Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 48
Healthy volunteers: yes

Brief summary:
The main objectives of this trial are to investigate safety, tolerability, and pharmacokinetics of BI 765080 in healthy male subjects following intravenous administration of single rising doses.

Detailed description:

Arms:
arm 1: BI 765080 arm 2: Placebo group arm 3: BI 765080 arm 4: BI 765080 arm 5: BI 765080 arm 6: BI 765080 arm 7: BI 765080

Interventions: intervention 1: BI 765080 intervention 2: Placebo
Intervention descriptions: intervention 1: BI 765080 intervention 2: Placebo; 0.9% saline for injection

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c31414158-03
EudraCT No.
2020-004262-19 
BI Trial No.
1450-0001
BI Investigational
Medicinal Product
BI 765080
Title
Safety, tolerability, pharmacokinetics, and pharmacodynamics of 
single rising intravenous doses of BI 765080 in healthy male 
subjects (single-blind, randomised, placebo-controlled, parallel-
group design) 
Lay Title
A study in healthy men to test how the body takes up and 
tolerates different doses of BI 765080
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: Fax: 
Principal 
Investigator
Phone: 
Fax:
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0
Date: 10 May 2021
Page 1 of 79
Proprietary confidential information
© 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
22 October 2020
Revision date
10 May 2021
BI trial number
1450-0001
Title of trial
Safety, tolerability, pharmacokinetics, and pharmacodynamics of single rising 
intravenous doses of BI 765080 in healthy male subjects (single-blind, randomised, 
placebo-controlled, parallel-group design)
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
In this first-in-human trial, the effects of single rising doses of BI 765080 on safety, 
tolerability, pharmacokinetics, and pharmacodynamics will be assessed as the basis 
for further development in patients with chronic kidney disease.
Trial objectives
To investigate safety, tolerability, pharmacokinetics, and pharmacodynamics 
following single rising intravenous doses of BI 765080
Trial endpoints
Primary endpoint to assess safety and tolerability of BI 765080 is the percentage of 
subjects with drug-related adverse events
Secondary endpoints:

AUC0-∞of BI 765080

Cmax of BI 765080
Trial design
Single-blind, randomised within dose groups, placebo-controlled, parallel-group 
design
Number of subjects 
total entered
48*
each treatment
8 per dose group (6 on BI 765080 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 48, but is not to exceed 80.
Diagnosis
Not applicable


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Main criteria
for inclusion
Healthy male subjects, age of 18 to 50 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product
BI 765080 powder for solution for injection/infusion, 50 mg/vial
dose
Single doses of 1 mg, 10 mg, 25 mg, 50 mg, 100 mg, and 200 mg 
mode of admin.
Intravenous as 30 min infusion 
Comparator product
Matching placebo for BI 765080 concentrate for infusion solution 
dose
Not applicable
mode of admin.
Intravenous as 30 min infusion 
Duration of treatment
Single dose
Statistical methods
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory16
PK blood 9
Body temperature
12-lead ECG
Continuous ECG 
monitoring
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-21 to -3
Screening (SCR) 1
A
x
x
x
2
-2
-48:00
08:00
Ambulatory visit14
B7
x
x
-1
-12:00
20:00
Admission to trial site
x5
x
x
1
-3:00
06:00
Allocation to treatment2
B 13
x2
x2
x2,10
x2
x2,17
0:00
08:00
Drug administration
start of infusion
▲
0:30
08:30
end of infusion
x
x
x8
│
x
x17
1:00
09:00
x
x8
│
x
x
1:30
09:30
x8
│
x
x
2:00
10:00
light breakfast3 
x
x
x8
│
x
x17
3:00
11:00
x
x8
│
x
x
4:00
12:00
lunch3
x13
x
x8
▼
x
x
6:00
14:00
x
x
x8
x
x
8:00
16:00
Snack (voluntary)3
x
x8
x
x
10:00
18:00
Dinner3
x
12:00
20:00
x
x
x8
x
x
2
24:00
08:00
Breakfast3
B13
x
x
x8
x
x
34:00
18:00
Dinner3
x
x
x8
x
x
3
48:00
08:00
Breakfast3
discharge from trial site 
(confirmation of fitness15)
x
x8
x
x
4
72:00
08:00
Ambulatory visit
B
x
x
x
x
7
144:00
08:00
Ambulatory visit
B
x
x
x
14
312:00
08:00
Ambulatory visit
x
x
x
21
480:00
08:00
Ambulatory visit
B
x
x
x
28
648:00
08:00
Ambulatory visit
x
x
x
56
1320:00
08:00
Ambulatory visit
B
x11
x
x
84
1992:00
08:00
Ambulatory visit
x11
x
x
3
84-87
End of trial (EoTrial) 
examination4
B
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs and body temperature, ECG, safety laboratory (including 
drug screening), demographics (including determination of body height, weight, smoking status, alcohol history, 
relevant medical history, concomitant therapy, and review of inclusion/exclusion criteria). 
2.
The time is approximate; procedures are to be performed and completed within the 3 h prior to drug administration. 
Allocation to treatment may be performed at any time following enrolment but must be completed prior to (first) drug 
administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, body weight, vital signs, ECG, safety 
laboratory, recording of AEs, and concomitant therapies. EOT to be performed not before last PK sampling.
5.
Only urine drug screening and alcohol breath test will be done at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.


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7.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to administration of study drug; this 
safety laboratory assessment can be omitted if the screening examination is performed on Days -5 to Day -3.
8.
The ECG recording has to be performed in triplicate ECGs at this time 
9.
Sampling times and periods may be adapted based on information obtained during the trial (e.g., due to preliminary PK 
data) including addition of samples and visits as long as the total blood volume removed does not exceed 500 mL per 
subject
10. At baseline (i.e. Day 1, prior to drug administration) 3 triplicate ECGs are recorded within approximately one hour. The 
recordings should be separated by at least 15 minutes.
11. In case blood levels still exceed LOQ, additional PK
samples may be collected beyond Day 28.
14. SARS-CoV-2 PCR test will be performed.
15. Confirmation of fitness includes physical examination.
16. Letters A and B describe different sets of safety laboratory examinations (see Section 5.2.3).
17. Local tolerability inclusive.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................15
Nonclinical pharmacology....................................................................15
Toxicology..............................................................................................15
Genotoxicity.............................................................................15
Single dose toxicity..................................................................16
Repeated dose toxicity.............................................................16
Special studies..........................................................................18
Reproductive and developmental toxicity ...............................19
Phototoxicity............................................................................19
Nonclinical pharmacokinetics..............................................................19
Prediction of human pharmacokinetics..............................................20
Clinical experience in humans.............................................................20
Residual Effect Period..........................................................................21
Drug product.........................................................................................21
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................22
Starting dose..........................................................................................22
Maximum dose and escalation.............................................................23
1.4
BENEFIT - RISK ASSESSMENT ...................................................................23
Procedure-related risks ........................................................................23
Drug-related risks and safety measures..............................................24
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 27
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......27
Main objectives......................................................................................27
Primary endpoint..................................................................................27
Secondary endpoints.............................................................................27
Safety and tolerability..............................................................27


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 29
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................31
3.3
SELECTION OF TRIAL POPULATION ......................................................31
Main diagnosis for trial entry..............................................................31
Inclusion criteria...................................................................................32
Exclusion criteria ..................................................................................32
Withdrawal of subjects from treatment or assessments ...................34
Discontinuation of trial treatment ............................................34
Withdrawal of consent to trial participation ............................35
Discontinuation of the trial by the sponsor..............................35
Replacement of subjects .......................................................................35
4.
TREATMENTS........................................................................................ 36
4.1
INVESTIGATIONAL TREATMENTS ..........................................................36
Identity of the Investigational Medicinal Products ...........................36
Selection of doses in the trial................................................................36
Method of assigning subjects to treatment groups ............................37
Drug assignment and administration of doses for each subject .......37
Blinding and procedures for unblinding ............................................38
Blinding ...................................................................................38
Unblinding and breaking the code...........................................38
Packaging, labelling, and re-supply ....................................................38
Storage conditions.................................................................................39
Drug accountability ..............................................................................39
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................39
Other treatments and emergency procedures....................................39
Restrictions............................................................................................40
Restrictions regarding concomitant treatment .........................40
Restrictions on diet and life style.............................................40
4.3
TREATMENT COMPLIANCE.......................................................................40
5.
ASSESSMENTS....................................................................................... 41
5.1
ASSESSMENT OF EFFICACY.......................................................................41
5.2
ASSESSMENT OF SAFETY............................................................................41
Physical examination ............................................................................41
Vital signs...............................................................................................41
Safety laboratory parameters..............................................................41
Electrocardiogram................................................................................44
12-lead resting ECG.................................................................44
Continuous ECG monitoring ...................................................46


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Other safety parameters.......................................................................46
Local tolerability......................................................................46
Oral body temperature .............................................................46
Assessment of adverse events...............................................................46
Definitions of adverse events...................................................46
Adverse event ............................................................46
Serious adverse event ................................................47
AEs considered ‘Always Serious’.............................47
Adverse events of special interest .............................48
Intensity (severity) of AEs.........................................48
Causal relationship of AEs ........................................48
Adverse event collection and reporting ...................................49
AE collection.............................................................49
AE reporting to the sponsor and timelines ................50
Information required..................................................50
Pregnancy ..................................................................50
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................51
Assessment of pharmacokinetics .........................................................51
Methods of sample collection...............................................................51
Blood sampling for pharmacokinetic analysis.........................51
5.5
BIOBANKING ...................................................................................................53
5.6
OTHER ASSESSMENTS .................................................................................54
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................54
6.
INVESTIGATIONAL PLAN.................................................................. 55
6.1
VISIT SCHEDULE............................................................................................55
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................55
Screening period....................................................................................55
Treatment period ..................................................................................56
Follow-up period and trial completion ...............................................56
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 57
7.1
STATISTICAL DESIGN – MODEL ...............................................................57
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................57


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7.3
PLANNED ANALYSES....................................................................................57
Primary endpoint analyses...................................................................58
Secondary endpoint analyses ...............................................................58
Safety analyses.......................................................................................59
7.4
INTERIM ANALYSES .....................................................................................60
7.5
HANDLING OF MISSING DATA ..................................................................61
Safety......................................................................................................61
Pharmacokinetics..................................................................................61
7.6
RANDOMISATION ..........................................................................................61
7.7
DETERMINATION OF SAMPLE SIZE ........................................................61
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 63
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................63
8.2
DATA QUALITY ASSURANCE .....................................................................64
8.3
RECORDS..........................................................................................................64
Source documents .................................................................................64
Direct access to source data and documents.......................................65
Storage period of records.....................................................................65
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................65
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......65
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................66
8.6
TRIAL MILESTONES .....................................................................................66
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................67
9.
REFERENCES......................................................................................... 68
9.1
PUBLISHED REFERENCES...........................................................................68
9.2
UNPUBLISHED REFERENCES.....................................................................70
10. APPENDICES .......................................................................................... 71
10.1
RECONSTITUTION INSTRUCTIONS .........................................................71
Description of trial medication ............................................................71
Temperature deviation during storage...............................................71
Instructions for preparation the study medication............................71
General Remarks......................................................................71
Consumables............................................................................71


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Preparation of the study medication ........................................72
Reconstitution of the lyophilized powder.............74
Dilution Procedure (DL 1)....................................74
Dilution Procedure (DL 2-6).................................74
Preparation of Placebo ..........................................75
In-Use stability statement ........................................................75
Infusion Instructions.............................................................................75
General Remarks......................................................................75
Administration .........................................................................75
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 77
11.1
GLOBAL AMENDMENT 1 .............................................................................77
11.2
GLOBAL AMENDMENT 2 .............................................................................79


