Clinical trial NCT04424290
Conditions: Diabetic Retinopathy
Sponsor: Boehringer Ingelheim
Start date: 2020-06-12; Completion date: 2023-04-28
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study in people with a type of diabetic eye disease called diabetic retinopathy with diabetic macular ischemia. People who have had laser treatment for their diabetic retinopathy can participate in the study. The laser treatment is called panretinal photocoagulation.

The purpose of the study is to find out how well different doses of a medicine called BI 764524 are tolerated. BI 764524 is injected into the eye. The study has 2 parts. In the first part, participants get different doses of BI 764524 only once. Participants are in the first part for about 5 months and visit the study site about 8 times. In the second part, participants are put into different groups by chance. Some participants get BI 764524 injections every 4 weeks. Other participants get sham injections every 4 weeks. A sham injection means that it is not a real injection and contains no medicine. Participants cannot tell whether they get the real injection or a sham injection. For the second part, participants are in the study for about 7 months. During this time, they visit the study site about 7 times. In this study, BI 764524 is given to humans for the first time.

The doctors compare how well people tolerate the BI 764524 injections and the sham injections.

The doctors also regularly check the general health of the participants.

Detailed description:

Arms: arm 1: Pan-retinal photocoagulation (PRP)-treated proliferative diabetic retinopathy (PDR) patients with diabetic macular ischaemia (DMI) received one intravitreal injection of low dose BI 764524. arm 2: Pan-retinal photocoagulation (PRP)-treated proliferative diabetic retinopathy (PDR) patients with diabetic macular ischaemia (DMI) received one intravitreal injection of medium dose BI 764524. arm 3: Pan-retinal photocoagulation (PRP)-treated proliferative diabetic retinopathy (PDR) patients with diabetic macular ischaemia (DMI) received one intravitreal injection of high dose BI 764524. arm 4: Pan-retinal photocoagulation (PRP)-treated proliferative diabetic retinopathy (PDR) patients with diabetic macular ischaemia (DMI) received three sham intravitreal injections, each separated by 4 weeks. arm 5: Pan-retinal photocoagulation (PRP)-treated proliferative diabetic retinopathy (PDR) patients with diabetic macular ischaemia (DMI) received three intravitreal injections of high dose BI 764524, each separated by 4 weeks.
Interventions: intervention 1: BI 764524 intervention 2: Sham control of BI 764524
Intervention descriptions: intervention 1: BI 764524 intervention 2: Sham control of BI 764524

Protocol documents:
Prot_000.pdf: 




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Trial objectives
The objective of this trial is to determine the maximum feasible dose 
(MFD) for further development of BI 764524 in patients with pan-
retinal coagulation treated proliferative diabetic retinopathy (PDR) 
patients with diabetic macular ischemia (DMI) based on the primary 
endpoint occurrence of dose limiting events (DLE) during MFD 
evaluation period of 7 days (single rising dose (SRD)) or 28 days 
after last administration (multiple dosing (MD)) and to investigate 
the safety, tolerability and early biological response after IVT 
injections of BI 764524.


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Trial endpoints
Primary endpoint
SRD part:
!
number of patients with dose limiting events (DLEs) from 
drug administration till day 8 (7 days after treatment).
MD part:
!
number of patients with drug related adverse events (AEs)
from drug administration till end of study (EOS)
Secondary endpoints:
SRD part:
!
number of patients with drug related AEs at EOS
!
number of patients with ocular AEs (eye disorders) at EOS
MD part:
!
change from baseline of the size of the foveal avascular zone
(FAZ) in optical coherence tomography angiography 
(OCTA) in superficial and combined vascular complex at 
Visit 5 
!
change from baseline of the size of the FAZ in optical 
coherence tomography angiography (OCTA) in superficial 
and combined vascular complex at Visit 7
!
change from baseline of BCVA (best corrected visual acuity)
at Visit 3
!
change from baseline of BCVA at Visit 4
!
change from baseline of BCVA at Visit 5
!
change from baseline of BCVA at Visit 6
!
change from baseline of BCVA at Visit 7
!
change from baseline of Central retinal thickness (SD-OCT) 
at Visit 3
!
change from baseline of Central retinal thickness (SD-OCT) 
at Visit 4
!
change from baseline of Central retinal thickness (SD-OCT) 
at Visit 5
!
change from baseline of Central retinal thickness (SD-OCT) 
at Visit 6
!
change from baseline of Central retinal thickness (SD-OCT) 
at Visit 7
!
number of patients with ocular AEs (eye disorders) at EOS
Trial design
This trial will consist of an SRD part followed by an MD part. SRD 
part will be non-randomized, open-label, and uncontrolled. MD part 
will be single-masked, randomized and sham-controlled (ratio 2:1).


