Clinical trial NCT05075772
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2021-10-25; Completion date: 2022-03-11
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study in healthy man to investigate the absolute bioavailability of 100mg BI 765080, once administered as subcutaneous (SC) injection and once administered as intravenous infusion.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BI 765080
Intervention descriptions: intervention 1: BI 765080

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c35408932-03
EudraCT No.
2021-003281-13
BI Trial No.
1450-0002
BI Investigational
Medicinal Product
BI 765080
Title
Absolute bioavailability, safety, tolerability, and 
pharmacodynamics following subcutaneous (SC) injection of 100
mg BI 765080 relative to intravenous (IV) dose in healthy male 
subjects
Lay Title
A study in healthy men to test how BI 765080 is taken up in the 
body when given as an injection under the skin compared with an 
infusion into the vein
Clinical Phase
I
Clinical Trial Leader 
Phone:
Fax: 
Principal 
Investigator
Phone: 
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0
Date: 20 Oct 2021
Page 1 of 67
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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BI Trial No.: 1450-0002
c35408932-03
Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
09 Aug 2021
Revision date
20 Oct 2021
BI trial number
1450-0002
Title of trial
Absolute bioavailability, safety, tolerability and pharmacodynamics following 
subcutaneous (SC) injection of 100 mg BI 765080 relative to intravenous (IV) dose 
in healthy male subjects 
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
To investigate the absolute bioavailability of BI 765080 following subcutaneous 
injection
Trial objectives
-
To investigate the absolute bioavailability of 100 mg BI 765080 administered 
as subcutaneous (SC) injection versus intravenous (IV) infusion 
-
To investigate safety, tolerability, pharmacokinetics
of 100 mg BI 765080 administered as subcutaneous injection and intravenous 
infusion
Trial design
Randomised, open-label, single-dose, matched parallel group design
Trial endpoints:
Primary endpoints: AUC0-tz, and Cmax of BI 765080
Secondary endpoints: 

AUC0-of BI 765080

Occurrence of drug-related adverse event
Number of subjects 
total entered
28
each treatment
14
Diagnosis
Not applicable


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Trial Protocol
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Main criteria
for inclusion
Healthy male subjects, age of 18 to 55 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
100 mg
mode of admin.
Subcutaneous (SC) injection as bolus (Test, T)
Intravenous (IV) as 30 min infusion (Reference, R)
Duration of treatment
Single dose 
Statistical methods
Absolute bioavailability will be estimated by the ratios of the geometric means 
(test/reference) for the primary and secondary PK endpoints. Additionally, their 
two-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-test procedure, each at a 5% significance level. 
Since the main focus is on estimation and not testing, a formal hypothesis test and 
associated acceptance range is not specified. The statistical model will be an 
analysis of variance (ANOVA) on the logarithmic scale including effects for 
treatment and the matched pair. CIs will be calculated based on the residual error 
from the ANOVA.
Drug-related adverse event will be described with descriptive statistics.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART - IV GROUP
Period
Visit
Day
Planned time (relative to 
first drug administration) 
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory
PK serum
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Query regarding local 
tolerability8
SCR
1
-21 to -3
Screening (SCR)1
x
x
x
2
-2
-48:00
8:00
Ambulatory visit 
x9,11
x
-1
-14:00
18:00
Admission to trial site
x5,9
x
1
-3:00
06:00
Allocation to treatment2
x2
x2
x2
x2
x2
0:00
08:00
Drug administration 
start of infusion
0:30
08:30
end of infusion
x
x
x
x
2:00
10:00
Light breakfast3
x
x
x
x
4:00
12:00
x
x
x
x
8:00
16:00
Snack (voluntary)3
x
x
x
12:00
20:00
x
x
x
x 
2
24:00
08:00
Breakfast3
x
x
x
x
x
34:00
18:00
Dinner3
x
x
x
3
48:00
08:00
Breakfast3,
discharge from trial site 
(confirmation of fitness7)
x
x
x
x
4
72:00
08:00
Ambulatory visit
x
x
6
120:00
08:00
Ambulatory visit
x
x
8
168:00
08:00
Ambulatory visit
x
x
x
x
x
11
240:00
08:00
Ambulatory visit
x
x
14
312:00
08:00
Ambulatory visit
x
x
x
x
x
21
480:00
08:00
Ambulatory visit
x
x
x
x
28
648:00
08:00
Ambulatory visit
x
x
x
x
x
56
1320:00
08:00
Ambulatory visit
x
x
x
x
x
FU
3
56 to 59
End of trial (EoTrial)
examination4
x
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, inclusive body temperature if it is still needed based on the status of pandemic,
ECG, safety laboratory (including drug screening), demographics (including determination of body height and weight, smoking status 
and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, 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.
7.
Confirmation of fitness includes physical examination. 
8.
Standardized assessment of local tolerability using the criteria swelling, induration, heat, redness, pain or other findings.
9.
SARS-CoV-2 PCR test will be performed prior to admission on Day -1 or Day -2 if it is needed in the current status of pandemic.
11. 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.


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FLOW CHART - SC GROUP
Period
Visit
Day
Planned time (relative to 
first drug administration) 
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory
PK serum
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Query regarding local 
tolerability8
SCR
1
-21 to -3
Screening (SCR)1
x
x
x
2
-2
-48:00
8:00
Ambulatory visit
x9,11
x
-1
-14:00
18:00
Admission to trial site
x5,9
x
1
-3:00
06:00
Allocation to treatment2
x2
x2
x2
x2
x2
0:00
08:00
Drug 
administration/injection
0:30
08:30
x
x
1:00
09:00
x
x
x
1:30
09:30
x
2:00
10:00
Light breakfast3
x
x
x
3:00
11:00
x
4:00
12:00
x
x
x
x
x
8:00
16:00
Snack (voluntary)3
x
x
x
12:00
20:00
x
x
x
x 
2
24:00
08:00
Breakfast3
x
x
x
x
x
x
3
48:00
08:00
x
x
x
x
x
4
72:00
08:00
Breakfast3,
discharge from trial site 
(confirmation of 
fitness7)
x
x
x
x
x
5
96:00
08:00
Ambulatory visit
x
x
x
6
120:00
08:00
Ambulatory visit
x
x
x
7
144:00
08:00
Ambulatory visit
x
x
x
x
x
x
8
168:00
08:00
Ambulatory visit
x
x
11
240:00
08:00
Ambulatory visit
x
x
14
312:00
08:00
Ambulatory visit
x
x
x
x
x
21
480:00
08:00
Ambulatory visit
x
x
x
x
28
648:00
08:00
Ambulatory visit
x
x
x
x
x
56
1320:00
08:00
Ambulatory visit
x
x
x
x
x
FU
3
56 to 59
End of trial (EoTrial)
examination4
x
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, inclusive body temperature if it is still needed based on the status of pandemic, 
ECG, safety laboratory (including drug screening), demographics (including determination of body height and weight, smoking status 
and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, 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.
7.
Confirmation of fitness includes physical examination.
8.
Standardized assessment of local tolerability using the criteria swelling, induration, heat, redness, pain or other findings.
9.
SARS-CoV-2 PCR test will be performed prior to admission on Day -1 or Day -2 if it is needed in the current status of pandemic.
11.
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.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART - IV GROUP............................................................................4
FLOW CHART - SC GROUP...........................................................................5
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................15
1.2.1
Nonclinical pharmacology....................................................................15
1.2.2
Toxicology..............................................................................................15
1.2.3
Clinical experience in humans.............................................................15
1.2.4
Residual Effect Period..........................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................17
1.4
BENEFIT - RISK ASSESSMENT ...................................................................18
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 20
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......20
2.1.1
Main objectives......................................................................................20
2.1.2
Primary endpoints ................................................................................20
2.1.3
Secondary endpoints.............................................................................20
2.2.2.2
Safety and tolerability..............................................................21
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 23
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................23
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................23
3.3
SELECTION OF TRIAL POPULATION ......................................................23
3.3.1
Main diagnosis for trial entry..............................................................23
3.3.2
Inclusion criteria...................................................................................23
3.3.3
Exclusion criteria ..................................................................................24
3.3.4
Withdrawal of subjects from treatment or assessments ...................26
3.3.4.1
Discontinuation of trial treatment............................................26
3.3.4.2
Withdrawal of consent to trial participation ............................27