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ABBREVIATIONS
ACE
Angiotensin-converting-enzyme
AE
Adverse event
AESI
Adverse events of special interest
ALCOA
Attributable, legible, contemporaneous, original, accurate
ALT
Alanine amino transferase
ARB
Angiotensin-receptor blocker
AST
Aspartate amino transferase
AUC
area under the concentration
AUC0-∞
Area under the concentration-time curve of the analyte in serum over the 
time interval from 0 extrapolated to infinity
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CKD
Chronic kidney disease
Cmax
Maximum measured concentration of the analyte in serum
CML
Clinical Monitor Local
COVID-19
Corona virus disease 2019
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTM
Clinical Trial Manager


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CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver injury
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EoTrial/EoT
End of trial
ESRD
End-stage renal disease
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
HD
Hemodialysis
HIV
Human Immunodeficiency Virus
HR
Heart rate
HUVEC
Human umbilical vein endothelial cells
IB
Investigator’s brochure
IEC
Independent Ethics Committee
iPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
i.v.
Intravenous
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum tolerated dose
NKcell
Natural killer cell
NOAEL
No-observed-adverse-effect level
PCR
Polymerase chain reaction
PD
Pharmacodynamic(s)


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PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter analysis set 
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)
Q2W
Every 2 weeks
Q3W
Every 3 weeks
REP
Residual effect period
RR
Respiratory rate
SAE
Serious adverse event
SCR
Screening
SGLT2
Sodium-glucose co-transporter-2
SOP
Standard operating procedure
SRD
Single-rising dose
TMDD
Target mediated drug disposition
TMF
Trial master file
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WFI
Water for Injection
WHO
World Health Organization
XTC
Ecstasy


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1.
INTRODUCTION
BI 765080 is intended for the treatment of chronic kidney disease (CKD). This is the first 
trial in humans.
1.1
MEDICAL BACKGROUND
The incidence and prevalence of CKD can vary as a result of the underlying aetiology
[R19-0901]. Overall, around 12% of the general population in Europe has CKD stages 3–5 
[R19-1388], with considerable variation across European countries, ranging from 4.1% to 
25.5% [R19-1184]. In developed countries, CKD is generally associated with diabetes, 
hypertension, old age, obesity, and cardiovascular disease. Diabetic glomerulosclerosis and 
hypertensive nephrosclerosis are the presumed pathological entities; however, exact diagnosis 
is often difficult. It has been shown that both reduced GFR and increased albuminuria are 
independent predictors of mortality [R17-2621, R17-2619]. 
Current treatment of CKD is based on clinical diagnosis and staging of GFR decline and 
severity of albuminuria. The current standard of care is angiotensin-converting-enzyme 
(ACE) inhibitors and angiotensin-receptor blockers (ARBs) [P11-14681], usually in 
association with diuretic drugs in patients with high concentrations of albuminuria 
[R19-0901]. Selective nonsteroidal mineralo-corticoid receptor antagonists such as 
finerenone and sodium-glucose co-transporter-2 (SGLT2) inhibitors may be considered as 
standard of care in the future [P18-03010, R19-1139, R19-1356].


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Although ACE inhibitors and ARBs have demonstrated efficacy in slowing the progression 
of diabetic nephropathy, it should be acknowledged that the relative risk reduction was small 
(16% in RENAAL and 19% in IDNT) for the triple composite primary endpoint of all-cause 
death, ESRD, or doubling of serum creatinine [R02-0327, R02-2101]. The residual risk is 
still considerably high. Therefore, there are high unmet needs for an effective and safe 
treatment that can further slow, halt, or reverse the progression of CKD.
1.2
DRUG PROFILE
For a comprehensive description of the BI 765080 profile, please refer to the current 
Investigator’s Brochure (IB) [c30981435].
Nonclinical pharmacology
The core safety pharmacology (neurological, cardiovascular, and respiratory functions) was 
evaluated as part of the 4-week (rat) and 13-week (monkey) GLP repeat dose toxicity studies 
(see Section 1.2.2.3).
 
Toxicology
Rationale for Toxicology Species Selection
Genotoxicity 
Genetic toxicity studies are generally not applicable to therapeutic antibodies, as they are not 
expected to interact directly with DNA. Therefore, genetic toxicity studies were not 
conducted per ICH S6 (R1): ‘Preclinical Safety Evaluation of Biotechnology-derived 
Pharmaceuticals’ [R11-1428].


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Single dose toxicity
No single-dose toxicity assessments have been conducted with BI 765080
Repeated dose toxicity
4-Week study in rats, GLP [n00277285]
13-Week study in cynomolgus monkeys, GLP [n00277281]


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In summary, BI 765080 administered to monkeys intravenously once weekly for 
13 consecutive weeks at 
eek was well tolerated in animals surviving 
until scheduled necropsy. 
 


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Special studies
Local tolerance
There was no evidence of local BI 765080-related effects at the injection sites during the 
4-week repeat dose toxicity study in rats [n00277285]. 
In the 13-week repeat dose toxicology study in monkeys [n00277281], one monkey given a 
 dose showed localized injection site reactions with clinical signs including swelling, 
exudate, and/or discharge at right and left cephalic vein dose sites. 
 


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Reproductive and developmental toxicity 
Developmental and reproductive toxicity studies have not been conducted with BI 765080. 
Phototoxicity
Therapeutic antibodies are not generally expected to be phototoxic unless related to the 
mechanism of action. Therefore, no phototoxicity studies were conducted. There were no 
toxicities in the skin or eyes related to light exposure observed in the repeat dose toxicity 
studies [n00277285, n00277281].
Nonclinical pharmacokinetics


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Prediction of human pharmacokinetics
Clinical experience in humans
This will be the first clinical trial in humans with BI 765080.


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Residual Effect Period
The residual effect period (REP) of BI 765080, when measurable drug levels or PD effects 
are still likely to be present, is not known for this first-in-human trial. Conservatively, a 
minimum observation period of approximately 4-fold the estimated t1/2 has been selected. 
Therefore, the individual subject’s end of trial is on Day 84-87 following dosing with 
investigational drug at the earliest (see Flow Chart).
Drug product
BI 765080 is 
 


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1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 765080 is 
 
In this first-in-human trial, the effects of single rising doses of BI 765080 on safety, 
tolerability, pharmacokinetics, and pharmacodynamics will be assessed as the basis for 
further development in patients with CKD.
Within each dose group, all actively treated individuals will receive the same BI 765080 
dose. The next higher dose will only be administered to the next group if the treatment in the 
preceding dose group was safe and well tolerated (see Section 3.1). The background for dose 
selection and escalation steps is described below.
Starting dose 
The starting dose in healthy humans in this initial Phase I single-rising dose (SRD) trial is 
1 mg (0.017 mg/kg). 


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Maximum dose and escalation
The following doses have been chosen for this trial: 1 mg, 10 mg, 25 mg, 50 mg, 100 mg and 
200 mg. The selected doses are expected to cover the range of subtherapeutic, anticipated 
therapeutic, and supratherapeutic doses. The dose of 200 mg will allow for the collection of 
safety data in case higher doses are needed to assess efficacy in future clinical trials. 
Predictions based on preclinical testing may turn out to be too optimistic and higher 
doses/exposure may be required, i.e. 400 mg, maximal 600 mg. The dose higher than 200 mg 
will only occur if safety and tolerability of 200 mg support increasing the dose and 200 mg 
does not achieve the estimated exposure, which will be provided by substantial CTP
amendment.
A dose of  200 mg is expected to be safe, since no adverse effects in rats or monkeys were 
associated with BI 765080 administration at dose levels up to 100 mg/kg (NOAEL; see 
Section 1.2). The planned maximum exposure in humans is predicted to be substantially 
lower than the exposures in the rat and monkey toxicity studies (Table 1.3.2: 1). The dose 
escalation up to and including the maximum dose will only occur if safety and tolerability of 
preceding dose levels support increasing the dose (see Section 3.1).
Table 1.3.2: 1
Planned maximum dose and estimated exposure multiples versus 
exposures in the rat and monkey
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of a new therapy 
for CKD. Subjects are exposed to risks of study procedures and risks related to the exposure 
to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising and, in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.


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The total volume of blood drawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures
Factors of risk may derive from particular knowledge or the lack thereof, regarding (1) the 
mode of action, (2) the nature of the target, (3) the relevance of animal models and/or (4) 
findings in non-clinical safety studies.
Mode of action and nature of the target
The mode of action of BI 765080 and nature of the target are described in Section 1.1. 
Relevance of animal species and models
Rat and cynomolgus monkey are considered suitable species for the nonclinical safety 
profiling of BI 765080 
 
Findings in non-clinical safety studies
The toxicity profile of BI 765080 has been assessed in repeat dose toxicity studies in rats and 
cynomolgus monkeys that included immunotoxicology and/or core safety pharmacology 
endpoints (cardiovascular, neurologic, and respiratory function), 
 
 No adverse findings were associated with 
BI 765080 administration at dose levels up to 100 mg/kg. The nonclinical safety package for 
BI 765080 supports clinical trials in humans with i.v. administration for up to 13 weeks. The 
potential for BI 765080 immunogenicity in humans is considered low. 
Safety measures
The following safety measures will be applied in order to minimise the risk for healthy 
volunteers:

Careful dose selection, as described in Section 1.3, with large safety margins up to the 
maximum dose, based on a sound preclinical data package including repeat dose 
toxicity studies in rats (4 weeks) and monkeys (13 weeks)

The i.v. administration as 30 min infusion allows immediate discontinuation and the 
ability to adapt further drug administration should any safety concerns arise (please 
refer to Section 4.1.1)

For safety reasons, each dose group is divided into 3 cohorts: on the first study day of 
each dose level, only 2 subjects will be treated: one will receive active treatment, the 
other subject will receive placebo. If BI 765080 treatment is safe and tolerated in this 
first cohort, 2 subjects on active will be treated in the second cohort no sooner than on 


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the next day. The remaining 4 subjects (either active or placebo) are the third cohort 
and will be treated no sooner than after 2 days following the first cohort. This design 
ensures that there is a time interval of at least 1 day between the first and second 
active dose of each dose level, which covers the tmax of BI 765080 (end of infusion) 
and the period of highest risk / peak effect. If BI 765080 is safe and shows acceptable 
tolerability in the first two cohorts, the remaining third cohort of the respective dose 
level can be dosed as close as 10 minutes apart.

Dose escalation will be shallow. In addition, a time interval of at least 14 days will be 
maintained between first administration of study drug in the actual dose level and first 
administration in the next dose level, which is expected to cover the period of highest 
risk / peak effect. The decision to proceed to the next dose will be based upon the 
safety and tolerability of the preceding dose. The next dose will only be given if no
safety concerns arise in the previous dose group (i.e. no dose-limiting events occur)
and if none of the pre-specified trial-specific stopping criteria are met (see
Section 3.3.4).

