean of 
the triple ECG measurements prior to drug administration. The derivation of the quantitative 
and qualitative ECG endpoints and their analyses will be described in the TSAP.
7.3.4
Preliminary PK analyses
A preliminary analysis of PK parameters (AUC0-168 and Cmax of BI 473494), provided as 
individual values and geometric means of at least the first 2 cohorts per dose level, will be 
performed for 

all dose levels up to n-2 before proceeding to dose level n (with n ≤ 1.6 mg)

all dose levels up to n-1 before proceeding to dose level n (with n > 1.6 mg) 
(Note: Data from the first two cohorts of the above mentioned dose levels will be sufficient as 
long as the data from at least 2 subjects on active were available)
No inferential statistical interim analysis is planned. However, after each dose group the 
investigator (or 
 deputy) is allowed to postpone further dose progression until a 
preliminary analysis of the data already obtained has been performed
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 473494 will be calculated 
according to the BI SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Subjects who are not included in the PKS (refer to Section 7.3.2) will be reported with their 
individual plasma / urine concentrations and individual pharmacokinetic parameters; 


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however, they will not be included in descriptive statistics for plasma / urine concentrations, 
pharmacokinetic parameters.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of 
the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
Point estimates and 95% CIs will be provided for the secondary endpoints (cf. 
Section 5.5.1.1). The secondary endpoints will be log-transformed prior to fitting the 
ANCOVA model (cf. Section 7.3.2).
The following descriptive statistics will be calculated for all PK parameters 
 
 N, arithmetic mean, standard deviation, minimum, median, maximum, arithmetic 
coefficient of variation, geometric mean, and geometric coefficient of variation. The data 
format for descriptive statistics of concentrations will be identical with the data format of the 
respective concentrations. The descriptive statistics of PK parameters will be calculated using 
the individual values with the number of decimal places as provided by the evaluation 
program. Then the individual values as well as the descriptive statistics will be reported with 
3 significant digits in the clinical trial report.
In addition to the non-compartmental analysis, a population pharmacokinetic analysis will be 
performed. This population pharmacokinetic analysis will not be part of the CTR, but will be 
reported separately.


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More details will be provided in the TSAP.
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma/urine drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the predose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.5
RANDOMISATION
Each dose group will be divided into three cohorts. The subjects of the first two cohorts will 
not be randomised to maintain a treatment sequence of ‘active-placebo’ in cohort 1 and 
‘active-active’ in cohort 2 due to safety reasons. In the third cohort of each dose level the 
subjects will be assigned to active or placebo treatment using a 3:1 allocation ratio.


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The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 88 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 8 subjects per dose group (6 on active treatment, and 2 on 
placebo) is commonly used in single-rising dose studies of the present type and is in general 
considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics [R95-0013].
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 88, but will not exceed 104 subjects entered.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs.
The Investigator should inform the Sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the Investigator or the trial site and 
the Sponsor. As a general rule, no trial results should be published prior to finalisation of the
CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the Sponsor or 
Sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.


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The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the Sponsor. For drug accountability, refer 
to Section 4.1.9.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The Sponsor must retain the essential documents according to the Sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.


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Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities, i.e. the competent authority 
(CA).
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last subject/subject out, unless specified differently in Section 6.2.4 of the 
CTP) or early termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R95-0013
Broom C. Design of first-administration studies in healthy man. Early 
Phase Drug Evaluation in Man. O'Grady J, Linet OI (Eds.), Macmillan 
Press: London, 1990, 206 213.
R01-0476
Guidance for industry: bioanalytical method validation. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo
rmation/Guidances/ucm0701 07.pdf (access date: 19 October 2011) ; U.S. 
Department of Health and Human Services, Food and Drug Administration; 
2001.
R05-2311
ICH E14: the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs (ICH harmonised 
tripartite guideline, recommended for adoption at step 4 of the ICH process 
on 12 May 2005 by the ICH Steering Committee). www.emea.eu.int 
2005:1-14.
R06-1037
Guidance for industry: estimating the maximum safe starting dose in initial 
clinical trials for therapeutics in adult healthy volunteers. U.S. Department 
of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER); 2005.
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R12-0309
European Medicines Agency (EMA). Committee for Medicinal Products 
for Human Use (CHMP): guideline on bioanalytical method validation 
(01 February 2012, EMEA/CHMP/EWP/192217/2009). 
www.ema.europa.eu; 2011.
R13-0801
E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs - Questions and 
Answers (R1). October 2012. 
website.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/ucm323656.htm.
R13-4095
European Medicines Agency (EMA). Committee for Medicinal Products 
for Human Use (CHMP): ICH guideline E14 - questions and answers: step 
5 (May 2012, EMA/CHMP/ICH/310133/2008). 
website.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/
2009/09/WC500002878.pdf.
R14-0281
Levin S, Semler D, Ruben Z. Effects of two weeks of feed restriction on 
some common toxicologic parameters in Sprague-Dawley rats. Toxicol 
Pathol 1993;21(1):1-14.