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3.3.4.3
Discontinuation of the trial by the sponsor..............................27
3.3.5
Replacement of subjects .......................................................................27
4.
TREATMENTS........................................................................................ 29
4.1
INVESTIGATIONAL TREATMENTS ..........................................................29
4.1.1
Identity of the Investigational Medicinal Products ...........................29
4.1.2
Selection of dose in the trial .................................................................29
4.1.3
Method of assigning subjects to treatment groups ............................30
4.1.4
Drug assignment and administration of doses for each subject .......30
4.1.5
Blinding and procedures for unblinding ............................................31
4.1.6
Packaging, labelling, and re-supply ....................................................31
4.1.7
Storage conditions.................................................................................31
4.1.8
Drug accountability ..............................................................................32
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................32
4.2.1
Other treatments and emergency procedures....................................32
4.2.2
Restrictions............................................................................................32
4.2.2.1
Restrictions regarding concomitant treatment .........................32
4.2.2.2
Restrictions on diet and life style.............................................33
4.3
TREATMENT COMPLIANCE.......................................................................33
5.
ASSESSMENTS....................................................................................... 34
5.1
ASSESSMENT OF EFFICACY.......................................................................34
5.2
ASSESSMENT OF SAFETY............................................................................34
5.2.1
Physical examination ............................................................................34
5.2.2
Vital signs...............................................................................................34
5.2.3
Safety laboratory parameters..............................................................34
5.2.4
Electrocardiogram................................................................................37
5.2.5
Other safety parameters.......................................................................37
5.2.5.1
Local tolerability......................................................................37
5.2.6
Assessment of adverse events...............................................................38
5.2.6.1
Definitions of adverse events...................................................38
5.2.6.1.1 Adverse event ............................................................38
5.2.6.1.2 Serious adverse event ................................................38
5.2.6.1.3 AEs considered ‘Always Serious’.............................39
5.2.6.1.4 Adverse events of special interest .............................39
5.2.6.1.5 Intensity (severity) of AEs.........................................40
5.2.6.1.6 Causal relationship of AEs ........................................40
5.2.6.2
Adverse event collection and reporting ...................................41
5.2.6.2.1 AE collection.............................................................41
5.2.6.2.2 AE reporting to the sponsor and timelines ................42
5.2.6.2.3 Information required..................................................42
5.2.6.2.4 Pregnancy ..................................................................42
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................42


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5.3.1
Assessment of pharmacokinetics .........................................................42
5.3.2
Methods of sample collection...............................................................43
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................43
5.5
BIOBANKING ...................................................................................................45
5.6
OTHER ASSESSMENTS .................................................................................45
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................45
6.
INVESTIGATIONAL PLAN.................................................................. 46
6.1
VISIT SCHEDULE............................................................................................46
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................46
6.2.1
Screening period....................................................................................46
6.2.2
Treatment period ..................................................................................47
6.2.3
Follow-up period and trial completion ...............................................47
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 48
7.1
STATISTICAL DESIGN – MODEL ...............................................................48
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................48
7.3
PLANNED ANALYSES....................................................................................48
7.3.1
Primary endpoint analyses...................................................................49
7.3.2
Secondary endpoint analyses ...............................................................50
7.3.3.2
Safety and tolerability analyses ...............................................50
7.3.4
Safety analyses.......................................................................................51
7.4
INTERIM ANALYSES .....................................................................................52
7.5
HANDLING OF MISSING DATA ..................................................................52
7.5.1
Safety......................................................................................................52
7.5.2
Pharmacokinetics..................................................................................52
7.6
RANDOMISATION ..........................................................................................52
7.7
DETERMINATION OF SAMPLE SIZE ........................................................52


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 54
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................54
8.2
DATA QUALITY ASSURANCE .....................................................................55
8.3
RECORDS..........................................................................................................55
8.3.1
Source documents .................................................................................55
8.3.2
Direct access to source data and documents.......................................56
8.3.3
Storage period of records.....................................................................56
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................56
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......57
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................57
8.6
TRIAL MILESTONES .....................................................................................57
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................58
9.
REFERENCES......................................................................................... 59
9.1
PUBLISHED REFERENCES...........................................................................59
9.2
UNPUBLISHED REFERENCES.....................................................................60
10. APPENDICES .......................................................................................... 61
10.1
RECONSTITUTION INSTRUCTIONS .........................................................61
10.1.1 Description of trial Medication............................................................61
10.1.2 Temperature deviation during storage...............................................61
10.1.3 Instructions for preparation of the study medication .......................61
10.1.3.1 General Remarks......................................................................61
10.1.3.2 Consumables............................................................................62
10.1.3.3 Preparation of the study medication – IV Dose.......................62
10.1.3.3.1
Reconstitution of the lyophilized powder.............62
10.1.3.3.2
Dilution Procedure – 100 mg IV dose ..................62
10.1.3.4 Preparation of the study medication –SC Dose .......................63
10.1.3.4.1
Reconstitution of the lyophilized powder.............63
10.1.3.4.2
Dose preparation (100 mg dose)...........................63
10.1.3.5 In-Use stability statement ........................................................63
10.1.3.5.1
Ready to administer drug product (IV 
administration)...........................................................63
10.1.3.5.2
Ready to administer drug product (SC 
administration)...........................................................64
10.1.4 Administration Instructions.................................................................64
10.1.4.1 General Remarks......................................................................64
10.1.4.2 Administration (IV Dose) ........................................................64
10.1.4.3 Administration (SC Dose)........................................................65


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11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 66
11.1
GLOBAL AMENDMENT 1 .............................................................................66
11.2
GLOBAL AMENDMENT 2 .............................................................................67


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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
ANGPT1
Angiopoietin 1
ANGPT2
Angiopoietin 2
ANOVA
Analysis of variance
ARB
Angiotensin-receptor blocker
AST
Aspartate amino transferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
Cmax
Maximum measured concentration of the analyte in plasma
CML
Clinical Monitor Local
COVID-19
Corona virus disease 2019
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form


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eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EoTrial/EOT
End of trial
ESRD
End-stage renal disease
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
FDA
Food and Drug Administration
FIH
First-in-human
FLD
Fibrinogen-like domain
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GFR
Glomerular filtration rate
GLP
Good Laboratory Practice
gMean
Geometric mean
HD
Hemodialysis
IB
Investigator’s brochure
IEC
Independent Ethics Committee
INR
International Normalization Ratio
IPD
Important protocol deviation
IPV
Important protocol violation
IRB
Institutional Review Board
ISF
Investigator site file
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV/i.v.
Intravenous
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
PCR
Polymerase chain reaction
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter analysis set
PR
Pulse rate