Doses will only be escalated if previously approved by the Principal Investigator (or
an authorised deputy) and the Clinical Trial Leader (or an authorised deputy) after in-
depth analysis of all available safety data in a documented Safety Review (see 
Section 3.1)

Extensive monitoring of ECG and vital signs is incorporated, with continuous ECG
monitoring over 4 hours post dose to cover the anticipated period of highest drug 
exposure. As an additional measure, triplicate ECGs and repeated single 12-lead 
ECGs are scheduled in the further course of the study. The rationale for the intensified 
ECG monitoring is not an expected increased risk of BI 765080 mediated effects on 
cardiac repolarization. Rather, it has been implemented to collect thorough ECG data 
at an early point in clinical development to perform ECG interval assessment under 
drug. In general, for biologics, QT prolongation is not usually an issue (unless there 
are mechanistic effects with the antibody that can lead indirectly to ECG changes 
[R09-2768], which is not expected to be the case for BI 765080)

Extensive safety laboratory testing will be performed

At each dose level, the subjects will stay at the site for at least 48 hours following 
drug administration

During in-house-confinement, the subjects will be under close medical observation 
and thoroughly monitored for both expected and unexpected adverse events


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Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.6.1.4, adverse events of special interest.
Conclusion
Although not tested in humans to date, BI 765080 has the potential to become an effective 
treatment for CKD, an indication with a large medical need.
Based on the mode of action, the pharmacological target, and the non-clinical toxicology 
data, BI 765080 is not considered a high-risk compound for adverse outcomes in clinical 
trials. Healthy subjects will not be exposed to undue risks in relation to the important 
information expected from this trial as a basis for further clinical development of this 
compound. Considering the medical need for an effective treatment for CKD, the benefit of 
this trial is considered to outweigh the potential minimal risks and justifies the exposure of 
healthy human volunteers.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
The main objectives of this trial are to investigate safety, tolerability, and pharmacokinetics
of BI 765080 in healthy male subjects following i.v. administration of single rising doses.
Primary endpoint
The primary endpoint for assessment of safety and tolerability of BI 765080 is the percentage 
of subjects with drug-related adverse events.
Secondary endpoints
The following pharmacokinetic parameters of BI 765080 will be determined if feasible:

AUC0-∞(area under the concentration-time curve of the analyte in serum over the time 
interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in serum)
Safety and tolerability
Safety and tolerability of BI 765080 will be assessed based on:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring 

Vital signs (blood pressure, pulse rate), oral body temperature

Local tolerability assessment


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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, randomised within dose groups, and 
placebo-controlled within parallel dose groups.
It is planned to include a total of 48 healthy male subjects in the trial. The subjects will be 
assigned to 6 groups consisting of 8 subjects per group; the groups will be dosed sequentially
(see Table 3.1: 1). The investigator (after consultation with the sponsor) is allowed to alter 
the scheduled dose groups (e.g., add low and/or intermediate dose groups) based on
experience gained during the study (for instance, based on preliminary PK data), provided the 
planned and approved highest dose is not exceeded. Thus, the actual number of subjects 
entered may be more than 48, but is not to exceed 80. Such changes may be implemented via 
non-substantial CTP amendments.
Within each dose group, 6 subjects will receive BI 765080 and 2 will receive placebo. Only 
one dose is tested within each dose group. For safety reasons, each dose group will consist of 
3 cohorts. The trial medication will be administered in the following order: 

Cohort 1: 1 subject on active treatment followed by 1 subject on placebo (in total 
2 subjects)

Cohort 2: 2 subjects on active treatment (in total 2 subjects)

Cohort 3: randomised to 3 subjects on active treatment and 1 subject on placebo (in 
total 4 subjects)
Between cohort 1 and cohort 2 there will be a time interval of at least 1 day, which is 
expected to be sufficient to detect relevant acute effects of BI 765080. Cohort 1 and cohort 3 
will be separated by at least 2 days. This design ensures that between first and second active 
dose of each dose level, there is a time interval of at least 1 day, which covers the tmax of 
BI 765080 (end of infusion) and the period of highest risk / peak effect. If BI 765080 was 
safe and showed acceptable tolerability in the first two cohorts, the remaining third cohort of 
the respective dose level could be dosed as close as 10 minutes apart.
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
Dose (mg)
1
10
25
50
100
200
Number of subjects
8
8
8
8
8
8
Subjects receiving placebo
2
2
2
2
2
2
Subjects receiving BI 765080 6
6
6
6
6
6


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The groups will be dosed consecutively in ascending order, and a time interval of at least 
14 days will be maintained between the last drug administration to subjects in the previous 
dose group and the first drug administration to subjects in the subsequent dose group. The 
decision to treat the next dose group will be based upon safety and tolerability of all the 
preceding dose groups. Preliminary PK 
 assessments may be performed between dose 
groups (see Section 7.4). The next dose group will only be treated if, in the opinion of the 
investigator, no safety concerns have arisen in the preceding dose groups (i.e. no dose-
limiting events occurred), and if none of the pre-specified trial-specific stopping criteria have 
been met (refer to Section 3.3.4.1).
A documented safety review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested anytime by the Principal Investigator (or 
an authorised deputy) or the sponsor of the study (for instance, due to the occurrence of any 
unforeseen adverse events). Dose escalation will only be permitted if no safety concerns exist 
in the opinion of the Principal Investigator (or an authorised deputy) and the clinical trial 
leader (or an authorised deputy). In addition, at least data from 6 evaluable subjects per dose
level need to be available for escalation to higher dose.
Although no formal Safety Review meeting will take place within a given dose group, safety 
will be continuously monitored during this trial, and an individual will only be dosed in the 
absence of any safety concern (i.e. no dose-limiting events occurred) and if none of the pre-
specified trial-specific stopping criteria have been met (refer to Section 3.3.4.1).
The minimum data up to at least 48 hours post dosing set for review consists of the 
following:

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 and continuous ECG monitoring in the current and 
preceding dose groups based on assessment of the study site.

Vital signs in the current and preceding dose groups

Clinical laboratory tests in the current and preceding dose groups

Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the Clinical Trial Leader (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs, and out-of-range 
laboratory results (if considered clinically significant). In addition and depending on the 
results and findings, suitable experts from the sponsor or external institutions may be 
consulted on an as needed basis. In these cases, expert recommendations will be documented 
in the minutes of the Safety Review and considered for the decision making. Dose escalation 
will only be permitted if no safety concerns exist neither in the opinion of the Principal 
Investigator (or an authorised deputy) nor the Clinical Trial Leader (or an authorised deputy). 


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Safety Reviews can be conducted face-to-face or by video/telephone conference. The Clinical 
Trial Leader is responsible for the organisation and minutes of the reviews. Minutes will be 
signed off by the Principal Investigator (or an authorised deputy) and Clinical Trial Leader 
(or an authorised deputy), and will be filed in the ISF and TMF. 
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.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For single-rising dose trials, the rising dose design described in Section 3.1 is viewed 
favourably under the provision not to expose the subjects involved to undue risks.
Single-blind conditions regarding the subject’s treatment (active or placebo) are maintained 
within each dose group. However, subjects and investigators will be aware of the dose of 
drug administered. The disadvantage of the trial design is a possible observer bias with regard 
to the dose-dependent effects; in addition, the sequential dosing of groups could potentially 
result in time-related effects. However, as such effects are expected to be small relative to the 
differences between the doses in the broad range investigated, unbiased comparisons between 
treatments can still be expected.
It is standard in single or multiple rising dose trials involving healthy volunteers to include a 
placebo group to control for safety, tolerability,
 effects of the trial 
medication. Each dose group consists of 8 subjects, with 6 on active treatment, and 2 on 
placebo. For data analysis purposes, the placebo control group will include all subjects of all 
dose groups treated with placebo. Six subjects per active treatment group are generally
considered to be sufficient for the exploratory evaluation of pharmacokinetics. 
The administration of the study drug as i.v. infusion is considered advantageous since the 
administration of BI 765080 can be immediately stopped in case safety concerns arise during 
the running infusion. A further advantage of the i.v. route is the possibility to investigate 
supratherapeutic exposure unbiased from individual variability in bioavailability. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 48 healthy male subjects will enter the study. The actual number of subjects 
entered may exceed the total of 48 if additional doses are tested (see Section 3.1). Subjects 
will be recruited from the volunteers' pool of the trial site. 
Only male subjects will be included in the trial because no data on reproductive toxicology 
are available at this time.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
Main diagnosis for trial entry 
The study will be performed in healthy subjects.


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Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-
lead ECG, and clinical laboratory tests 
2. Age of 18 to 50 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4. Signed and dated written informed consent prior to admission to the study, in 
accordance with GCP and local legislation
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 
mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate 
outside the range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be 
of clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the 
investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological 
or hormonal disorders
6. Diseases of the central nervous system (including but not limited to any kind of 
seizures or stroke), and other relevant neurological or psychiatric disorders
7. History of relevant orthostatic hypotension, fainting spells, or blackouts
8. Chronic or relevant acute infections
9. History of relevant allergy or hypersensitivity (including allergy to the trial medication
or its excipients) 
10. Use of drugs with a long half-life (more than 24 h) within 30 days or less than 10 half-
lives of the respective drugs prior to administration of trial medication.
11. Within 10 days prior to administration of trial medication, use of drugs that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc 
interval prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more 30 g per day)


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16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, 
or has a condition that would not allow safe participation in the study 
23. Male subjects with WOCBP partner who are unwilling to use a highly effective 
method of birth control from time point of administration of trial medication until 60 
days thereafter. Highly effective methods of birth control are:
- Male subject is sexually abstinent
- Male subjects is vasectomised (vasectomy at least 1 year prior to enrolment), plus 
condom in male subject
- Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) by 
female partner
- Use of progestogen-only hormonal contraception by female partner that inhibits 
ovulation (only injectables or implants), plus condom in male subject
- Use of combined (estrogen and progestogen containing) hormonal contraception by 
female partner that prevents ovulation (oral, intravaginal or transdermal), plus 
condom in male subject
- Female partner is surgically sterilised (including hysterectomy)
- Female partner is postmenopausal, defined as no menses for 1 year without an 
alternative medical cause)
Subjects are required to use condoms to prevent unintended exposure of the partner 
(both, male and female) to the study drug via seminal fluid. Male subjects should use a 
condom throughout the study and for 60 days after investigational medicinal product ( 
IMP) administration.
Alternatively, true abstinence is acceptable when it is in line with the subject’s 
preferred and usual lifestyle.
If a subject is usually not sexually active but becomes active, with their partner, they 
must comply with the contraceptive requirements detailed above.
Male subjects should not donate sperm for the duration of the study until at least 60 days after
IMP administration. In addition, the following SARS-CoV-2-specific exclusion criteria 
apply:
24. A positive PCR test for SARS-CoV-2 and clinical symptoms suggestive for this 
disease on Day -2.
For study restrictions, refer to Section 4.2.2.


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Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) and will 
not be reported in the clinical trial report (CTR). If a subject is removed from or withdraws 
from the trial after the administration of trial medication, this will be documented and the 
reason for discontinuation must be recorded in the CRF; in addition, the data will be included 
in the CRF and will be reported in the CTR.
At the time of discontinuation, a complete end of trial examination will be performed, if 
possible, and the information will be recorded in the CRF. If the discontinuation occurs 
before the end of the REP (see Section 1.2.6), the discontinued subject should if possible be 
questioned for AEs and concomitant therapies at or after the end of the REP in order to 
ensure collection of AEs and concomitant therapies throughout the REP, if not contrary to 
any consent withdrawal of the subject.
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the 
decision
2. The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
3. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
4. An AE or clinically significant laboratory change or abnormality occurs that the 
investigator assesses as warranting discontinuation of treatment. This may include 
cases of sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP 
>180/100 mmHg), clinically relevant changes in ECG requiring intervention, or
unexplained hepatic enzyme elevations at any time during the trial
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of 
total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be 
followed up according to the DILI checklist provided in the ISF
6. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing 
or able to adhere to the trial requirements in the future.
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.


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Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information
invalidating the earlier positive benefit-risk assessment. Dose escalation will be 
terminated if more than 50% of the subjects at one dose level show drug-related and 
clinically relevant adverse events of moderate or severe intensity, or if at least one 
drug-related serious adverse event is reported.
3. Violation of GCP, the CTP, or the contract with BI, impairing 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 if at least 2 subjects on active treatment at one dose 
level have relevant individual QT prolongations, i.e. a QTc increase of greater than 60 
ms from baseline in connection with absolute QT or QTc greater than 500 ms, as
confirmed by a repeat ECG recording
6. Occurrence of severe non-serious adverse events considered as drug-related by the 
investigator in 2 subjects of the same dose group (8 subjects) 
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
Replacement of subjects
If some subjects do not complete the trial, the Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. A replacement subject will be assigned a unique trial subject number, and will be 
assigned to the same treatment as the subject
 replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product BI 765080 was manufactured by BI Pharma GmbH & Co. KG. 
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Substance:
BI 765080
Pharmaceutical formulation: Powder for solution for injection/infusion
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
50 mg/vial
Posology:
1-0-0
Route of administration:
i.v. infusion
Duration of use:
Single dose
The characteristics of the reference product (placebo) are given below:
Substance:
Matching placebo (0.9% saline for injection)
Pharmaceutical formulation: Solution for infusion
Source:
Purchase by
(e.g.
)
Unit strength:
Not applicable
Posology:
1-0-0
Route of administration:
i.v. infusion
Duration of use:
Single dose
At the time of use, the i.v. solution for dosing will be prepared as detailed in the instruction 
given in Appendix 10.1.
Selection of doses in the trial
The doses selected for this trial cover the range of subtherapeutic, anticipated therapeutic, and 
supratherapeutic doses and include a safety margin (see Section 1.2).