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R14-1973
Singh-Franco D, Perez A, Harrington C. The effect of pramlintide acetate 
on glycemic control and weight in patients with type 2 diabetes mellitus and 
in obese patients without diabetes: a systematic review and meta-analysis. 
Diabetes Obes Metab 2011;13(2):169-180.
R16-0373
Recommendations related to contraception and pregnancy testing in clinical 
trials (final version - 2014-09-15). 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contracepti
on.pdf (access date: 2 February 2016) ; Clinical Trial Facilitation Group 
(CTFG), Head of Medicine Agencies (HMA); 2014.
R17-0597
Smith SR, Aronne LJ, Burns CM, Kesty NC, Halseth AE, Weyer C.
Sustained weight loss following 12-month pramlintide treatment as an
adjunct to lifestyle intervention in obesity. Diabetes Care 2008;31(9):1816-
1823.
R17-0883
Isotone Natriumchloridlösung 0,9% Braun Injektionslösung (B. Braun 
Melsungen AG), apothekenpflichtig, Fachinformation Stand Juli 2014.
R17-0949
Nyholm B. Amylin receptor agonists: A novel pharmacological approach in 
the management of insulin-treated diabetes mellitus. 24 Feb 2005.
R17-0990
Strickley RG. Parenteral formulations of small molecules therapeutics 
marketed in the United States (1999) - part I. PDA J Pharm Sci Technol 
1999;53(6):324-349.
R17-0991
Brazeau GA, Cooper B, Svetic KA, Smith CL, Gupta P. Current 
perspectives on pain upon injection of drugs. J Pharm Sci 1998;87(6):667-
677.
R17-0994
Symlin (pramlintide acetate) injection for subcutaneous use (AstraZeneca) 
(U.S. prescribing information, revised: 06/2014). 2014.


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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c14085574
Investigator’s Brochure 1400.P1-P2 (BI 473494)  21 Apr 2017.
n00253475
. BI 473494: Toxicity Study By Subcutaneous Administration to
Cynomolgus Monkeys for 6 Weeks Followed by a 4 Week Recovery Period
(Part: Toxicokinetics). (Report in preparation).


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
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
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11760893
1.0
clinical-trial-protocol
Safety, tolerability, pharmacokinetics and pharmacodynamics of single rising
subcutaneous doses of BI 473494 in healthy male subjects (single-blind, partially
randomised, placebo-controlled parallel group design)
Author-Trial Statistician
02 May 2017 15:19 CEST
Author-Trial Clinical
Pharmacokineticist
02 May 2017 16:36 CEST
Approval-Trial Clinical Monitor
02 May 2017 17:27 CEST
Author-Team Member Medicine
02 May 2017 18:58 CEST
Verification-Paper Signature
Completion
03 May 2017 15:08 CEST
Approval-Therapeutic Area 
03 May 2017 16:19 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11760893
1.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c26500341-01
BI Trial No.:
1400-0001
Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of
single rising subcutaneous doses of BI 473494 in healthy male 
subjects (single-blind, partially randomised, placebo-controlled 
parallel group design)
Including Protocol Amendment 1 [c11760893-02]
Investigational
Product:
BI 473494
Responsible trial 
statisticians:
Phone: 
Fax: 
Phone:
Fax:
Date of statistical 
analysis plan:
29 JAN 2019 SIGNED 
Version:
Final
Page 1 of 33
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINT .....................................................................................10
5.2
SECONDARY ENDPOINTS.............................................................................10
5.2.1
Key secondary endpoints....................................................................................10
5.2.2
Secondary endpoints...........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................13
6.1
TREATMENTS...................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................15
6.3
SUBJECT SETS ANALYSED...........................................................................17
6.5
POOLING OF CENTRES .................................................................................18
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................19
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................19
7.
PLANNED ANALYSIS......................................................................................22
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........23
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................23
7.3
TREATMENT COMPLIANCE........................................................................24
7.4
PRIMARY ENDPOINTS...................................................................................24
7.5
SECONDARY ENDPOINTS.............................................................................24
7.5.1
Key secondary endpoints....................................................................................24
7.5.2
Secondary endpoints...........................................................................................24
7.7
EXTENT OF EXPOSURE.................................................................................26
7.8
SAFETY ANALYSIS..........................................................................................26
7.8.1
Adverse events.....................................................................................................26
7.8.2
Laboratory data ..................................................................................................28
7.8.3
Vital signs.............................................................................................................28
7.8.4
ECG......................................................................................................................28
7.8.5
Others...................................................................................................................29
8.
REFERENCES....................................................................................................30