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QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SC/s.c.
subcutaneous
SCR
Screening
SGLT2
Sodium-glucose co-transporter-2
SNP
Single nucleotide polymorphism
SOP
Standard operating procedure
SRD
Single-rising dose
T
Test product or treatment
Tie2
Angiopoetin-1 receptor, TEK tyrosine kinase
TMDD
Target mediated drug disposition
TMF
Trial master file
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WBC
White blood cells
WFI
Water for Injection
WHO
World Health Organisation
WOCBP
Women of child-bearing potential
XTC
Ecstasy 


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1.
INTRODUCTION
BI 765080 is intended for the treatment of chronic kidney disease (CKD). The first trial in 
humans (SRD 1450-0001 [c31414158]) is ongoing. This is the second 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]. In developed countries, CKD is generally associated with diabetes, hypertension, 
old age, obesity, and cardiovascular disease.
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].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].
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
The Tie2 antagonist angiopoietin 2 (ANGPT2) blocks ANGPT1-mediated Tie2 activation in 
glomerular endothelial cells. In patients with diabetic nephropathy, a SNP in ANGPT2 was 
associated with a 20% elevation in the circulating protein and increased disease severity 
[R20-1041]. Glomerular ANGPT2 mRNA expression is elevated in diabetic nephropathy 
[R20-1027]. However, glomerular expression of ANGPT1, the endogenous agonist of Tie2 
[R20-1027], and circulating ANGPT1 protein [R20-1028, R20-1029] are unchanged in 
diabetic nephropathy thereby favouring ANGPT2-bound Tie2 in the context of renal disease 
progression.
Key clinical observations linking dysregulation of the ANGPT2-Tie2 pathway with CKD 
were born from trials where patients were stratified by disease severity (from stage 1 to end-
stage renal disease (ESRD) / hemodialysis (HD)) and where circulating ANGPT2 was 
progressively elevated [R20-1029] and inversely correlated with a decline in inulin-measured 
glomerular filtration rate (GFR) [R20-1030].
BI 765080 is a high affinity neutralizing antibody to ANGPT2, expected to limit antagonistic 
binding of ANGPT2 to Tie2, restore podocyte to endothelial cell cross-talk, and enable 
ANGPT1-Tie2 signalling. Enhanced Tie2 signalling via ANGPT1 is expected to stabilize the 
glomerular capillary structure, reduce endothelial activation, and restore filtration barrier 


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integrity. In total, these effects are expected to decrease proteinuria and preserve renal 
function resulting in a slowed disease progression in patients with CKD.
1.2
DRUG PROFILE
1.2.1
Nonclinical pharmacology 
BI 765080 binds the ANGPT2 fibrinogen-like domain (FLD) and blocks the physical 
interaction between the ANGPT2 FLD and the extracellular domain of the Tie2 receptor. 
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. 
No adverse findings were associated with BI 765080 administration at dose levels up to 
100 mg/kg.
1.2.2
Toxicology
Rat and cynomolgus monkey were chosen as the rodent and non-rodent toxicology species 
due to conserved biological function of ANGPT2 among these species and humans. 4-week 
(rat) and 13-week (monkey) GLP repeat dose toxicity studies were evaluated. BI 765080 
administered up to 100 mg/kg/week was well tolerated in animals. Genetic toxicity studies 
are generally not applicable to therapeutic antibodies, as they are not expected to interact 
directly with DNA.
For a more detailed description of BI 765080 profile, please refer to the current Investigator’s 
Brochure (IB) [c30981435]
1.2.3
Clinical experience in humans
In Phase I, BI 765080 is evaluated in a first-in-human (FIH) SRD trial.
FIH-Study (Trial 1450-0001)
The FIH (first-in-human) trial [c31414158] is ongoing and explored safety, tolerability, 
pharmacokinetics, and pharmacodynamics of intravenously administered BI 765080 in 
healthy male subjects. Subjects received single ascending IV doses of 1 mg up to 
200 mg BI 765080 or placebo. Overall, the study included 48 male subjects with 36
subjects treated with BI 765080 and 12 subjects treated with placebo.
At preferred term level, all the reported treatment-emergent AEs are shown below:


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headache (BI 765080: 3/38 subjects [8.3 %]; placebo: 1/12 subjects [8.3%]), upper 
respiratory tract infection (BI 765080: 2/36 subjects [5.6 %]; placebo: 0), post vaccine 
reactogenicity (BI 765080: 1/36 subjects [2.8 %]; placebo: 0), headache post vaccine Covid-
19 (BI 765080: 1/36 subjects [2.8 %]; placebo: 0), vomiting (BI 765080: 1/36 subjects [2.8
%]; placebo: 0), vision blurred (BI 765080: 1/36 subjects [2.8 %]; placebo: 0), back pain (BI
765080: 1/36 subjects [2.8 %]; placebo: 0), bronchitis (BI 765080: 1/36 subjects [2.8 %]; 
placebo: 0), tooth abscess (BI 765080: 1/36 subjects [2.8 %]; placebo: 0), myalgia right upper 
leg (BI 765080: 1/36 subjects [2.8 %]; placebo: 0), throat irritation (BI 765080: 0; placebo: 
1/12 subjects [8.3 %]), weight increased (BI 765080: 0; placebo: 1/12 subjects [8.3 %]),
herpes zoster reactivation (BI 765080: 0; placebo: 1/12 subjects [8.3 %]),
All of treatment-emergent AEs were assessed as not drug-related. There were six AEs of 
moderate intensity (four AEs with BI 765080 and two AEs with placebo). Four moderate 
AEs with BI 765080 included tooth abscess, headache post vaccine Covid-19 and upper 
respiratory infection in two subjects. Two moderate AEs with placebo included headache and 
herpes zoster reactivation. All remaining AEs were of mild intensity.
There were no relevant changes compared to placebo for laboratory safety, including clinical 
chemistry, hematology, coagulation parameters, and urinalysis. Deaths, serious AEs, and 
protocol-specified AEs of special interest were not reported in this trial. No clinically relevant 
changes were observed in 12 lead ECGs, vital signs, and physical examinations. In addition, 
no adverse event related to local tolerability was reported.
Pharmacokinetics
The preliminary single-dose PK parameters of BI 765080 from dose groups 1 to 6 (1 to 200 
mg) are summarized in Table 1.2.3: 1. The preliminary data show that after iv infusion, 
AUC0-∞exposure increased with dose in a supraproportional fashion up to the 100 mg dose, 
consistent with target-mediated drug disposition (TMDD). Dose-adjusted AUC0-∞was about 
the same for the 200 mg dose as the 100 mg dose, suggesting TMDD may have neared 
saturation at the 100 mg dose. Cmax increased in a near dose-linear fashion at doses ≥ 10 mg.
The elimination half-life increased with increasing dose ranging from 12 hours at the 1 mg 
dose to 267 h at the 200 mg dose.