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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 
(3 cohorts per dose group) according to their temporal availability. As soon as enough 
subjects are allocated to 1 of the 18 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. Because the study includes healthy subjects from a homogenous 
population, relevant imbalances between the dose groups are not expected. 
Subjects will be assigned to treatments (active treatment or placebo) prior to the first 
administration of trial medication. For this purpose, the randomisation list will be provided to 
the trial site in advance. Numbers of the randomisation list will be allocated to subjects by 
drawing lots. Subjects are then assigned to treatment according to the randomisation list.
The randomisation procedure is described in Section 7.6.
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 3.1: 1 and Appendix 10.1, 
Table 10.1.3.3: 1. The dose volume for placebo corresponds to the dose volume of the 
corresponding dose level. Subjects receiving placebo are equally distributed across dose 
groups. Start- and end time of the infusion will be recorded.
Detailed instructions for the dilution of the trial product, the preparation of the infusion 
solution, the volume to be administered and the infusion time is provided in Appendix 10.1. 
In all subjects, the infusion solution will be intravenously administered over 30 minutes 
approximately between 8.00 h and 10.00 h of the respective study day.
In case of safety concerns, e.g. due to infusion reactions, it is in the discretion of the 
investigator or his/her designee to adapt the infusion scheme, including but not limited 
slowing down the infusion rate, stopping of the infusion and provided no further safety 
concern exist restarting at a slower rate. Further based on 
 medical judgment he/she will 
provide medications such as steroids, etc. as needed.
For administration of the infusion, an intravenous indwelling catheter is placed into an arm 
vein of the subject and closed with a mandrin. A second indwelling catheter used for 
collection of blood samples will be placed on the contralateral arm.
The administration of the trial medication will be done under supervision of the investigating 
physician or a designee. For drug administration, the so-called four-eye principle (two-person 
rule) should be applied. For this, one authorised employee of the trial site should witness the 
administration of trial medication, and – if applicable – its preparation (e.g. reconstitution), if 
correct dosage cannot be ensured otherwise. For the purpose of drug accountability, the 
infusion set will be weighed before and after drug administration.
Water is allowed except for 1 hour before start of infusion and 1.5 h after end of infusion. On 
Day 1, from 2 hours post-dose, liquid intake is restricted at additional 3000 mL until the 
morning of Day 2. Standardised meals will be served as outlined in the Flow Chart. Subjects 
will be kept under close medical surveillance until 48 h following drug administration. On 


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Day 3, subjects will be discharged from the trial site and further assessments will be 
conducted in an ambulatory fashion. For restrictions with regard to diet, see also Section 
4.2.2.2.
Blinding and procedures for unblinding
Blinding
The trial is designed single blind. The treatments administered (active or placebo) will be 
blinded to subjects, but will be known to the investigators (outcome assessors). Only the 
current dose level will be known to the subjects due to the rising dose design.
A single-blind design is considered acceptable because the potential bias in this type of study 
seems to be low and according to study procedures it is assured that the investigator's 
knowledge of the next treatment does not influence the decision to enter a subject. 
All trial data will be handled open label. This means that trial functions of the sponsor are 
unblinded (including clinical trial leader, data manager, statistician, bioanalyst, 
pharmacokineticist, pharmacometrician, drug metabolism scientist as well as dedicated 
personnel of the trial site). 
Within the
 the staff involved with interval measurements and assessments
will be blinded with respect to the treatment and also with regard to the recording date and 
time as well as planned time points of the ECGs. The interval measurements for a given 
subject will be performed in a random and blinded sequence by a single technician.
Access to the randomisation schedule will be controlled and documented by a signed 
confidentiality statement, which will be stored in the TMF. 
Unblinding and breaking the code
As this trial will be conducted single blind, subjects’ treatment assignments will be known to 
investigators. Therefore, no emergency envelopes will be provided.
Packaging, labelling, and re-supply
The investigational medicinal product BI 765080 will be provided by BI. It will be packaged 
and labelled in accordance with local law and the principles of Good Manufacturing Practice. 
The placebo solution will be provided by the trial site.
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms.
Examples of the labels will be available in the ISF.
No re-supply is planned.


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Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
Drug accountability
The investigator or designee will receive the investigational drugs from the sponsor when the 
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused trial medication will be disposed of locally by the trial site upon written 
authorisation of the trial clinical monitor. Receipt, usage, and disposal of trial medication 
must be documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 


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kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
Restrictions
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.
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. On Day 1, no food is allowed for at least 10 h before and 1.5 h 
after administration of the study drug (= end of infusion).
On Day 1, no fluid intake is allowed starting 1 hour before drug administration until 1.5 h 
after the end of infusion. From breakfast until 24 hours post-dose water intake will be within 
1000 to 3000 mL. Total fluid intake on all in-house days is recommended to be at least 1.5 L 
and should not exceed 3.5 L. 
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed on in-house days. On the ambulatory days, it is restricted to a 
maximum of 200 mL (coffee, tea, cola, red bull, energy drinks) or 50 g (chocolate and 
chocolate products).
Smoking is not allowed during in-house confinement while admitted to the trial site.
Alcoholic beverages are not permitted starting 7 days before the first administration of trial 
medication until Day 14.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the administration of trial medication until Day 7. 
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/ serum
concentrations will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable. No efficacy endpoints will be evaluated in this trial.
5.2
ASSESSMENT OF SAFETY
Physical examination
At Screening, the medical examination will include documentation of demographics, height and body weight, 
smoking and alcohol history, !"#$%&%# 
&'()%*+ *,(-#)( .%) /".0")%*+ )% 1, ,.),*,0 '.)% 234 %*
)% 1, *,5%*),06 relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR) and body temperature, 12-lead ECG, 
laboratory tests, and a physical examination. At the end of trial examination, it will include 
review of vital signs, 12-lead ECG, laboratory tests, and a physical examination including 
determination of weight.
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate in healthy volunteers) will be measured by a blood 
pressure monitor (Dinamap Pro 100, 
) at the times indicated in 
the Flow Chart, after subjects have rested for at least 5 min in a supine position. All 
recordings should be made using the same type of blood pressure recording instrument on the 
same arm, if possible.
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required. The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. 
Reference ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively. 


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; Lymphocytes/Leukocytes 
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils Bands; 
Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
Lipase
Amylase
Serum tryptase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
Hormones
Thyroid Stimulating Hormone 
Free T3 - Triiodothyronine
Free T4 – Thyroxine
X
X
X
--
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
Chloride
Calcium
Phosphate (as Phosphorus, Inorganic)
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 and Visit 3 (for time points refer to Flow Chart)


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Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
BI test name [comment/abbreviation]
A
B
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment and 
microscopic examination
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 2 and Visit 3 (for time points refer to Flow Chart)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. It is planned to perform these tests at screening only, except for drug screening and the 
SARS-CoV-2 PCR test, which will be performed on Day -1 and Day -2 respectively.
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 (qualitative)
SARS-CoV-2 PCR test
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
6510 and Alcotest® 5510, 
) will be performed prior to treatment 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.
In case of a potential systemic allergic reaction blood samples for the determination of serum 
tryptase will be collected 0.5 h, 2 h, 6 h, and 24 h after onset of the event.


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The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
, with the exception of drug screening tests. These tests will be 
performed at the trial site using Alere Triage TOX Drug Screen or a comparable test system.
will be performed at 
 
Laboratory data will be transmitted electronically from the laboratory to the trial site.
Electrocardiogram
12-lead resting ECG
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (Motara Device, 
) at the time 
points given in the Flow Chart. Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists).
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled 
for the same time (except for blood drawing from an intravenous cannula that is already in 
place) to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database. 
Storing
All ECGs will be stored electronically at the site.
Data transfer
For time points specified in the Flow Chart as triplicate ECGs, ECGs will be transferred 
electronically to the 
for evaluation and/or 
storage except for ECG from screening and EoTrial which will not be transferred.


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In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the
 whereas the initially recorded ECGs will be discarded. 
Unscheduled ECGs (for safety reasons) will be transferred to the
but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the
 to the sponsor is described in the ECG data transfer 
agreement (see TMF).
Evaluation
a)
evaluation will be performed (during the study and/or after the 
study) for the first of three replicate ECGs per time point in the Flow Chart. For 
baseline, where 3 triplicate ECGs are recorded, only the first triplicate ECG (i.e. 3 
single ECGs) will be evaluated. The remaining second and third replicate ECGs will 
be stored for additional analyses if required.
This will include the determination of cardiac QRS-axis as assessed by the ECG 
machine’s algorithm as well as the intervals RR, PR, QRS, and QT measured semi-
automatically.
Heart rate (HR) and the QT interval corrected for HR (QTc e.g. QTcF and QTcB) will 
be determined by the sponsor (see TSAP for details).
All semi-automatic interval measurements in one subject will be performed on the 
same lead. The intervals will be measured from four cardiac cycles (beats) in lead II. 
If lead II shows a flat T wave or is not measurable for any reason, lead V5 will be 
used, or if that lead is not measurable, then lead I will be used. The lead actually used 
will be reported in the CTR.
For automatic interval measurements, no lead will be provided. After quality control, 
the fiducial point markings will be reviewed by the cardiologist assigned to the study.
For blinding arrangements, see Section 4.1.5. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular subject should be evaluated by 
a single reader. For quality assurance and control of the measurements, all ECGs of a 
subject will be subsequently reviewed by the ECG technician supervisor or his/her 
designee to assess the overall variance of the measured intervals and, to detect 
accidental switching of leads and/or false subject assignments of the ECGs. After 
quality control, the fiducial point markings will be reviewed by the cardiologist 
assigned to the study. 
Evaluation of ECGs will comply with the ICH E14 guidance document and 
supplements [R07-4722, R16-0366] as well as the FDA requirements for annotated 
digital ECGs [R09-4830].
b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of 
cardiac safety during the study, the QT and QTcB values generated by the 


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computerised ECG system or their manual corrections by the investigators will be 
used. In doubtful cases, ECGs may be sent upfront (i.e. prior to the regular data 
transfer) for cardiologic assessment by the
 In this case, these centrally 
measured results would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening) if judged 
clinically relevant by the investigator. Any ECG abnormalities will be monitored carefully 
and, if necessary, the subject will be removed from the trial and will receive the appropriate 
medical treatment. 
Continuous ECG monitoring
Cardiac rhythm (including heart rate) will be monitored by means of continuous 2-lead ECG 
recording using the Dräger Telemetry monitoring system, Infinity M300 for at least 15 min 
before drug administration (for baseline assessment) and for 4 h following drug 
administration). This continuous ECG monitoring supports the early detection of adverse 
events such as clinically relevant bradycardia, tachycardia, or arrhythmia at the trial site.
Beyond this clinical evaluation at the trial site, no further data collection or analyses are 
performed based on continuous ECG monitoring.
ECG data from continuous ECG recording will not be transferred to the clinical trial 
database. Abnormal findings during continuous ECG recording will be recorded as AEs if 
judged clinically relevant by the Investigator.
Other safety parameters
Local tolerability
Local tolerability will be assessed by the investigator on the basis of swelling, induration, 
heat, redness, pain, and other findings.
Oral body temperature
Oral body temperature will be measured at the times indicated in the Flow Chart using a 
standard device.
Assessment of adverse events
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.