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10.
HISTORY TABLE..............................................................................................33


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR .........................................................13
Table 6.2: 1
Important protocol deviations...........................................................................16
Table 6.3: 1
Analysis sets for endpoints/data description ....................................................18
Table 6.7: 1
Time schedule of 12-lead ECG recordings.......................................................20
Table 10: 1
History table .....................................................................................................33


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Anti-drug Antibody
ADS
Analysis Dataset
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
ANOVA
Analyis of Variance
AST
Aspartate Aminotransferase
AUC
Area Under The Concentration-Time Curve
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data point
BI
Boehringer Ingelheim
CARE
Clinical Analysis and Reporting Environment
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic Coefficient of Variation
DB
Dose Proportionality, Between-Subject Design
DBLM
Database Lock Meeting
DILI
Drug induced liver injury
ECG
Electrocardiogram
EudraCT
European Union Drug Regulating Authorities Clinical Trials


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Term
Definition / description
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
HR
Heart Rate
ICH
International Conference On Harmonisation
ISF
Investigators Site File
iPD
Important Protocol Deviation
LLT
Lower Level Term
Max
Maximum
MedDRA
Medical Dictionary For Regulatory Activities
Min
Minimum
N
Number non-missing observations
O*C
Oracle Clinical
P10
10th percentile
P90
90th percentile
PD
Pharmacodynamics
PDS
Pharmacodynamic Analysis Set
PK
Pharmacokinetics
PKS
PK Parameter Analysis Set
PR
Pulse Rate
PT
Preferred Term
Q1
1st quartile
Q3
3rd quartile
QRS
Complex of three closely related waves on the ECG (Q, R and S wave)
QT
Time between start of the Q-wave and the end of the T-wave on the ECG
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) or 
Bazett (QTcB)
RAGe
Report Appendix Generator system
REP
Residual Effect Period
RPM
Report Planning Meeting
SAS®
Statistical Analysis System


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Term
Definition / description
SD
Standard Deviation
SOC
System Organ Class
TMCP
Translational Medicine and Clinical Pharmacology
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary
XPKISTAT
Library of SAS® Macros for PK analysis


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM (O*C) system.
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated Clinical Analysis and 
Reporting Environment (CARE), including SASTM (current Version 9.4, by SAS Institute 
Inc., Cary, NC, USA), and a number of SASTM-based tools (e.g., macros for the analyses of 
AE data or laboratory data; Report Appendix Generator system (RAGe) for 
compilation/formatting of the Clinical trial Report (CTR) appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in the TSAP are outlined in the CTP. The following changes compared 
to the protocol will be made:
Dose escalation was stopped after the second dose group (75 μg BI 473494). Therefore, all 
analyses will be performed for the first and second dose group only.
-
As there are only two dose groups available, no dose proportionality analysis will 
be done. Secondary endpoints (AUC0-tz and Cmax of BI 473494) 
 