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Table 1.2.3: 1
gMean (gCV%) values of BI 765080 PK parameters after single iv 
infusion of BI 765080 – SRD Trial 1450-0001 [c31414158]
Parameter
Dose (mg)
1
10
25
50
100
200
AUC0-tz
(h∙µgl/L)
4330 
(50.4%)
241000 
(24.9%)
868000 
(31.3%)
2500000 
(39.5%)
7100000 
(25.4%)
13200000 
(16.0%)
AUC0-∞ 
(h∙µg/L/L)
4930 
(48.4%)
258000 
(20.7%)
870000 
(31.3)
2520000   
(39.9%)
7160000 
(25.2%)
16300000 
(27.3%)
Cmax (nmol/L)
274 
(21.4%)
3490 
(11.0%)
7930 
(16.2%)
16900 
(29.0%)
35400 
(13.7%)
64500 
(11.6%)
tmax (h)*
1.0 (0.5-1.0)
1.0 (0.5-2.0)
1.0 (0.5-1.0)
2.5 (1.0-10)
2.0 (1.0-4.0)
2.5 (0.5-4.0)
t½ (h)
12.1 
19.4%)
43.6 
(20.0%)
68.6 
(14.1%)
89.3 
(26.4%)
137 
(29.0%)
NC
CL (mL/min)
3.38 
(48.4%)
0.645 
(20.7%)
0.479 
(31.3%)
0.330 
(39.9%)
0.233 
(25.2%)
NC
* median (min-max)
NC – Not Calculated, incomplete data in elimination phase
1.2.4
Residual Effect Period
The Residual Effect Period (REP) is the period after the last dose with measurable drug levels 
and/or PD effects still likely to be present.
For BI 765080, a REP has not yet been determined. Conservatively, an observation period of 
8 weeks has been selected, which is about 9-fold of the estimated t1/2 at 100 mg (approx. 6 
days). Therefore, the individual subject’s end of trial is on Day 56 to 59 following 
administration of investigational drug at the earliest (see Flow Chart).
1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 765080 is in development for the treatment of CKD, currently in Phase I development.
In FIH BI 765080 was administered as intravenous infusion. However, the subcutaneous 
injection route is considered for the further clinical studies. For this reason absolute 
bioavailability is investigated and local tolerability is examined following subcutaneous 
injection. 


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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 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 sensitivity, and/or pain for an indefinite 
period.
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 drawing of this volume of blood.
Drug-related risks and safety measures
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), as well as in vitro cytokine
release assay and for tissue cross reactivity. 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 clinical safety and tolerability profile of BI 765080 was comparable to placebo in male 
subjects following intravenous doses of up to 200 mg administered as single dose. There 
were no deaths or other serious adverse events. There were no drug-related adverse events. 
There were no dose or exposure related abnormalities in safety laboratory parameters and no 
safety or tolerability concerns that would preclude further clinical development of BI 765080.
Based on SRD study (1450-0001 [c31414158]) in healthy subjects, no specific drug-related 
risks are anticipated. Nevertheless, the following safety measures will be applied in this study 
in order to minimize the risk for the healthy subjects:

At any time during the ongoing study, further dosing will be stopped in case of safety
and tolerability concerns based on the criteria defined in Section 3.1.

Monitoring of ECG, vital signs, and extensive safety laboratory testing (Table 5.2.3:1) 
is conducted throughout the study.

After dosing, the subjects with IV will stay at the site for at least 48 hours and the 
subjects with SC will stay at the site for at least 72 hours.

BI 765080 will be administered in a hospital setting and subjects will be under close 
medical observation during their hospitalisation (see Section 6.2), as well as after their 


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discharge and until the end of observation period. Safety will be closely monitored 
during site visits for both expected and unexpected adverse events.
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.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the absolute bioavailability of 100 mg of BI 
765080 administered in healthy male subjects as subcutaneous (SC) injection versus 
intravenous (IV) infusion.
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for BI 765080:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoints

AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the  
time interval from 0 extrapolated to infinity)

To assess safety and tolerability of BI 765080: Occurrence of drug-related adverse 
event


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2.2.2.2
Safety and tolerability
Safety and tolerability of BI 765080 will be assessed based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a randomised, open-label, matched parallel group trial in
healthy male subjects in order to compare subcutaneous injection administration (T) to
intravenous infusion (R). The treatments will be one single 100 mg BI 765080. For details,
refer to Section 4.1.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
This study will explore the absolute bioavailability, safety, tolerability and 
pharmacodynamics following intravenous (IV) infusion or subcutaneous (SC) injection of BI 
765080 in matched pairs of healthy male subjects (matching is done based on age and body 
weight, see Section 3.3). By dosing test and reference treatment to a matched pair on the 
same day the influence of confounding factors can be reduced to a minimum.
The trial will be conducted open-label. Blinding is not possible because the treatments are 
distinguishable. The open-label treatment is not expected to bias results, since the study 
endpoints are derived from measurement of plasma concentrations of the analyte, which are 
provided by a bioanalytical laboratory that is blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 28 healthy male subjects (14 subjects with IV and 14 subjects with SC) will 
enter the study to have at least 12 evaluable subjects available in each group. They will be 
recruited from the volunteers' pool of the trial site.
Participants in SC and IV groups will be matched for age (18-36 or 37-55 years at screening) 
and body weight (±10% inclusive). That means, that the 2 subjects of one matched pair are 
either 18-36 years (inclusive) or 37-55 years old (inclusive) and that the difference of their 
body weight does not exceed 10% (e.g. 80 kg and 88 kg).
Only Caucasian male subjects will be included in the study.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:


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1. Healthy Caucasian male subjects according to the assessment of the investigator, as 
based on a complete medical history, a physical examination, vital signs (BP, PR), 12-
lead ECG, and clinical laboratory tests 
2. Age of 18 to 55 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
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including 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. Use of drugs within 10 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc 
interval prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned
administration of investigational drug in the current trial, or concurrent participation 
in another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 30 g per day)
16. Drug abuse or positive drug screening


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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 in males) 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 90 
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 90 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 90 days after 
IMP administration. 
In addition, the following SARS-CoV-2-specific exclusion criteria apply:
24. A positive PCR test for SARS-CoV-2 or clinical symptoms suggestive for this disease 
prior to the admission.


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For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the 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 1.2.4 ), the discontinued subject should if possible be 
questioned for AEs and concomitant therapies at or after the end of the REP in order to 
ensure collection of AEs and concomitant therapies throughout the REP, if not contrary to 
any consent withdrawal of the subject.
3.3.4.1
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 has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing 
or able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of 
total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be 
followed up according to the DILI checklist provided in the ISF
6. 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


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In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
If new efficacy or safety information becomes available, Boehringer Ingelheim will review
the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all
subjects or take any other appropriate action to guarantee the safety of the trial subjects.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (if reasons 4 and/or 5 are met, the trial should be discontinued 
immediately):
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. The sponsor decides to discontinue the further development of the investigational 
product
3. Deviation from GCP, or the CTP, or the contract with BI impairing the appropriate 
conduct of the trial.
4. New toxicological findings, serious adverse events, or any safety information
invalidating the earlier positive benefit-risk-assessment. 
5. More specifically, the trial will be terminated if more than 50% of the subjects have
drug-related and clinically relevant adverse events of moderate or severe intensity, or 
if at least 1 drug-related serious adverse event is reported
6. Further dosing will be stopped if at least 2 subjects at one group (14 subjects) 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
7. Occurrence of severe non-serious adverse events considered as drug-related by the 
investigator in 2 subjects of one group (14 subjects)
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case more than two subjects per treatment group 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 


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trial subject number and will be assigned to the same treatment as the subject he replaces.
Matching conditions (body weight, age) have to be considered for replacement subjects. 
Subjects may not be replaced if they drop out for safety reasons, e.g. increase in liver 
transaminases.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product BI 765080 has been manufactured by BI Pharma GmbH & Co. 
KG. 
 