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The following should also be recorded as an AE in the eCRF and BI SAE form (if 
applicable):

Worsening of pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
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 time since discontinuation of the trial medication and must be reported 
as described in Section 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
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.


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Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
Hepatic injury is considered an AESI in this trial. A hepatic injury is defined by the following 
alterations of hepatic laboratory parameters:

An elevation of AST (aspartate transaminase) and/or ALT (alanine transaminase) ≥3-fold 
ULN combined with an elevation of total bilirubin ≥2-fold ULN measured in the same 
blood sample, or

Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF. In 
case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure that these parameters 
are analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced


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
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are subsequently noted. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.


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The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial:
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no 
further information can be obtained.
Pregnancy
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). The ISF will contain the Pregnancy Monitoring Form for 


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Clinical Trials (Part A and Part B) as well as non-trial specific information and consent for 
the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
Date and clock times of drug administration and pharmacokinetic sampling will be recorded
in the eCRFs.
Exact times of blood sampling will be derived from the electronic data capturing system 
ClinSpark and documented in the eCRFs by the medical personnel or sent as electronic files
to the trial data manager. The actual sampling times will be used for determination of 
pharmacokinetic parameters.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. as a result of preliminary PK data), including addition of 
samples and visits, as long as the total blood volume taken per subject does not exceed 
500 mL. Such changes would be implemented via non-substantial CTP Amendments.
Methods of sample collection
Blood sampling for pharmacokinetic analysis
For quantification of BI 765080 concentrations in serum, approximately 3.0 mL of blood will 
be drawn from an antecubital or forearm vein into a serum collection tube (SST II Advance 
tube or equivalent) at the times indicated in the Flow Chart. Blood will be withdrawn by 
means of either an indwelling venous catheter or by venepuncture with a metal needle.
The sample tubes will be inverted six times without shaking and left upright for at least 30 
minutes to allow the sample to thoroughly clot.  Serum is prepared by centrifugation for 
approximately 10 -15 minutes at approximately 1500 g to 2000 g at room temperature. 
Immediately transfer 0.5 mL serum from the collection tube into each of the labelled 
cryotubes.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time, aliquot #1 or #2, serum, and PK. 
The time each aliquot was placed in the freezer will be documented. Until transfer on dry ice 
to the analytical laboratory, the aliquots will be stored upright at approximately -70°C/-94ºF
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 serum samples will be stored at approximately -70°C/-94ºF or below until 
analysis.


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After completion of the trial, the serum samples may be used for further methodological 
investigations (e.g., for stability testing). However, only data related to the analyte will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations, but not later than 5 years after the CTR is
archived.


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5.5
BIOBANKING
Not applicable.


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5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic 
 
 parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that 
might occur as a result of administration of trial medication. The safety assessments are 
standard, are accepted for evaluation of safety and tolerability of an orally administered drug, 
and are widely used in clinical trials. The pharmacokinetic parameters and measurements 
outlined in Section 5.4 are generally used assessments of drug exposure. 
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration (including blank values for PK and biomarkers).
The acceptable deviation from the scheduled time for vital signs and ECG will be:

±20 min up to and including 12 h

±30 min from 12h up to and including 48 h

±60 min from 48 h up to Day 8

±4h from Day 8 onwards up to the last measurements
The tolerance for blood sampling for PK, 
 and laboratory parameters will be:

±1 min up to and including 30 min

±5 min from 30 min up to and including 12 h

±15 min from 12 h up to and including 48 h

±60 min from 48 h up to Day 8

±4h from Day 8 onwards up to the last measurements
If several activities are scheduled at the same time point in the Flow Chart, ECG should be 
the first and meal the last activity. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on physiological 
parameters.
For planned individual blood concentration sampling times, refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times 
will be recorded and used for the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study. For information 


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regarding laboratory tests (including drug and virus screening), ECG, vital signs, and 
physical examination, refer to Sections 5.2.3 to 5.2.5.
Treatment period
Each subject will receive one dose of trial medication (BI 765080 or placebo) at Visit 2.
Trial medication will be administered as i.v. infusion by the investigating physician or 
 
designee. Details on treatments and procedures of administration are described in 
Section 4.1.4.
Study participants will be admitted to the trial site on Day -1 and kept under close medical 
surveillance for at least 48 h following drug administration. The subjects will then be allowed 
to leave the trial site after formal assessment and confirmation of their fitness by the 
investigator or 
designee. On all other study days, subjects will be treated in an ambulatory 
fashion.
For details on time points and procedures for collection of blood samples for PK analysis, 
refer to Flow Chart and Section 5.3.2. 
The safety measurements performed during the treatment period are specified in Section 5.3
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objectives of this trial will be assessed by calculating descriptive statistics for 
safety as well as for PK 
 parameters, which will be compared between the treatment 
groups. Further analyses of these endpoints comprise the power model for assessment of dose 
proportionality.
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in this study.
Any confidence intervals computed are to be interpreted in the perspective of the exploratory 
character of the study; i.e., confidence intervals are considered as interval estimates for 
effects.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treatment assignment will be 
determined based on the first treatment the subjects received. The treated set will be 
used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was not excluded due to a 
protocol violation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a subject will be 
included in the PKS, even if he/she contributes only one PK parameter value for one 
period to the statistical assessment. Descriptive and model based analyses of PK 
parameters will be based on the PKS.
Descriptions of possible additional analysis sets will be provided in the TSAP, to be finalised 
prior to database lock.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be specified in the iPD specification file prior to trial initiation; iPDs 
will be identified no later than in the Report Planning Meeting and the iPD categories will be 
updated as needed.


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Pharmacokinetics
The pharmacokinetic parameters listed in Sections 2.1 and 2.2 for BI 765080 will be 
calculated according to the relevant SOP of the Sponsor [001-MCS-36-472]. 
Serum concentration data and parameters of a subject will be included in the pharmacokinetic 
(PK) analyses if they are not flagged for exclusion due to a protocol deviation relevant to the 
evaluation of PK (to be decided no later than in the Report Planning Meeting) or due to PK 
non-evaluability (as revealed during data analysis, based on the criteria specified below). 
Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Randomized study drug not administered or wrong trial drug administered

Incorrect dose of trial medication taken

Missed/missing PK samples at important phases of PK disposition curve
A PK concentration or parameter will be considered as non-evaluable, if for example the 
subject did not receive the complete assigned infusion volume.
Serum concentration data and parameters of a subject that is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format as in the bioanalytical report (that is 
to the same number of decimal places provided in the bioanalytical report). 
Primary endpoint analyses
The primary endpoint as specified in Section 2.1.2 will be derived according to BI standards. 
The analysis will be based on the treated set (TS) and will be descriptive in nature.
Secondary endpoint analyses
Primary analyses
The secondary endpoints (refer to Section 2.1.3) will be analysed descriptively.


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Safety analyses
Safety will be assessed as defined by the endpoints listed in Sections 2.1.2 and 2.2.2 based on 
the treated set (TS). Safety analyses will be descriptive in nature and will be based on BI 
standards. 
For all analyses the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. The placebo group in the safety evaluation 
will consist of all subjects treated with placebo, regardless of the dose group in which they 
were treated. The test treatment groups will be compared to the placebo group in a descriptive 
way. Tabulations of frequencies/proportions will be used for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyse continuous 
(quantitative) data.
Measurements (such as ECGs, vital signs, or laboratory parameters) or AEs will be assigned 
to treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment-emergent AEs). 
Therefore, measurements planned or AEs recorded prior to the intake of trial medication will 
be assigned to the screening period; those between the trial medication intake and the end of 


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trial examination (including the anticipated REP) will be assigned to the treatment period.
These assignments including the corresponding time intervals will be defined in detail in the 
TSAP. Note that AEs occurring after the last per protocol contact but entered before database 
lock will be reported to Pharmacovigilance only and will not be captured in the trial database.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.6.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as possibly clinically significant values will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline. 
The ECG variables QT, PR, QRS, and RR obtained from the centralised evaluation of 12-
lead ECG recordings will be the basis for the derivation of quantitative and categorical ECG 
endpoints with regard to QT/QTc interval, HR, PR interval and QRS duration. These 
endpoints and their analyses will be described in the TSAP.
7.4
INTERIM ANALYSES
No formal interim analysis is planned. Prior to each dose escalation a documented safety 
review will be performed as described in Section 3.1.
A preliminary analysis of PK parameters 
 Cmax of BI 765080) and 
provided as individual values 
and geometric means, may be performed.
The PK parameters will be calculated according to the BI SOP 'Standards and processes for 
analyses performed within Clinical Pharmacokinetics/Pharmacodynamics' 
[001-MCS-36-472]. The non-compartmental analysis will be performed using a validated 
software program such as Phoenix WinNonlinTM software (version 8.1 or higher, 
 
) or SAS® Version 9.4 (or later version). A quality check of 
the preliminary data will be performed.
In contrast to the final PK
 calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows. Therefore, minor deviations may occur between preliminary and final results.


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The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without subject identification information.
The preliminary results will be distributed to the investigator and the trial team. 
Depending on tolerability and safety of the compound, changes to the dosing schedule (e.g., 
additional intermediate doses) may be performed if requested by the Clinical Trial Leader, 
the investigator, or Trial Clinical Pharmacokineticist. Preliminary PK
 results will not be 
reported in the CTR.
No inferential statistical interim analysis is planned. However, after completion of each dose 
group the investigator (or his or her deputy) is allowed to postpone further dose progression 
until a preliminary analysis of the data has been performed.
7.5
HANDLING OF MISSING DATA
Safety
It is not planned to impute missing values for safety parameters.
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure [001-MCS-36-472].
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Subjects will be randomised within cohort 3 of each dose group in a 3:1 ratio (active drug to 
placebo). Trial medication in cohorts 1 and 2 of each dose group will be administered in a 
fixed order (active - placebo - active - active; see Section 3.1).
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 48 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.


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Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose will not be exceeded. Thus, the actual number of subjects entered 
may exceed 48, but will not exceed 80 subjects entered.


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


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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number,
and social security number) have properly been removed or redacted to ensure subject
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication


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
Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7. 


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Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
Collection, storage and future use of biological samples and 
corresponding data
Measures are in place to comply with the applicable rules for the collection and future use of 
biological samples and clinical data, in particular

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries 
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state.


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A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the 
 of 
under the supervision of the Principal Investigator
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates, and investigators of participating trial sites
The trial medication will be provided by the 
 
 (BI 765080) and Placebo NaCl will be obtained by clinical 
trial site from public pharmacy (NaCl 0,9%). 
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
 
Analyses of BI 765080 concentrations in serum will be performed at 
 
 
 
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation 
for evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI. 
Data management and statistical evaluation will be done by BI or CRO appointed by BI
according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P11-14681
Gross JL, Azevedo MJ de, Silveiro SP, Canani LH, Caramori ML, 
Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention, and treatment.
Diabetes Care 2005; 28(1); 164-176.
P18-03010
Dekkers CCJ, Gansevoort RT, Heerspink HJL. New diabetes therapies and 
diabetic kidney disease progression: the role of SGLT-2 inhibitors. Curr 
Diabetes Rep 2018; 18(5); 27.
R02-0327
Brenner BM, Cooper ME, Zeeuw D de, et al. Effects of losartan on renal 
and cardiovascular outcomes in patients with type 2 diabetes and 
nephropathy. N Engl J Med 2001; 345(12); 861-869.
R02-2101
Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the 
angiotensin-receptor antagonist irbesartan in patients with nephropathy due 
to type 2 diabetes. N Engl J Med 2001; 345(12); 851-860.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER) (2005).
R09-2768
Vargas HM, Bass AS, Breidenbach A, et al. Scientific review and 
recommendations on preclinical cardiovascular safety evaluation of 
biologics. J Pharmacol Toxicol Methods 2008; 58(2); 72-76.
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R11-1428
ICH Expert Working Group. ICH harmonised tripartite guideline: 
preclinical safety evaluation of biotechnology-derived pharmaceuticals, 
S6(R1) (parent guideline dated 16 July 1997, current step 4 version, 
addendum dated 12 June 2011 incorporated at the end of June 2011). 
websites: emea.europa.eu and 
ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S6_R 
1/Step4/S6_R1_Guideline.pdf (access date: 7 September 2011); 2011.