will be analysed 
descriptively only.
-
As there are only two dose groups available and only little exposure levels 
expected, no ECG exposure-repsonse analyses will be done.
As an abbreviated CTR will be written, the change from baseline in body weight will be 
analysed descriptively only.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Section 5.2.1 of the CTP: Primary endpoint to assess safety and tolerability of BI 473494 is 
the number [N (%)] of subjects with drug-related adverse events.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 5.5.1.1 of the CTP: The following pharmacokinetic parameters will be determined 
for BI 473494 if feasible:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
It was planned that in total 88 healthy male subjects participate in the trial, according to 11 
sequential groups comprising 8 subjects per group (6 on active drug and 2 on placebo).
For details of dosage and formulation see Table 6.1: 1 below.
Table 6.1: 1
Labels for treatments for use in the CTR
Treatment
Short label
P*
Placebo solution, sc, qd
Placebo
A
BI 473494, solution for injection, 35 ug
BI 35 ug
B
BI 473494, solution for injection, 75 ug
BI 75 ug
C
BI 473494, solution for injection, 150 ug
BI 150 ug
D
BI 473494, solution for injection, 300 ug
BI 300 ug
E
BI 473494, solution for injection, 550 ug
BI 550 ug
F
BI 473494, solution for injection, 1.0 mg
BI 1.0 mg
G
BI 473494, solution for injection, 1.6 mg
BI 1.6 mg
H
BI 473494, solution for injection, 2.6 mg
BI 2.6 mg
I
BI 473494, solution for injection, 4.0 mg
BI 4.0 mg
J
BI 473494, solution for injection, 6.0 mg
BI 6.0 mg
K
BI 473494, solution for injection, 8.5 mg
BI 8.5 mg
*: The placebo control group in the safety evaluation will consist of all placebo treated 
subjects, regardless of the dose group in which they were treated.
Dose escalation was stopped after the second dose group (Treatment B / 75µg BI 473494). 
Therefore, all analyses will be performed for the first and second dose group only (treatments
Placebo, 35µg BI 473494 and 75µg BI 473494).
The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from 0:00 h on day of informed consent until administration time 
of study drug (BI 473494 or Placebo))

On treatment 

BI 473494/Placebo treatment (separately for each treatment, ranging from the 
time of administration of BI 473494 / Placebo until 0:00h on the day after trial 
termination date)
Please note that all AEs reported between start of trial drug administration and the last per-
protocol contact will be considered on treatment (i.e. no follow-up period is considered in this 
trial).


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Displays of AEs will be presented separately for the treatments Placebo, 35µg BI 473494 and 
75µg BI 473494. 
Two types of AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT only) of the 
CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening will not be included in this analysis. 
The following total will be provided in addition (Section 15.3 only):

a total over all BI 473494 treated phases ("BI Total")

a total over all on treatment phases included in this analysis ("Total on treatment")
(Section 15.3 only)
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of the 
CTR displays:

Screening 

On treatment (labelled with the name of the study treatment (short label))
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:

a total over all BI 473494 treated phases ("BI Total")

a total over all study phases ("Total")
Tables of vital signs and laboratory values will present results by the above mentioned on
treatment phase.
For detailed information on the handling of the treatments in the O*C views refer to Technical 
TSAP ADS (analysis data set) plan and Analysis Data Reviewers guide.


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


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


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6.3
SUBJECT SETS ANALYSED

Treated set (TS):
This subject set includes all subjects who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.
This is the full analysis set population in the sense of ICH-E9 (1).
It is used for demographics, baseline characteristics, and safety analyses. 
The ECG analyses are performed on the TS.
Section 7.3.2 of the CTP: Pharmacokinetic parameters of a subject will be included in the 
analysis unless the subject has an important protocol deviation relevant for the evaluation. 
Whether a protocol deviation is important will be decided no later than in the Report 
Planning Meeting.
Reasons for exclusion of single pharmacokinetic parameters may be:

The subject experiences emesis at or before two times median tmax. Median tmax is to be 
determined for the test product excluding the subjects experiencing emesis.

The subject experiences emesis at any time during the labelled dosing interval.

Time deviations

Use of restricted medications
The subject set for the evaluation of PK endpoints […] will include all treated subjects that
provide at least one observation for at least one secondary endpoint without important 
protocol deviations with respect to the statistical evaluation of PK endpoints. 

PK parameter analysis set (PKS):
The PK parameter analysis set (PKS) includes all subjects from the TS receiving 
BI 473494 who provide at least one secondary PK parameter that was not excluded 
according to the description above.
Section 7.3.2 of the CTP: It will be decided in the Report Planning Meeting which subjects 
are to be included in the PKS.
Excluded subjects will be listed with their individual plasma concentrations and individual 
pharmacokinetic parameters, however, will not be included in descriptive statistics for 
plasma concentrations, pharmacokinetic parameters or other statistical assessment.
The descriptive analysis of PK concentrations will be based on the analysis data set (ADS) 
ADPC as described at the beginning of Section 7.