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the reference (R) 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:
2-0-0
Route of administration:
IV infusion
Duration of use:
Single dose
The characteristics of the test (T) 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:
2-0-0
Route of administration:
SC administration
Duration of use:
Single dose 
At the time of use, the IV and SC solution for dosing will be prepared as detailed in the 
instruction given in Appendix 10.1.
4.1.2
Selection of dose in the trial
The dose of 100 mg of BI 765080 selected for this trial has been selected to correspond to the 


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potential dose for maintenance treatment in clinical trials in patients.
4.1.3
Method of assigning subjects to treatment groups
Prior to the start of the study, subjects willing to participate in this study will be recruited to
treatment groups according to their temporal availability (this includes the ability to 
participate as well in the IV-arm as in the SC-arm). From the eligible subjects matched pairs 
(based on age and body weight, see Section 3.3) are formed by the investigator.
The randomisation list will be provided to the trial site in advance. Subjects are then assigned 
to treatment according to the randomization list with a block size of 2. The allocation of these 
two random numbers to one matched pair of subjects will be done by drawing lots in the 
morning of Day 1.
Once a random number has been assigned to a subject, it cannot be reassigned to any other 
subject.
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. Each subject will receive 
one single dose of trial medication. Detailed instructions for the dilution of the trial product, 
the preparation of the IV infusion and SC injection solutions, the volume to be administered 
and the infusion/injection time is provided in Appendix 10.1. In the subjects with IV, the 
infusion solution will be intravenously administered over 30 minutes.
Table 4.1.4: 1
Dosage and treatment schedule
Dose Group
Route of 
administration
Application volume
Total dose
1
IV
50 mL
100 mg
2
SC
2 mL
100 mg
Subcutaneous injection
Following an overnight fast of at least 10 hours, the medication will be administered. Trial 
drug will be injected subcutaneously within 60 seconds in the abdominal region. Detailed 
handling instruction see Appendix 10.1. Subjects will be kept under close medical 
surveillance until 72 hours following drug administration. On Day 4, subjects will be 
discharged from the trial site and further assessments will be conducted in an ambulatory 
fashion For restrictions with regards to diet, see Section 4.2.2.2.
Intravenous infusion
Following an overnight fast of at least 10 hours, the medication will be administered. The 
infusion solution will be administered intravenously over 30 minutes. Start and time of the 


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infusion will be recorded. Detailed handling instruction for the infusion see Appendix 10.1.
Subjects will be kept under close medical surveillance until 48 h following drug 
administration. Day 3, subjects will be discharged from the trial site and further assessments 
will be conducted in an ambulatory fashion. For restrictions regarding diet, see also Section 
4.2.2.2.
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.
4.1.5
Blinding and procedures for unblinding
No blinding will be performed. This Phase I trial will be handled in an open fashion 
throughout (that is, during the conduct, including data cleaning and preparation of the 
analysis). This is considered acceptable because the potential for bias is low and does not 
outweigh practical considerations.
Emergency envelopes will not be provided, because the trial medication is known to 
investigators and subjects.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the
analytical site.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The 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.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.


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4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
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 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
4.2.1
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, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.


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4.2.2.2
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/injection).
On Day 1, no fluid intake is allowed starting 1 hour before drug administration until 1.5 h 
after the end of injection/ 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.
Alcoholic beverages are not permitted starting 7 days before the first administration of trial 
medication until Day 14.
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.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first 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 of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (alcohol history results not mandatory to be entered into CRF or 
to be reported), relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 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.
5.2.2
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) 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.
Oral body temperature will be measured using a standard device if it is still needed in the 
current status of pandemic.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 10 h
(Subjects are advised to come fasted overnight when visiting in the morning, 4h when 
visiting in the afternoon for the screening) . 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 t examination 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]
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes
Platelet Count/Thrombocytes (quant)
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ Leukocytes; 
Monocytes/Leukocytes; Lymphocytes/Leukocytes 
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; Monocytes, 
absol.; Lymphocytes, absol.
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
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB 
Lactic Dehydrogenase
Lipase
Amylase
Hormones
Thyroid Stimulating Hormone (only at SCR)
Free T3 - Triiodothyronine (only at SCR)
Free T4 – Thyroxine(only at SCR)
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant) 
Uric Acid 
Cholesterol, total 
Triglyceride


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
Electrolytes
Sodium
Potassium
Chloride
Calcium
Phosphate (as Phosphorus, Inorganic)
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
Urine sediment 
Only positive findings will be reported (for instance, the presence of sediment 
bacteria, casts in sediment, squamous epithelial cells, erythrocytes, leukocytes)
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 during screening only, except for drug screening and 
the SARS-CoV-2 PCR test, which will be performed prior to admission, if it is needed in the 
current status of pandemic . 
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 
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.


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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 Triage TOX Drug Screen or a comparable test system.
SARS-CoV-2 PCR test will be performed by
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (
) at the times 
provided in the Flow Chart.
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 approximately10 sec duration after subjects have rested for at 
least 5 min in a supine position. ECG assessment will always precede all other study 
procedures scheduled for the same time to avoid compromising ECG quality. 
All ECGs will be recorded, interpreted and stored electronically at the site. 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). 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
5.2.5.1
Local tolerability
Local tolerability will be assessed by the investigator on the basis of swelling, induration, 
heat, redness, pain, and other findings.


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5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the 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


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5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of 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. A copy of the latest list of
‘Always Serious AEs’ will be provided upon request. These events should always be reported
as SAEs as described Section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.6.2.2.
The following are considered as AESIs:

Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is defined 
by the following alterations of hepatic laboratory parameters: 
o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the
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.
No other AESIs have been defined for this trial.


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


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


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


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5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 765080 concentrations in serum, 3mL 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 at least 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.
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.
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, ECG parameters, and local tolerability 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 IV and SC 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).
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests
will be:

± 30 min up to and including 48 h

± 120 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,
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 scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.


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For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
6.2.2
Treatment period
Each subject will receive one dose of trial medication (BI 765080) at Visit 2. 
Trial medication will be administered as IV infusion or SC injection 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 (IV group) or 72 h (SC group) 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.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see 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.
If needed in the opinion of the investigator, additional visits may be scheduled after the 
EoTrial Visit for continued safety monitoring.
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 objective of this trial is to investigate the absolute bioavailability of (SC) injection
of100 mg BI 765080 (Test, T) compared with IV dose of 100 mg BI 765080 (Reference, R) 
following administration on the basis of the primary and secondary safety and 
pharmacokinetic endpoints, as listed in Section 2.1.2 and 2.1.3. The trial is designed to allow 
inter-subject comparisons and will be evaluated statistically by use of a linear model for 
logarithmically transformed PK endpoints and descriptive analysis for AEs.
The assessment of safety and tolerability as well as local tolerability is a further objective of 
this trial, and will be evaluated by descriptive statistics for the parameters specified in Section 
2.2.2.2 and 2.2.2.3.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The absolute bioavailability of SC injection compared with IV dose will be estimated by the 
ratios of the geometric means (test/reference), and their corresponding 2-sided 90% 
confidence intervals (CIs) will be provided. This method corresponds to the two one-sided t-
test procedure, each at the 5% significance level. Since the main focus is on estimation and 
not testing, a formal hypothesis test and associated acceptance range is not specified.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were allocated and treated 
with at least one dose of study drug. 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 defined as primary or 
secondary and 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 to the statistical assessment. Descriptive and 
model based analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol violation 
(IPV) categories will be specified in the IPD specification file prior to trial initiation, IPVs 
will be identified no later than in the Report Planning Meeting, and the IPV categories will be 
updated as needed.