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R16-0366
E14 Implementation Working Group
ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs: questions & 
answers (R3) (current version dated 10 December 2015).
webpage.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Effi
cacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2016); 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (2015)
R17-2619
Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney 
disease and cardiovascular risk: epidemiology, mechanisms, and 
prevention. Lancet 2013; 382; 339-352.
R17-2621
Chronic Kidney Disease Prognosis Consortium. Association of estimated 
glomerular filtration rate and albuminuria with all-cause and cardiovascular 
mortality in general population cohorts: a collaborative meta-analysis.
Lancet 2010; 375; 2073-2081.
R19-0901
Levey AS, Coresh J. Chronic kidney disease. Lancet 2012; 379; 165-180.
R19-1139
Bakris GL, Agarwal R, Chan JC, et al. Mineralocorticoid Receptor 
Antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN) Study 
Group. Effect of finerenone on albuminuria in patients with diabetic 
nephropathy: a randomized clinical trial. JAMA 2015; 314(9); 884-894.
R19-1184
Stel VS, Bruck K, Fraser S, Zoccali C, Massy ZA, Jager KJ. International 
differences in chronic kidney disease prevalence: a key public health and 
epidemiologic research issue. Nephrol Dial Transplant 2017; 32; II129-
II135.
R19-1356
Perkovic V, Jardine MJ, Neal B, et al, CREDENCE Trial Investigators. 
Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. New 
England Journal of Medicine, published on April 14, 2019, doi: 
10.1056/NEJMoa1811744; 2019: 2295-2306.
R19-1388
Hill NR, Fatoba ST, Oke JL, et al. Global prevalence of chronic kidney 
disease - a systematic review and meta-analysis. Plos One 2016; 11(7); 
e0158765.


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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics
 Current version.
c30981435
Investigator's Brochure BI 765080 CKD, 09 Sep 2020.
n00277223
Prediction of BI 765080 Pharmacokinetics in Human.
n00277281
BI-765080: A 13-Week Intravenous Injection Toxicity Study in 
Cynomolgus Monkeys.
n00277285
BI-765080: A 4-Week Intravenous (Slow Bolus) Toxicity Study in Rats.


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10.
APPENDICES
10.1
RECONSTITUTION INSTRUCTIONS
Description of trial medication 
Vials containing 50 mg BI 765080 powder for solution for injection / infusion (50mg/vial). 
presented in a 2 mL vial, will be provided by the Sponsor Boehringer Ingelheim. These vials 
will be labelled according to regulatory requirements
Temperature deviation during storage
The study drug product will be stored in the original packaging in a limited access area at the 
temperature specified on the drug label. For temperature monitoring all medication kits have 
an attached Mini-tag®. In case of a storage temperature excursion the Mini-tag® have to be 
read out and the results have to be documented in the form Mini-tag® Alarm Sequences 
which is available in the Investigator Site File (ISF). In case of at least one red Mini-Tag® 
submit a Product/Device Complaint Form (available in the ISF) the form Mini-tag® Alarm 
Sequences to the CTSU Complaint Team (CTSU_Complaints.bibatboehringer-
ingelheim.com). The medication should be put in quarantine until the Complaint team has 
communicated the decision to release the concerned vials or to consider them as unusable.
Instructions for preparation the study medication
General Remarks
The pharmacist, his/her deputy or other appropriately licensed and authorized drug-
preparation personnel will prepare the trial medication as requested by the investigator.
Handling and preparation of the medicinal product should be performed according to routine 
site procedures using aseptic techniques. Prior to the preparation and the infusion, the vials 
should be checked for any changes (e.g. colour) and for the absence of particles. After 
reconstitution the should be colourless to slightly brownish yellow. If you have any questions 
or concerns regarding appearance of the solution, please do not use the solution. Please retain 
the solution and contact your CRA or the Clinical trial manager who may require you to 
complete a Complaints Form.
The final solution for infusion should be delivered to the unit or ward where the medication
will be administered as soon as possible after preparation. Labelling of medication containers 
will be done according to institute standards.
Consumables 
Materials tested to be compatible the study medication are listed in Table 10.1.3.2: 1 for 
preparation and in Table 10.1.3.2: 2 for administration.


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Table 10.1.3.2: 1
Overview of materials used for preparation of BI 765080 Powder for 
solution for injection/infusion 50 mg/vial (50 mg/mL)
Type
Qualitative composition 
Syringe 50 mL intended for use with syringe pumps (Graduation: 1 mL)
Polypropylene
Syringe 10 mL (Graduation: 0.2 mL)
Polypropylene
Syringe 5 mL (Graduation: 0.2 mL)
Polypropylene
Syringe 3 mL; Graduation: 0.1 mL
Polypropylene; Plunger: PE
Syringe 1 mL (Graduation: 0.01 mL)
Polypropylene
Syringe closure
Polyethylene
20G 1½ needle 
Stainless steel / Polypropylene
25G needle 
Stainless steel / Polypropylene
Discofix-
PA
Table 10.1.3.2: 2
Reconstitution Medium and Dilution medium 
Description 
Purpose  
Water for Injection 
Reconstitution of lyophilized powder 
0.9% Saline Solution 
Diluting the reconstituted drug product prior 
administration
Preparation of the study medication
In order to achieve the target doses after reconstitution with water for injection the drug 
product must be further diluted using isotonic saline to the concentrations assigned for each 
dose level. The target doses will be achieved by volume aliquotation. Further information on 
the concentrations to be administered per dose level and the resulting volume aliquot to be 
administered are provided in Table 10.1.3.3: 1.
Please note: In order to prepare dilutions with a concentration of 0.1 mg/mL 2 dilution steps 
are required. 


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Table 10.1.3.3: 1
Dilution Scheme 
Dose 
level
Target Dose 
[mg]
Target 
Concentration 
[mg/mL]
VBI 765080 [mL]
V0.9% Saline [mL]
Administration 
Volume [mL]
1
1
0.1
1
49
--
5
45
10
2
10
1
1
49
10
3
25
25
4
50
50
5
100
2
2
48
50
6
200
4
4
46
50
The site may prepare syringes containing an overfill as per site standard policies. The overfill 
is required in order to accommodate the dead volume of the infusion set.
Administration of the ready to use syringes will be done according to Section 4.


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Reconstitution of the lyophilized powder
1. Attach a 3 mL syringe to the bottle containing water for injection (WFI) and withdraw 
1.2 mL WFI.
2. Attach a 20G needle to the syringe and adjust the volume to 1.1 mL and gently inject 
the complete content of the syringe through the stopper, to the wall of the  vial 
containing BI 765080 powder for solution for injection / infusion (50mg/vial). 
3. Discard needle and syringe, and then gently swirl the vial until the lyophilizate is 
dissolved and homogenized. Do not shake. Avoid the generation of foam. The full 
reconstitution should be finished within 10 minutes.
4. In case of foam generation during reconstitution, wait with further processing until 
foam has settled. This should take not more than 60 min. 
Dilution Procedure (DL 1)
1. Withdraw the volume aliquot of 0.9% saline defined in Table 10.1.3.2: 2 in a 50 mL 
syringe (compatible with syringe pump).
2. Withdraw the drug product volume defined in Table 10.1.3.2: 2 from the vial 
containing reconstituted BI 765080 50 mg / mL using an appropriate syringe. 
3. Combine both syringes with a syringe adapter and mix the content of the syringes by 
gently transferring back and forth gently transferring back and forth 10 times. The 
resulting concentration is 1 mg/ mL.
4. Transfer 5 mL of the diluted drug product in a 5 mL syringe and discard the 50 mL 
syringe. 
5. Withdraw 45 mL isotonic saline in a 50 mL syringe (compatible with syringe pump), 
combine both syringes via syringe adapter / discofix connector and mix the content of 
both syringes by gently transferring back and forth 10 times. The resulting 
concentration is 0.1 mg/ mL.
6. Collect the complete volume in the 50 mL syringe. Make sure that the complete 
volume has been transferred to the 50 mL syringe prior disconnecting the smaller 
syringe and the adapter. Lock the syringe using a syringe closure. 
Dilution Procedure (DL 2-6)
1. Withdraw the volume aliquot of 0.9% Saline defined in Table 10.1.3.2: 2 in a 50 mL 
syringe (compatible with syringe pump).
2. Pool the drug product volume defined in Table 10.1.3.2: 2 from the vials containing 
reconstituted BI 765080 50 mg/mL using an appropriate syringe. 
3. Combine both syringes with a syringe adapter / discofix connector and mix the 
content of the syringes by gently transferring back and forth gently transferring back 
and forth 10 times
4. Collect the complete volume in the 50 mL syringe. Make sure that the complete 
volume has been transferred to the 50 mL syringe prior disconnecting the smaller 
syringe and the adapter. Lock the syringe using a syringe closure. 


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Preparation of Placebo 
Note: Commercially available 0.9% Saline for injection will be used as Placebo. 
1. Withdraw the amount 0.9% Saline for Injection matching the administration volume 
of active drug product defined in Table 10.1.3.2: 2 in a 50 mL syringe (compatible 
with syringe pump).
In-Use stability statement
Chemical and physical in-use stability of BI 765080 has been demonstrated for a 
concentration range from 0.1 mg/mL to 8 mg/mL diluted with 0.9% saline solution for 24 
hours at 2-8°C (36-46°F) followed by 6 h (4 h storage and 2 h infusion time) at 30°C (86°F) 
in clinical sets as described. Do not freeze.
From a microbiological point of view, the solution for infusion should be used immediately. 
The solution for infusion is not intended to be stored unless dilution has taken place under 
controlled and validated aseptic conditions. If not used immediately, in-use storage times and 
conditions are the responsibility of the user.
Infusion Instructions 
General Remarks
In order to avoid an infusion reaction caused by the administration of low temperature 
solution the infusion container must be brought to room temperature before infusion.
Connect the infusion set (= infusion container connected with administration set and 0.2 µm 
in-line filter) with the catheter and administer the complete content of the infusion container 
over 30 min to the subject. 
In case of technical issues or complications during infusion, please refer to the protocol.
Administration 
Information on administration consumables:
The following medical consumables were tested within the in-use stability study.