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Table 6.3: 1
Analysis sets for endpoints/data description
Endpoint/data description
Analysis set
TS
PKS
PDS
Primary and further safety endpoints 
(incl. ECG) 
X
Secondary
PK endpoints
X
Demographic/baseline data
X
Important protocol deviations
X
Disposition
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.4.
The only exception where imputation might be necessary for safety evaluation is AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-36-
472_RD-01) (5).
If single cardiac cycles of an ECG (out of the generally four) are missing, the arithmetic mean 
for this single ECG will be computed with the reduced (1, 2 or 3) number of cardiac cycles.
If replicate ECG recordings are missing, the arithmetic means per time point will be computed 
with the reduced number (1 or 2) of recordings.
For the classification of the on-treatment QTc/QT intervals into “no new onset” / “new onset” 
categories, a missing value is obtained only in case that
(i)
all on-treatment values are missing and
(ii)
the baseline value is less than or equal to 500 msec, or missing.
If condition (i) is fulfilled but the baseline value is greater than 500 msec, this case will be 
categorized as ‘no new onset’. If baseline is missing and the maximum on treatment 
QTc interval is greater than 450 msec (or 500 msec for QT interval, respectively), this is 
classified as a ‘new onset’ in the respective category. If baseline is missing and the maximum 
QTc interval is less than or equal to 450 msec (or 500 msec for QT interval, respectively), this 
will be categorized as ‘no new onset’. If baseline is missing, a QTc/QT interval > 500 msec at 
any time on treatment will be a notable finding.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For vital signs or laboratory measurements, baseline is defined as the last measurement before 
drug administration (BI or Placebo). 
Section 6.1 of the CTP: Exact times of measurements outside the permitted time windows 
will be documented. The acceptable time windows for screening and end of trial examination 
are given in the CTP Flow Chart.
Study measurements and assessments scheduled to occur‘before’
 trial medication
administration on Day 1 of Visits 2 or 3 are to be performed and completed within a 2 h-
period prior to the trial drug administration (including blank values for PK 
Starting from 96 h post administration a deviation from the scheduled time for PK sampling
ECG and blood sampling for ADA of ± 70 min is acceptable. However, ECGs should always 
be time-matched with blood PK sampling.
The acceptable deviation from the scheduled time for vital signs and laboratory tests will be 
± 30 min for the first 72 h after trial drug administration. Starting from 96 h post


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administration a deviation from the scheduled time for vital signs and laboratory tests of ± 70
min is acceptable.
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.
There will be a centralised evaluation of the 12-lead ECG recordings at the time points and 
for the ECG recordings specified in the Table 6.7: 1 below:
Table 6.7: 1
Time schedule of 12-lead ECG recordings
Visit
Day
Planned time 
[hh:mm]
(relative to drug 
administration)
Study phase
Central evaluation
1
-21 to -2
Screening
NA
2
-1
-24:00
NA
3
1
-1:00
first of three replicate ECG
-0:45
first of three replicate ECG
-00:30
first of three replicate ECG
06:00
On treatment
first of three replicate ECG
09:00
first of three replicate ECG
12:00
first of three replicate ECG
2
24:00
first of three replicate ECG
28:00
first of three replicate ECG
34:00
first of three replicate ECG
3
48:00
first of three replicate ECG
60:00
first of three replicate ECG
4
72:00
first of three replicate ECG
5
96:00
first of three replicate ECG
6
120:00
first of three replicate ECG
8
168:00
first of three replicate ECG
11
240:00
first of three replicate ECG
15
336:00
first of three replicate ECG
22
504:00
first of three replicate ECG
29
672:00
first of three replicate ECG
4
33 to 40 
End of trial 
examination
NA
Triple ECGs (3 single ECGs of 10 sec duration each, recorded within 180 sec) will be 
recorded at all time points, except for Screening, planned time -24:00h and End-of-trial visit. 


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At these time-points single ECGs will be recorded. Three pre-dose triplicate ECGs within 60 
minutes are to be recorded as baseline.
Section 6.1 of the CTP: Only the first of the three replicate ECGs at a single time point or at 
baseline will be evaluated.
The baseline value of an ECG variable is defined as the mean of the first single ECG 
measurement of each triple ECG prior to first drug administration.


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7.
PLANNED ANALYSIS
The placebo group in the safety evaluation will consist of all placebo treated subjects, 
regardless of the dose group in which they were treated.
Safety analysis (refer to Section 7.8) will be performed by
and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Descriptive data analysis of PK
parameters and concentrations will be performed by
the department Translational Medicine and Clinical Pharmacology (TMCP) at BI and will be 
presented in Section 15.6 and 15.7 of the CTR.
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of Clinical Trials and Project Summaries” [001-MCG-159] (6) with the 
exception of those generated for PK-calculations.
The individual values of all subjects will be listed, sorted by treatment group, subject number,
and visit. 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile


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The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment group. Percentages will be rounded to one decimal place and will be based on all 
subjects in the respective subject set whether they have non-missing values or not. The 
category 'missing' will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
Exclusion of PK parameters
The analysis data set (ADS) ADPP contains column variables APEXC and APEXCO 
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for 
exclusion, that is APEXCO is equal to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/ time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO 
is set to ‘HALF LIFE’ the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03
“Description of Analytical Transfer Files and PK/PD Data Files” (11).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarized by treatment group and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.