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Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for drug BI 765080 will be calculated 
according to the relevant SOP of the Sponsor (current version). 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
violation 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 violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve.
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.3.1
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following source of variation: treatment and matching pair. The 
effect of treatment will be considered as fixed. For each matched pair in the study a pair 
number will be assigned for analysis purpose. The resulting variable ‘matched pair’ will be 
considered as random effect. The model is described by the following equation:
ykm = + k + sm + ekm, where
ykm = logarithm of response measured on subject m receiving treatment k,


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= the overall mean,
k = the kth treatment effect, k = 1, 2,
sm = the effect associated with the mth matching pair, m = 1, 2,…, 14,
ekm = the random error associated with the mth subject who received treatment k.
where s~ N(0,σB2) i.i.d., e ~ N(0, σ
 ) i.i.d., σ
 and s, e are independent random
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means).
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.3.2
Secondary endpoint analyses
The secondary PK endpoints (refer to Section 2.1.3) will be calculated according to the BI 
SOP ‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ and will be assessed statistically using the same methods as described 
for the primary endpoints.
Drug-related adverse event will be presented descriptively by treatment group.
7.3.3.2
Safety and tolerability analyses
Further safety and tolerability endpoints will analysed descriptively.


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7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2 and 2.2.2.3. All 
treated subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety 
analyses will be descriptive in nature and based on BI standards. No hypothesis testing is 
planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the treatment will be discussed in the minutes of the Report 
Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, those between first trial medication intake and end of 
trial examination (including the anticipated REP (see Section 1.2.3)) 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 final 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 values defined as possibly clinically significant 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.
Relevant ECG findings will be reported as AEs.


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7.4
INTERIM ANALYSES
No formal interim analysis is planned. A preliminary analysis of PK parameters and safety 
may be performed, if requested by the Clinical Trial Leader, the investigator, or Trial Clinical 
Pharmacokinetics.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (current version).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
This is a randomized trial. Consecutive subject numbers will be assigned via the eDC system. 
Subjects will be randomized within each matched pair in a 1:1 ratio (IV to SC).
The sponsor will arrange for the randomization as well as packaging and labelling of trial 
medication. The randomization list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomization list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 28 subjects in the trial, because this sample size is considered 
sufficient to achieve the aims of this exploratory trial. With this sample size, the following 
precision in estimating the ratio of geometric means (test/reference) can be expected with 
95% probability. Precision is defined as the ratio of upper CI limit to the relative BA 
estimate. Note that the precision is independent of the actual ratio of geometric means.
The observed geometric coefficient of variation (gCV) for BI 765080 in the 1450-0001 trial
[c31414158] was roughly 14% for Cmax and 25% for AUC.


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For various assumptions around the gCV of 25%, Table 7.7: 1 provides an overview of the 
achievable precision for estimating the ratio of geometric means (test/reference). For 
illustrative purposes, the expected 90% confidence intervals are displayed for different values 
of the ratios T/R of geometric means.
Table 7.7: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a matched pair parallel trial 
(N=28)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
22.5
1.13
25
22.10
28.28
22.5
1.13
60
53.04
67.87
22.5
1.13
90
79.56
101.81
25.0
1.15
25
21.81
28.66
25.0
1.15
60
52.34
68.78
25.0
1.15
90
78.51
103.18
27.5
1.16
25
21.52
29.04
27.5
1.16
60
51.65
69.70
27.5
1.16
90
77.48
104.55
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The expected 90% confidence interval limits in the table were derived by
CI limit, = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 4.0.1.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. 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.
Term and conditions can be provided to the investigator or subject upon request ,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 respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form 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.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication


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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.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial sitemust retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.


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8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs
informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial
(‘Last Subject Completed’).
Early termination of the trial is defined as the premature termination of the trial due to any
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority
request.


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The EC/competent authority will be notified about the trial milestones according to the laws 
of the EU member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial, 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.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the
 under the supervision of the Principal Investigator. 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
BI has appointed a Clinical Trial 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 (BI 765080) will be provided by the
 
.
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 
, 
.
, 
.
 
 but may be not analyzed.
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 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.
R02-2101
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.
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.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
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.
R19-1356
Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in
type 2 diabetes and nephropathy. New Engl J Med 2019;380(24):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.
R20-1027
Dessapt-Baradez C, Woolf AS, White KE, et al. Targeted glomerular
angiopoietin-1 therapy for early diabetic kidney disease. J Am Soc Nephrol
2014 Jan;25(1):33-42.
R20-1028
Chang FC, Lai TS, Chiang CK, et al. Angiopoietin-2 is associated with
albuminuria and microinflammation in chronic kidney disease. PLoS One
2013;8(3):e54668.
R20-1029
Chang FC, Chiang WC, Tsai MH, et al. Angiopoietin-2-induced arterial
stiffness in CKD. J Am Soc Nephrol 2014;25(6):1198-209.
R20-1030
David S, Kümpers P, Lukasz A, et al. Circulating angiopoietin-2 levels 
increase with progress of chronic kidney disease. Nephrol Dial Transplant 
2010;25(8):2571-6.


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R20-1041
Quan H, Haiming L, Baosheng Z, Xinhua T, Luzhi J. Association of
1233A/G polymorphism of angiopoietin-2 gene with type 2 diabetes
mellitus and diabetic nephropathy. Chin J Med Gen 2012;29(1):72-76.
9.2
UNPUBLISHED REFERENCES
c30981435
 Investigator's Brochure BI 765080 CKD. 09 Sep 2020.
c31414158
 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). 1450-0001, 10 May 2021.


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10.
APPENDICES
10.1
RECONSTITUTION INSTRUCTIONS
10.1.1
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
10.1.2
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 
). 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.
In case of a significant temperature excursion, the Sponsor must be notified as described in 
the ISF using the “Product/Device Complaints Form”.
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.
10.1.3
Instructions for preparation of the study medication
10.1.3.1
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/injection, 
the vials should be checked for any changes (e.g. color) and for the absence of particles. After 
reconstitution the solution should be colorless 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/injection 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.