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Table 10.1.4.2: 1
Overview of materials for administration of BI 765080 Solution for 
Infusion
Type
Material
0.2 µm Filter
PES, e.g. Sterifix 4099303
Catheter 24G
PUR
Stopcock Discofix C
PA, PC, PP
Original Perfusor tubing 200 cm
PE
Compact plus syringe pump
 perfusor compact plus
Plastipak syringe 50 mL
PE
Syringe pump compatible with the 50 mL syringe used for preparation.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1 
Date of amendment
08 December 2020
EudraCT number
EU number
2020-004262-19
BI Trial number
1450-0001
BI Investigational Medicinal 
Product
BI 765080
Title of protocol
Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of single rising intravenous 
doses of BI 765080 in healthy male subjects (single-
blind, randomised, placebo-controlled, parallel-
group design)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Synopsis: Secondary endpoints; Test product
Flow chart
1.3.2: Maximum dose and escalation
Table 1.3.2:1: Planned maximum dose and estimated 
exposure multiples versus exposure in the rat and 
monkey
1.4.2: Drug-related risks and safety measures
2.1.3: Secondary endpoints
3.1: Overall trial design and plan
Table 3.1:1: Dose groups
3.3.3: Exclusion criteria
Table 5.2.3:1: Routine laboratory tests
5.3.2.1: Blood sampling for pharmacokinetic 
analysis
 
10.1: Reconstitution instruction
Description of change
Synopsis: changed the format of secondary 
endpoints;
 


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deleted 400 mg and 600 mg in the part of Text 
product;
Flow chart: time-points for local tolerability was 
added;
1:3:2: Maximal dose was changed to 200 mg; Added 
“If the doses up 200 mg are needed, the substantial 
CTP will be provided”;
Table 1.3.2:1: maximal 600 mg was replaced by 200 
mg;
”;
3.1: deleted “If 200 mg does not achieve the 
expected exposure, additional dose groups may be 
added up to a maximum of 600 mg.”;
Table 3.1:1: deleted wording of 400 mg and 600 mg 
groups;
3.3.3: exclusion criteria No. 23:  changed 
contraception measures application from 30 days to 
60 days. Sperm donation is allowed until at least 60 
days after IMP administration;
Table: 5.2.3:1: deleted glutamate dehydrogenase
(GLDH) test;
5.3.2.1: updated blood sampling handling for PK 
analysis;
 
”;
10.1: deleted information of 400 mg and 600 mg
Rationale for change
Changes based on the request by BE FAMHP
Minor editorial changes


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11.2
GLOBAL AMENDMENT 2 
Date of amendment
10 May 2021
EudraCT number
EU number
2020-004262-19
BI Trial number
1450-0001
BI Investigational Medicinal 
Product
BI 765080
Title of protocol
Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of single rising intravenous 
doses of BI 765080 in healthy male subjects (single-
blind, randomised, placebo-controlled, parallel-
group design)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
3.1: Overall trial design and plan
Table 10.1.4.2: 1: Overview of materials for 
administration of BI 765080 Solution for Infusion
Description of change
 
Table 10.1.4.2:1: updated materials for infusion
Rationale for change
Infusion material updating
Minor editorial changes


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c31414158
3.0
clinical-trial-protocol-version-03
Safety, tolerability, pharmacokinetics, and pharmacodynamics of single rising
intravenous doses of BI 765080 in healthy male subjects (single-blind, randomised,
placebo-controlled, parallel-group design)
Author-Clinical Trial Leader
10 May 2021 14:34 CEST
Author-Trial Statistician
10 May 2021 14:49 CEST
Approval-Team Member Medicine
10 May 2021 20:11 CEST
Verification-Paper Signature
Completion
11 May 2021 13:40 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c31414158
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c36670861-01
BI Trial No.:
1450-0001
Title:
Safety, tolerability, pharmacokinetics, and pharmacodynamics of 
single rising intravenous doses of BI 765080 in healthy male 
subjects (single-blind, randomised, placebo-controlled, parallel-
group design) 
Including Protocol Amendment 2 [c31414158-03]
Investigational
Product:
BI 765080
Responsible trial 
statistician:
Phone:
Fax:
Date of statistical 
analysis plan:
21-Sep-2021 SIGNED
Version:
Final
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
5.3.1
Safety parameters .................................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................13
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................18
7.4
PRIMARY ENDPOINTS...................................................................................18
7.4.1
Primary analysis of the primary endpoints......................................................18
7.5
SECONDARY ENDPOINTS.............................................................................18
7.5.1
Key secondary endpoints....................................................................................18
7.5.2
Secondary endpoints...........................................................................................19
7.5.2.1
Secondary endpoint analysis.................................................................................19
7.6.1
Safety parameters ...............................................................................................20


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7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse Events ....................................................................................................21
7.8.2
Laboratory data ..................................................................................................22
7.8.3
Vital signs.............................................................................................................23
7.8.4
ECG......................................................................................................................23
7.8.5
Others...................................................................................................................25
7.8.5.1
Physical examination ............................................................................................25
7.8.5.2
Oral body temperature ..........................................................................................26
7.8.5.3
Local tolerability assessment ................................................................................26
7.8.5.4
Body weight ..........................................................................................................26
8. TIMEPOINT OF RELEASE OF TREATMENT INFORMATION............................27
11.
HISTORY TABLE..............................................................................................33


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LIST OF TABLES
Table 6.1: 1
Analysis phases for statistical analysis of AEs, and actual treatment for 
analysis of laboratory data, vital signs, ECG and local tolerability.................12
Table 6.3: 1
Subject sets analyzed........................................................................................14
Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation ..........16
Table 11: 1
History table .....................................................................................................33


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in serum over the
time interval from 0 extrapolated to infinity
BI 
Boehringer Ingelheim
Cmax
Maximum measured concentration of the analyte in serum
COVID
Coronavirus disease
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
ECGPCS
ECG PK concentration set
gCV
geometric coefficient of variation
gMean
Geometric mean
HR
Heart rate
ICH
International Conference On Harmonisation
IPD
Important protocol deviations
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary For Regulatory Activities
PD
Pharmacodynamics
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter analysis set
PR
Pulse rate
QRS 
complex
Combination of the Q, R, and S waves
QT interval
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTcB
QT interval, heart rate corrected according to Bazetts formula


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Term
Definition / description
QTcF
QT interval, heart rate corrected according to Fridericias formula
RAGe
Report appendix generator
RPM
Report Planning Meeting
RR interval
ECG interval from the peak of the R wave to the peak of the subsequent R 
wave
SAE
Serious adverse event
SD
Standard Deviation
SOC
System Organ Class
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal range


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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 revised CTP, and to 
include detailed procedures for executing the statistical analysis of the primary variables and 
other data.
This TSAP assumes familiarity with the CTP and its 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 revised 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 as collected in the eCRF will be stored in a trial database within the RAVE EDC 
system. All study data also including external data will then be uploaded to the CDR data 
warehouse.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, 
), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version Phoenix 6.3, 
).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP are in accordance with the statistical methods described 
in the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Primary endpoint is the percentage of subjects with drug-related adverse events.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
Secondary endpoints are PK endpoints of BI 765080, as defined in Section 2.1.3 of the CTP:

AUC0-∞(area under the concentration-time curve of the analyte in serum over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in serum)
5.3.1
Safety parameters
Safety and tolerability of BI 765080 will be assessed based on further safety parameters 
defined in Section 2.2.2.1 of the CTP:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring 

Vital signs (blood pressure and pulse rate), oral body temperature

Local tolerability assessment
Local tolerability
Local tolerability will be assessed as absence or presence of "swelling", "induration", "heat", 
"redness", "pain", or "other findings".
12-lead ECG endpoints
For the definition of baseline and a summary of time points please refer to Section 6.7.
Quantitative ECG endpoints:


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The following quantitative ECG endpoints will be determined for the ECG variables QTcF, 
QT, HR, PR, QRS, RR and QTcB derived as described in Additional Section 10.1:

absolute values (per time point)

changes from baseline (per time point)

percent changes from baseline (per time point; for HR, PR, QRS)
Categorical ECG endpoints
The following categorical ECG endpoints will be determined based on the quantitative ECG 
endpoints, except for QTcB. QTcB will only be listed.

New onset (meaning that this or a higher category was not present at baseline) of 
maximum QTcF interval > 450 to 480 msec, > 480 to 500 msec, or > 500 msec on 
treatment. For assignment of a particular subject to one of the above categories, all time 
points on-treatment (refer to Table 6.7: 1) will be considered. 

Maximum change from baseline in QT interval of ≤ 60 msec, or > 60 msec on treatment

Maximum change from baseline in QTcF interval of ≤ 30 msec, > 30 to ≤ 60 msec, or 
> 60 msec on treatment
The occurrence of any of the following will be viewed as "notable findings":

New onset (not present at baseline) of uncorrected QT interval > 500 msec at any time on 
treatment 

New onset of QTcF interval > 500 msec at any time on treatment

Change from baseline of QTcF > 60 msec at any time on treatment

Percent change from baseline of HR ≥ 25%, when corresponding on-treatment value of 
HR is > 100 beats/min, or percent change from baseline of HR ≤ - 25%, when 
corresponding on-treatment value of HR is < 50 beats/min, at any time on treatment

Percent change from baseline of PR ≥ 25%, when corresponding on-treatment value of 
PR interval is > 200 msec, at any time on treatment 

Percent change from baseline of QRS ≥ 10%, when corresponding on-treatment value of 
QRS duration is > 110 msec, at any time on treatment
For a detailed description of ‘new onset’, refer to Additional Section 10.3.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment 
groups, and selection of doses, cf. Section 4 of the CTP.
Subjects will receive a 30 minutes intravenous infusion containing

powder for solution of either a single dose of 1, 10, 25, 50, 100 or 200 mg of 
BI 765080 (test treatments)
or

a matching placebo (reference treatment)
All placebo subjects will be analysed in one pooled placebo group (i.e. no distinction between 
dose groups will be made for placebo subjects).
For statistical analysis of AEs, the following analysis phases are defined for each subject. 
Table 6.1: 1
Analysis phases for statistical analysis of AEs, and actual treatment for 
analysis of laboratory data, vital signs, ECG and local tolerability
Study analysis 
phase
Label
Start
End
Screening1
Screening
Date of informed consent
Date/time of start of infusion
On treatment
Placebo,
1 mg BI,
10 mg BI,
25 mg BI,
50 mg BI,
100 mg BI or
200 mg BI
respectively
Date/time of start of infusion
12:00 a.m. on day after last 
contact date
1 See Section 6.7 for definition of baseline, which will be used in the statistical analyses of safety laboratory data, ECG and 
vital signs.
AE summary tables will present results for the on-treatment phase only. All AEs will be 
listed.
In AE tables in CTR Section 15.3 (but not in Appendix 16.1.13.1.8.1 and Appendix 
16.1.13.1.8.2 AE tables), the following total will be provided in addition: 

"Total BI", defined as the total over all on-treatment phases involving BI


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
"Total on-trt", defined as the total over all on-treatment phases, including placebo
Safety laboratory data, ECG, vital signs, PK, immunogenicity and exploratory biomarker 
parameters will be analysed based on treatment groups (Placebo, 1 mg BI, 10 mg BI, 25 mg 
BI, 50 mg BI, 100 mg BI or 200 mg BI) with clear differentiation between baseline (cf. 
Section 6.7) and on-treatment measurements. Measurements will be considered on-treatment, 
if they were taken within the on-treatment phases as defined in Table 6.1: 1.
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting. At this meeting, it will be 
decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an important PD (IPD). For definition of IPDs, and for the process of 
identification of these, refer to the BI reference document "Identify and Manage Important 
Protocol Deviations (IPD)" (2) and the DV domain template.
If any IPDs are identified, they are to be summarised into categories and will be captured in 
the decision log. Categories which are considered to be IPDs in this trial are defined in the 
DV domain template. If the data show other IPDs, the definition in the DV domain template
will be supplemented accordingly by the time of the Report Planning Meeting.
IPDs will be summarized and listed. Which kind of IPDs could potentially lead to exclusion 
from which analysis set is specified in the DV domain template. The decision on exclusion of 
subjects from analysis sets will be made at the latest at the Report Planning Meeting, after 
discussion of exceptional cases and implications for analyses.
Non-important COVID-19 related PDs will only be listed.
6.3
SUBJECT SETS ANALYSED
The treated set (TS) and pharmacokinetic parameter analysis set (PKS) will be used as 
defined in the CTP, Section 7.3.
In addition, the following subject sets will be used:
All ECG analyses are performed on the TS, except for the exposure-response analyses, which 
are performed on the ECGPCS defined below.