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Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the latest version of 
the World Health Organization Drug Dictionary (WHO-DD). The coding version number will 
be displayed as a footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM. 
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre under supervision of the investigating physician or a designee. The 
measured plasma concentrations of investigational and non-investigational medicinal 
products and urinary excretion of BI 473494 will provide additional confirmation of 
compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM/DBLM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 473494.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoints
Descriptive statistics of plasma concentrations and PK endpoints will be done by the 
department TMCP at BI and will be presented in Section 15.6 of the CTR.
The analysis of PK parameters as well as the tables and graphs for the pharmacokinetic non-
compartmental analyses will follow specific definitions of this TSAP or, otherwise, the BI 
standard procedure “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics” [001-MCS-36-472] (7).


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
If not stated otherwise, the safety results will be sorted by treatment group. The safety data for 
treated subjects who failed to complete the study (dropouts or withdrawals) will be reported 
as far as their data are available. All withdrawals will be documented and the reason for 
withdrawal recorded.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials” [001-MCG-156] (8).
The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs). 
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:
•
All AE attributes are identical (LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AE of special interest)
•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
two occurrences is given if the second occurrence started within one hour after end of the 
first occurrence).
For further details on summarization of AE data, please refer to [001-MCG-156] (8,4).
Section 5.2.2.1 of the CTP: The following are considered as AESIs in this trial:

Hepatic injury: A hepatic injury is defined by the following alterations of hepatic
laboratory parameters:

an elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, and/or


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
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure these parameters are analysed, if necessary in an unscheduled blood test. 
Should the results meet the criteria of hepatic injury alert, the procedures described in 
the DILI checklist should be followed.
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events.
Section 5.2.2.2 of the CTP: The REP for BI 473494, when measurable drug levels or PD 
effects are still likely to be present after the last administration, is not known for this first-in-
human trial. Therefore, all AEs reported until the end of trial examination (last per protocol 
contact) will be considered on treatment […].
For more details see the TSAP ADS plan.
According to ICH E3 (9), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at the RPM at the latest. 
An overall summary of AEs (including AESIs) will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with other 
significant AEs according to ICH E3 (9), for subjects with serious AEs, for subjects with 
drug-related AEs, for subjects with drug related serious adverse events and for subjects with 
AESIs.
The SOC and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
[001-MCG-157] (10).
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possible 
clinically significant will be flagged in the data listings.
It is the investigator's responsibility to decide whether a lab value is clinically significant 
abnormal or not (at the RPM/DBLM at the latest).
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate as well as body weight). 
7.8.4
ECG
12-lead ECG
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during the 
trial) if judged clinically relevant by the investigator.  
All evaluations of ECG data will be based on the TS.
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR only listings will be provided. Occurrences of notable findings will be flagged.
Comments regarding the ECGs will be listed.
Categorical endpoints
For the categorical endpoints, frequency tables will be provided.
For all subjects with any notable finding in ECG intervals, a separate listing will be created as 
end-of-text display (based on the same display template as in Appendix 16.2), and the 
corresponding time profiles will be shown.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the changes from 
baseline over time of QTcF, HR, QT, PR and QRS. The time profiles of mean and SD for the 
changes from baseline on treatment will be displayed graphically by treatment.


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


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: “Identify and Manage Important Protocol Deviations (iPD)”, current 
version, BIRDS
3.
BI-KMED-COPS-TMP-0001: "iPD log", current version; KMED
4.
001-MCG-156_RD-01: “Handling of Missing and Incomplete AE Dates”, current 
version; IDEA for CON.
5.
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic
Analyses of Clinical Studies”, current version; IDEA for CON.
6.
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current version; 
IDEA for CON.
7.
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
8.
001-MCG-156: “Analysis and Presentation of Adverse Event Data from Clinical Trials”, 
current version; IDEA for CON.
9.
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, current 
version.
10. 001-MCG-157: “Handling, Display and Analysis of Laboratory Data”, current version; 
IDEA for CON.
11. 001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.
12. Ring A. Statistical models for heart rate correction of the QT interval. Stat Med 2010 
[R10-2920]


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
29-JAN-19
None
This is the final TSAP without any 
modification