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10.1.3.2
Consumables 
Materials tested to be compatible the study medication are listed in Table 10.1.3.2: 1 for 
preparation and in Table 10.1.4.2: 1 for I.V. administration.
Table 10.1.3.2: 1
Overview of materials used for preparation of BI 765080 Powder for 
solution for injection/infusion 50 mg/vial 
Type
Qualitative composition
Syringe 50 mL intended for use with syringe pumps (Graduation: 1 mL)
Polypropylene
Syringe 3 mL; Graduation: 0.1 mL
Polypropylene
Syringe 1 mL (Graduation: 0.01 mL)
Polycarbonate/ Polypropylene
Syringe closure
Polyethylene
20G 1½ needle
Stainless steel / Polypropylene
18G x 1 ½” blunt filter needle
Stainless steel 
Syringe adapter or Discofix 3-way stopcock
Polyethylene or Polyamid
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
10.1.3.3
Preparation of the study medication – IV Dose
10.1.3.3.1 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.
3. Discard needle and syringe and swirl the vial gently until the lyophilizate is dissolved 
and homogenized. Do not shake. Avoid the generation of foam. The full 
reconstitution should be finished within 10 minutes. The resulting concentration is 50 
mg/mL.
4. In case foam generation during reconstitution wait with further processing until foam 
has settled. This should take not more than 60 min. 
10.1.3.3.2 Dilution Procedure – 100 mg IV dose 
1. Withdraw 48 mL 0.9% Saline in a 50 mL syringe (compatible with syringe pump).


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2. Pool 2 mL of reconstituted drug product in a 3 mL syringe.
3. Combine both syringes with a syringe adapter / discofix connector and mix the 
content of the syringes by gently transferring back and forth times. The resulting 
concentration is 2 mg/mL.
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. 
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.
10.1.3.4
Preparation of the study medication –SC Dose
10.1.3.4.1 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. Discard needle and 
syringe and swirl the vial gently until the lyophilizate is dissolved and homogenized. 
Do not shake. Avoid the generation of foam. The full reconstitution should be finished 
within 10 minutes. The resulting concentration is 50 mg/mL.
3.
In case foam generation during reconstitution wait with further processing until foam 
has settled. This should take not more than 60 min.
10.1.3.4.2 Dose preparation (100 mg dose)
1.
Attach an 18G filter needle to a 3 mL syringe and pool slightly more than the target 
injection volume of 2 mL of the reconstituted drug product.
2.
Replace the filter needle by a syringe closure if the medication will not be injected 
immediately.
10.1.3.5
In-Use stability statement 
10.1.3.5.1 Ready to administer drug product (IV administration) 
Chemical and physical in-use stability of BI 765080 has been demonstrated for a 
concentration range from 0.1 mg/mL to 8mg/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.


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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.
10.1.3.5.2 Ready to administer drug product (SC administration) 
Chemical and physical in-use stability of BI 765080 has been demonstrated for a 
concentration range from 5 mg/mL to 50 mg/mL diluted with 0.9% saline solution or 
undiluted for 4 h at ambient conditions in the syringe intended for administration. 
Do not freeze.
From a microbiological point of view, the solution for injection should be used immediately. 
The solution for injection 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.
10.1.4
Administration Instructions 
10.1.4.1
General Remarks
In order to avoid an infusion/injection reaction caused by the administration of low 
temperature solution the infusion/injection container/syringe must be brought to room 
temperature before infusion/injection.
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. The SC injection will be given as one bolus.
In case of complications during infusion, please refer to the protocol.
10.1.4.2
Administration (IV Dose)
Information on administration consumables:
The following medical consumables were tested within the in-use stability study.
Table 10.1.4.2: 1
Overview of materials for administration of BI 765080 Solution for 
Infusion
Type
Material
Tubing intended for syringe pump use, ≤300cm 
Polyethylene
0.2 µm Filter
Polyethersulfone (uncharged), e.g. Sterifix 4099303
Discofix C
Polyamide, Polycarbonate, Polypropylene
Catheter 24G
Polyurethane
Syringe pump compatible with the 50 mL syringe used for preparation.


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10.1.4.3
Administration (SC Dose)
1. Replace the syringe closure by a 27G x ½" needle and adjust the volume to 2 mL.
2. For administration of s.c. injection, trial drug will be injected subcutaneously within 
60 seconds in the abdominal region.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
16 Sep 2021
EudraCT number
EU number
2021-003281-13
BI Trial number
1450-0002
BI Investigational Medicinal 
Product(s)
BI 765080
Title of protocol
Absolute bioavailability, safety, tolerability, and 
pharmacodynamics following subcutaneous (SC) 
injection of 100 mg BI 765080 relative to 
intravenous (IV) dose in healthy male subjects
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
1.2.3
Clinical experience in humans
3.3.3 Exclusion criteria
Description of change
1.2.3: added local tolerability assessment “no 
adverse event related to local tolerability was 
reported”;
3.3.3:  changed contraception measures application 
from 60 days to 90 days. Sperm donation is not 
allowed until at least 90 days after IMP 
administration
Rationale for change
Changes based on the recommend by EC
Local tolerability assessment updating


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11.2
GLOBAL AMENDMENT 2
Date of amendment
20 Oct 2021
EudraCT number
EU number
2021-003281-13
BI Trial number
1450-0002
BI Investigational Medicinal 
Product(s)
BI 765080
Title of protocol
Absolute bioavailability, safety, tolerability, and 
pharmacodynamics following subcutaneous (SC) 
injection of 100 mg BI 765080 relative to 
intravenous (IV) dose in healthy male subjects
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
6.1    Visit schedule
10.1  Reconstitution instructions
Description of change
6.1:  PD added to have it consistence with PK
10.1: Inserted the priming of the needles for sc 
injection to take the void volume into account.
Rationale for change
Minor editorial changes.
Clarification and correction.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c35408932
3.0
clinical-trial-protocol-version-03
Absolute bioavailability, safety, tolerability, and pharmacodynamics following
subcutaneous (SC) injection of 100 mg BI 765080 relative to intravenous (IV) dose
in healthy male subjects
Approval-Clinical Trial Leader
20 Oct 2021 15:01 CEST
Author-Trial Statistician
20 Oct 2021 17:18 CEST
Approval-Team Member Medicine
21 Oct 2021 01:55 CEST
Verification-Paper Signature
Completion
21 Oct 2021 09:20 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c35408932
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c38232923-01
BI Trial No.:
1450-0002
Title:
Absolute bioavailability, safety, tolerability, and pharmacodynamics 
following subcutaneous (SC) injection of 100 mg BI 765080 relative 
to intravenous (IV) dose in healthy male subjects
Including Protocol Amendment 2 [c35408932-03]
Investigational
Product:
BI 765080
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
08-Apr-2022 SIGNED
Version:
1
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TSAP for BI Trial No: 1450-0002
c38232923-01
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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 ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................12
6.5
POOLING OF CENTRES .................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................13
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................14
7.
PLANNED ANALYSIS......................................................................................15
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........16
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................16
7.3
TREATMENT COMPLIANCE........................................................................16
7.4
PRIMARY ENDPOINTS...................................................................................16
7.4.1
Primary analysis of the primary endpoints......................................................16
7.5
SECONDARY ENDPOINTS.............................................................................18
7.5.1
Key secondary endpoints....................................................................................18
7.5.2
Secondary endpoints...........................................................................................18
7.5.2.1
Secondary endpoint analysis.................................................................................18
7.6.1
Safety parameters ...............................................................................................18


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7.7
EXTENT OF EXPOSURE.................................................................................19
7.8
SAFETY ANALYSIS..........................................................................................19
7.8.1
Adverse Events ....................................................................................................19
7.8.2
Laboratory data ..................................................................................................20
7.8.3
Vital signs.............................................................................................................21
7.8.4
ECG......................................................................................................................21
7.8.5
Local tolerability .................................................................................................21
7.8.6
Others...................................................................................................................22
7.8.6.1
Physical examination ............................................................................................22
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............23
9.
REFERENCES....................................................................................................24
10.
ADDITIONAL SECTIONS ...............................................................................25
11.
HISTORY TABLE..............................................................................................26


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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 and vital signs .......................................................11
Table 6.3: 1
Subject sets analyzed........................................................................................13
Table 11: 1
History table .....................................................................................................26


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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
AUC0-tz
Area under the concentration-time curve of the analyte in serum over the 
time interval from 0 to the last quantifiable data point
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
gCV
geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
IPD
Important protocol deviations
MedDRA
Medical Dictionary For Regulatory Activities
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter analysis set
RAGe
Report appendix generator
RPM
Report Planning Meeting
SAE
Serious adverse event
SD
Standard Deviation
SOC
System Organ Class
TS
Treated set
TSAP
Trial Statistical Analysis Plan


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Term
Definition / description
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, by 
), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version Phoenix 8.1, 
).