ECG PK concentration set (ECGPCS):
This subject set includes all subjects from the TS who provide at least one pair of a 
valid drug serum concentration and a corresponding (i.e. time-matched) ECG 
endpoint to be used in the exposure-response analyses. For placebo subjects, the 


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serum concentration is set to zero and hence always considered as valid. The decision 
whether a time deviation between PK blood sampling and ECG recording is 
acceptable (and thus whether the pair of values will be used) is to be made no later 
than at the RPM before data base lock. For subjects treated with active drug, the 
decision about concentration value validity needs to be made within the Clinical 
Pharmacology Group.
Table 6.3: 1
Subject sets analyzed
Subject sets
Class of endpoint
TS
PKS  
ECGPCS
Primary endpoint 
X
Secondary PK endpoints 
X
Safety parameters 
(except for exposure-response 
analyses of ECG data)
X
Exposure-response analyses of 
ECG data
X
Demographic/baseline 
characteristics
X
Treatment exposure
X


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6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
CTP: “If a subject is removed or withdraws from the trial prior to the administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) and will 
not be reported in the clinical trial report (CTR). If a subject is removed or withdraws from 
the trial after the administration of trial medication, this will be documented and the reason 
for discontinuation must be recorded in the CRF. In addition, the data will be included in the 
CRF and will be reported in the CTR.”
CTP: “It is not planned to impute missing values for safety parameters.”
One exception where imputation might be necessary for safety evaluation is AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).
If single cardiac cycles of an ECG 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, the handling of missing value is described in Additional Section 10.3.
For the exposure-response analyses
, missing serum
concentration values with ‘BLQ’ in the comment field will be replaced by ½ LLOQ for 
subjects on active drug. For placebo subjects, the missing serum concentration values will be 
replaced by 0.
 
Missing data and outliers of PK 
 data are handled according to BI standards (4) and 
(5).
CTP: “Pharmacokinetic parameters that cannot be reasonably calculated based on the 
available drug concentration-time data will not be imputed.”
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
In all analyses (except for analyses of ECG variables), baseline is defined as the last available
value prior to start of infusion.
A centralised evaluation of 12-lead ECG recordings is performed at the time points specified 
in Table 6.7: 1


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Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation
Visit
Day
Planned time [hh:mm]
- relative to start of infusion
Study phase
2
1
-3:00
Baseline
00:30
On-treatment
01:00
01:301
02:00
03:00
04:00
06:00
08:00
12:00
2
24:00
34:00
3
48:00
1 According to CTP flow chart, there is no time-matched PK sample for the ECG measurement at planned time 1:30. This
ECG measurement will not be used in the exposure-response model, which will be applied to time matched pairs of ECG 
measurements and PK samples.
Three triplicate ECGs will be recorded as the baseline before drug administration, but only 
the first ECG of each of the 3 baseline triplicate will be transferred to the database. At all 
other time points, 1 triplicate ECG will be recorded, but only the first single ECG of the 
triplicate will be transferred to the database. The baseline value of an ECG variable is defined 
as the mean of the ECG variable values prior to drug administration. 
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database. Unscheduled ECGs (for 
safety reasons) will be transferred to the central ECG lab but will not be included into the 
statistical analysis of interval lengths.
For the exposure response analyses, pairs of ECG variables and corresponding serum
concentrations will be built using the same planned time points, e.g., the HR change from 
baseline and the serum concentration measured at planned time 0:30 will build one pair. 
Whether a time deviation between PK blood sampling time and corresponding ECG 
recording is too big for a reliable assessment and the pair has to be excluded from the 
analysis will be decided no later than at the RPM.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the Report Planning Meeting.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (6).
The individual values of all subjects will be listed. Listings will be sorted by treatment or 
sequence group, subject number and visit (if visit is applicable in the respective listing). AE 
listings will be sorted by assigned treatment (see Section 7.8.1 below for details). The listings 
will be contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For serum concentrations as well as for all PK parameters 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:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of serum 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 (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR. These will be based on the 
TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary. Concomitant non-drug therapies will be coded 
according to the most recent version of MedDRA.
Only descriptive statistics are planned for this section of the CTR.
CTP: Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
A medication will be considered concomitant to a dose group, if it

is ongoing at the time of study drug administration, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analyzed as a specific endpoint. Any deviations from 
complete intake will be addressed in the Report Planning Meeting (cf. Section 6.2) and 
described in the CTR.
7.4
PRIMARY ENDPOINTS
7.4.1
Primary analysis of the primary endpoints
Refer to Section 7.8.1 for a description of the analysis of AEs, and in particular the analysis 
of the percentage of subjects with drug related AEs, which is the primary endpoint of this 
trial.
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.


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7.5.2
Secondary endpoints
The analysis of secondary endpoints will be based on the PKS.
7.5.2.1
Secondary endpoint analysis
The PK endpoints will be assessed descriptively. The analysis of standard PK parameters is 
performed according to BI standards (4) [001-MCS-36-472_RD-01].
Exclusion of PK parameters
The 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 are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
CTP: Serum concentration data and parameters of a subject which is flagged for exclusion 
will be reported with its individual values but will not be included in the statistical analyses.
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 only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies"(4)REF5 and "Description of Analytical Transfer Files and 
PK/PD Data Files" (5)


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7.6.1
Safety parameters
Safety endpoints and tolerability will be analysed as described in Section 7.8 of this TSAP.


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7.7
EXTENT OF EXPOSURE
Since only a single dose is administered per subject a listing will be sufficient to give account 
of the extent of exposure.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS, except for the exposure-response analysis 
which will be based on the ECGPCS.
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. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3). 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means
that all AEs will be assigned to screening or on-treatment phase as defined in Section 6.1. 
AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of AESIs.
CTP: Hepatic injury is considered an AESI in this trial. A hepatic injury is defined by the 
following alterations of hepatic laboratory parameters:

An elevation of AST (aspartate transaminase) and/or ALT (alanine transaminase) ≥3 
fold ULN combined with an elevation of total bilirubin ≥2 fold ULN measured in the 
same blood sample, or

Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN


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The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (8), in addition to Deaths and Serious Adverse Events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced 
or interrupted).
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related will be 
summarised separately. Separate tables will also be provided for subjects with SAEs and
subjects with AESIs. AEs will also be summarized by maximum intensity.
The SOCs and preferred terms within SOCs will be sorted by descending frequency over all 
treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will 
also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarized.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarized by treatment, primary SOC and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards "Display and Analysis of Laboratory Data" (9).
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
Unscheduled measurements of laboratory data will be assumed to be repeat measurements of 
the most recent scheduled measurement (e.g. for follow-up or confirmation of a particular 
value). Therefore, unscheduled measurements will be assigned to the planned time point of 
the previous scheduled measurement. Descriptive statistics will be calculated by planned time 
point based on the worst value of the subject at that planned time point (or assigned to that 
planned time point).


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Clinically significant abnormal laboratory values are only those identified either in the 
Investigator's comments or at the Report Planning Meeting at the latest. It is the Investigator's 
responsibility to decide whether a lab value is clinically significant abnormal or not. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as possibly clinically significant values will be highlighted in the listings.
Possibly clinically significant laboratory values will be listed separately.
Clinically relevant findings in laboratory data will be reported as baseline conditions (prior to
start of infusion) or as AEs (after start of infusion) if judged clinically relevant by the 
investigator, and will be analyzed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see 
Section 6.7) will be provided.
Unscheduled measurements of vital signs will be assigned to planned time points in the same 
way as described above for laboratory data. However, for vital signs, descriptive statistics 
will be calculated by planned time point based on the last value of the subject at that planned 
time point (or assigned to that planned time point).
Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to
start of infusion) or as AEs (after start of infusion) if judged clinically relevant by the 
investigator, and will be analyzed as such.
7.8.4
ECG
For continuous ECG and 12-lead ECG, abnormal findings, irrespective of whether they 
originate from central or local evaluation, will be reported as baseline conditions (prior to 
start of infusion) or as AEs (after start of infusion) if judged clinically relevant by the 
investigator. 
Descriptive analysis of ECG endpoints will be based on the TS. The evaluation of the 
relationship between serum concentration and change in ECG endpoints (exposure-response 
analysis) will be based on the ECGPCS.
ECG measurements will not be included in the statistical analysis if one of the following 
applies:

No date or time available for ECG measurement

Pre-dose measurement done after start of infusion

On-treatment measurement done before start of infusion

Measurement is a repeated measurement


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
More than 3 single ECGs (i.e., measurements from 4th single ECG onwards will not 
be included)

Unscheduled measurements
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.
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 presented in figures.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the absolute 
values and changes from baseline over time of QTcF, HR, QT, PR and QRS. The time 
profiles of mean and SD for the changes from baseline on treatment will be displayed 
graphically by treatment.
Exposure-response analysis
For QTcF and HR changes from baseline, the relationship to the corresponding serum
concentrations will be evaluated using a random coefficient model. For subjects in the 
ECGPCS, all time points with available ECG endpoints and valid time-matched drug serum
concentrations will be included. For the handling of missing values, see Section 6.6.
The response variable will be the change from baseline in QTcF (ΔQTcF). The placebo 
subjects will be included in the analysis, setting their serum concentrations to zero.
As a first step, it is investigated if there is a potential delayed or accelerated (e.g. due to 
metabolites) effect of the drug on QTcF. A general visual impression will be provided by 
overlaying time profiles of serum concentrations and QTcF changes from baseline (ΔQTcF). 
These figures will be generated for each subject (presented in the Statistical Appendix of the 
CTR), as well as for means per dose group (presented in the End-of-Text part of the CTR).
The relationship between BI 765080 serum concentrations and QTcF changes from baseline 
will be investigated in an exploratory manner using a random coefficient model to estimate 
the difference in mean QTcF change from baseline between BI 765080 and placebo and its 
90% confidence interval at the geometric mean of Cmax for each dose group. Additionally, the 
estimated overall slope with its 90% confidence interval will be provided. The used random 
coefficient model is based on a white paper from Garnett et. al. [R18-0143] (10) with ΔQTcF 
as response variable, centered baseline QTcF and serum concentration as continuous 


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covariates, treatment, time and day as fixed categorical effects, and a random intercept and 
slope for each subject.
Restricted maximum likelihood estimation will be performed, and the Kenward-Roger 
method will be applied to adjust standard errors and estimate denominator degrees of 
freedom.
For more details refer to Section 10.4.
For visualization, a scatterplot of the BI 765080 serum concentration against the following 
individual QTcF values will be provided: For each subject on active treatment and each time 
point, subtract the mean value of all individual observed ΔQTcF values from the placebo 
group for this time point from the individual observed ΔQTcF value for this subject and time 
point. This results in estimates for “individual ΔΔQTcF” values, which should only be used 
for plotting purposes. The corresponding regression line and its pointwise confidence bands 
as well as the geometric mean of Cmax for each dose will additionally be displayed in the plot.
The goodness of fit of the above model will be checked. The visual checks will include the 
inspection of concentration-QTcF quantile plots (see [R18-0143] (10)) and residual plots.
To check model assumptions, the conditional residuals will be plotted and presented in the 
Statistical Appendix of the CTR. In case of non-linearity or if there is evidence for a delayed 
effect, further models will be explored in order to better characterise the PK-ECG 
relationship (e.g. effect compartment models, non-linear models, etc.).
All of the above described graphical and statistical analyses for the exposure-reponse analysis 
will be also performed for HR in place of QTcF.
Appropriateness of heart rate correction methods of QT interval
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of QTcF interval versus RR interval will be estimated separately for off-drug 
values and active treatment, by applying the random coefficient model described in Section 
10.2 using the QTcF and RR variable values per time point. A scatterplot of QTcF vs RR 
including the overall regression lines will be included in the Statistical Appendix of the CTR.
The resulting (fixed effect) slope together with two-sided 95% confidence intervals will be 
included in the footnote for this plot.
7.8.5
Others
7.8.5.1
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(if a condition already exists before first administration of study treatment) or as AE (if 
condition emerges after first administration of study treatment) and will be summarized as 
such. No separate listing or analysis of physical examination findings will be prepared.


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7.8.5.2
Oral body temperature
Analysis of oral body temperature will be descriptive in nature. 
7.8.5.3
Local tolerability assessment
Local tolerability (absence or presence of "swelling", "induration", "heat", "redness", "pain", 
or "other findings") will be summarized with counts and percentages overall (i.e. over all on-
treatment time points, cf. Section 6.1) as well as by time point.
7.8.5.4
Body weight
Body weight will only be listed.


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8. TIMEPOINT OF RELEASE OF TREATMENT INFORMATION 
The treatment information will be loaded into the trial database at trial initiation, i.e., the 
database will be handled open-label in accordance with the CTP.


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