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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.
In this trial, PK 
 are measured in serum. However, at some places in the CTP 
‘plasma’ was written where actually it should be ‘serum’, e.g. in the definition of PK 
endpoints. 
In this TSAP these passages were corrected, i.e. ‘plasma’ was replaced by ‘serum’.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Primary endpoints are PK endpoints of BI 765080, as defined in Section 2.1.2. of the CTP: 

AUC0-tz (area under the concentration-time curve of the analyte in serum over the time 
interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in serum)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
Secondary PK endpoint of BI 765080, is 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)
Secondary endpoint for assessment of safety and tolerability of BI 765080 is the occurrence
(absolute number and percentage) of drug-related adverse events.
5.3.1
Safety parameters
Safety and tolerability of BI 765080 will be assessed based on further safety parameters 
defined in Section 2.2.2.2 of the CTP:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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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 100 mg BI 765080 either as 

subcutaneous injection as bolus (Test Treatment T)
or as

30 minute intravenous infusion (Reference Treatment R)
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 and vital signs
Study analysis phase
Label
Start
End
Screening1
Screening
Date of informed consent
Date/time of start of 
administration of study drug
On-treatment
BI SC or 
BI IV
Date/time of start of 
administration of study drug
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), the following total will 
be provided in addition: 

"Total", defined as the total over on-treatment phases BI injection and BI infusion
Safety laboratory data, vital signs and PK
parameters will be analysed based on 
treatment groups 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.


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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 also be summarised and 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.


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Table 6.3: 1
Subject sets analyzed
Subject set
Class of endpoint
TS
PKS  
Disposition
X
iPDs
X
Primary PK endpoints
X
Secondary PK endpoint
X
Secondary Safety endpoint
X
Safety parameters 
X
Local tolerability 
X
Demographic/baseline characteristics
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
CTP: “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 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).
Missing data and outliers of PK 
 data are handled according to BI standards (4) and 
(5).


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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, baseline is defined as the last available value prior to start of 
infusion/injection.


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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, 
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 study drug, 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 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
The analysis of primary endpoints will be based on the PKS.
CTP: The statistical model used for the analysis of the primary endpoints will be an analysis 
of variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following source of variation: treatment and matching pair. The 
effect of treatment will be considered as fixed. For each matched pair in the study a pair 
number will be assigned for analysis purpose. The resulting variable ‘matched pair’ will be 
considered as random effect. The model is described by the following equation:
ykm
= + k+ sm+ ekm, where
ykm
= logarithm of response measured on subject m receiving treatment k


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
= the overall mean,
k
= the kth treatment effect, k = 1, 2,
sm
= the effect associated with the mth matching pair, m = 1, 2,…, 14,
ekm
= the random error associated with the mth subject who received treatment k. 
where s ~ N(0,σB2) i.i.d., e ~ N(0, σW2 ) i.i.d., σW2 and sm , ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided. 
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means).
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
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 serum/urine 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) and “Description of Analytical Transfer Files and PK/PD 
Data Files” (5).


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
7.5.2.1
Secondary endpoint analysis
CTP: The secondary PK endpoints (refer to Section 2.1.3) will be calculated according to the 
BI SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ and will be assessed statistically using the same 
methods as described for the primary endpoints.
Drug-related adverse event will be presented descriptively by treatment group.
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
Only listings are planned for this section of the report.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
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: A potential severe Drug Induced Liver Injury (DILI) is considered an AESI in this trial. 
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up 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 in samples drawn within 30 days of each other, 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 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).
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. 


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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 in Section 15.4.1.
Clinically relevant findings in laboratory data will be reported as baseline conditions (prior to 
start of administration of study treatment) or as AEs (after start of administration of study
treatment) 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, 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 (i.e., they will be assigned to the previous planned 
time point). 
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). This is based on 
the assumption, that the last value is a repeat measurement due to quality reasons and is 
therefore more reliable than the first measurement. The assumption of a repeat measurement 
due to quality reasons is only plausible if the unscheduled measurement is shortly after the 
scheduled measurement. In order to assess the time difference (during data validation and 
Report Planning Meeting), the date and clock time of both measurements has to be available. 
If the time of measurement is missing for a scheduled or unscheduled post-baseline 
measurement (or both), the scheduled measurement will be used in calculation of descriptive 
statistics (since it cannot be assessed whether the assumption of a repeat measurement for 
quality reasons is plausible, or not). All measurements will be listed.
Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to 
start of administration of study treatment) or as AEs (after start of administration of study
treatment) if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.4
ECG
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during 
the trial) if judged clinically relevant by the investigator and will be analyzed as such.
No separate listing or analysis of ECG data will be prepared.
7.8.5
Local tolerability
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.


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7.8.6
Others
7.8.6.1
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(if a condition already exists before start of administration of study treatment) or as AE (if 
condition emerges after start of administration of study treatment) and will be summarized as 
such. No separate listing or analysis of physical examination findings will be prepared.


Boehringer Ingelheim
TSAP for BI Trial No: 1450-0002
c38232923-01
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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION 
The treatment information will be loaded into the trial database after completion of 
enrolment, i.e. the randomization has been completed.


Boehringer Ingelheim
TSAP for BI Trial No: 1450-0002
c38232923-01
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9.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note For Guidance on Design, Conduct, Analysis and Evaluation of 
Clinical Trials, current version
2
BI-VQD-12045_40-413: "Identify and Manage Important Protocol Deviations 
(iPD)", current version; KMED
3
KM Asset BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE 
dates", current version; KMED
4
KM Asset BI-KMED-TMCP-MAN -0014: "Noncompartmental PK/PD Analyses of 
Clinical Studies", current version; KMED
5
KM Asset BI-KMED-TMCP-MAN-0010: "Description of Analytical Transfer Files, 
PK/PD Data Files and ADA files", current version; KMED
6
KM Asset BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials 
and Project Summaries", current version; KMED
7
KM Asset BI-KMED-BDS-HTG-0066: "Analysis and Presentation of Adverse 
Event Data from Clinical Trials", current version; KMED
8
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
9
KM Asset BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of 
Laboratory Data", current version; KMED


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10.
ADDITIONAL SECTIONS
Not applicable as no additional information is needed. 


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TSAP for BI Trial No: 1450-0002
c38232923-01
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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1
08-APR-22
None
This is the final TSAP