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Number of patients
Approximately 45 patients in total
total entered 
each treatment
Up to 15 patients in the SRD part (depending on the dose escalation) 
and 30 patients in the MD part.
Diagnosis
Pan-retinal photocoagulation (PRP) treated proliferative diabetic 
retinopathy (PDR) in patients with diabetic macular ischemia (DMI)
Main criteria
for inclusion
Patients to be included are pan-retinal photo coagulation (PRP) 
treated proliferative diabetic retinopathy (PDR) patients with 
diabetic macular ischemia (DMI)
Test product
BI 764524, powder for solution for injection
dose
SRD part: 
, 
and
 (single doses)
MD part: The highest dose (e.g.
) (q4w) established as safe 
and tolerable during the SRD part
mode of admin. Intravitreal
Comparator 
product
Not applicable
dose
Not applicable
mode of admin. Not applicable
Duration of 
treatment
SRD part: single intravitreal dose
MD part: 3 intravitreal doses in 4-weekly intervals (q4w)
Statistical methods
Descriptive statistics will be provided for all endpoints.


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FLOW CHART I (SINGLE RISING DOSE PART)
Trial Periods
Screening 
Period
Treat-
ment 
Visit
Follow-up period
End of 
study
Visit
1
2
3
4
5
6
7
8
Study Days
Study Weeks
Duration 3 
to 28 days
Day 1
4
8
Week 1
15
Week 2
29
Week 4
57
Week 8
99
Week 14
Time window for visits 
(days)
none
±1
±2
±2
±3
±7
±7
Informed consent
X
Demographics
X
Medical history
X
Physical examination
(including weight)
X
X(1)
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Laboratory tests
X
X
X
X
X
X
X
12 lead-ECG(2)
X
X
X
X
X
X
Review of in-/exclusion 
criteria
X
X
Dose Assignment
X
IVT drug administration
X
Pregnancy test(3)
XS
Xs
XU
XU
XU
XU
XU
PK Sampling(4)
X
X
X
X
X
X
X
X
X
X
X
BCVA testing
X
X
X
X
X
X
X
X
SD-OCT
X
X
X
X
X
X
X
X
OCT Angiography
X
X
X
X
X
X
X
X
Fundus Photo
X
X
X
X
X
X
X
Slit lamp and intra-ocular 
pressure (IOP)
X
X
X
X
X
X
X
X
All AEs/SAEs/AESIs
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
Completion of patient 
participation (5)
X
(1)
Could be repeated as deemed necessary at investigator´s discretion.


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(2)
See Section 5.2.5; the ECGs are to be recorded shortly before the PK sampling at the respective time points, see 
Appendix 10.1
(3)
Pregnancy testing: serum pregnancy test (XS) is done at screening and on day 1 if more than a week elapsed 
between screening and day 1, and at the other visits as a reflex when urine testing (XU) is positive.
(4)
See separate flow chart for PK and 
 sampling (Appendix 10.1). 
(5)
Completion of patient participation also needs to be completed if the patient withdraws prematurely following 
assignment to dose level (see Section 3.3.4)


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FLOW CHART II (MULTIPLE DOSING PART)
Trial Periods
Screening 
Period
Treatment Period
Follow-up Period
End of 
Study
Visit
1(1)
2
3
4
5
6
7
Study Day/ 
Week
Duration 3 
to 28 days
1
29
Week 4
57
Week 8
85
Week 12
113
Week 16
155
Week 22
Time window for visits (days)
none
±3
±3
±7
±7
±7
Informed consent
X
Informed consent Aqueous 
sampling (optional)
X
Demographics
X
Medical history
X
Physical examination
(including weight)
X
X
Vital signs
X
X
X
X
X
X
X
Laboratory tests
X
X
X
X
X
X
X
12 lead-ECG(2)
X
X
X
X
X
Review of in-/exclusion 
criteria
X
X
Dose Assignment
X
Randomization
X
IVT drug administration/Sham 
injection
X
X
X
Pregnancy test(3)
XS
XS
XU
XU
XU
XU
XU
X
X
X
PK Sampling(4)
X
X
X
X
X
X
Optional Aqueous sampling(4)
X
X
X
X
BCVA testing
X
X
X
X
X
X
X
SD-OCT
X
X
X
X
X
X
X
OCT Angiography
X
X
X
X
X
X
X
Fundus Photo
X
X
X
X
X
X
X
Slit lamp and intra-ocular 
pressure (IOP)
X
X
X
X
X
X
X
X
X
X
X
X
X
All AEs/SAEs/AESIs
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
Completion of patient 
participation (5)
X


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(1)
Screening visit should be performed in two visits. After Informed consent is obtained, visual acuity testing, SD-
OCT, OCT Angiography and fundus photography should be performed and sent to central reading service. If 
patient is eligible based on the results from the reading centre, the patient should return to complete the rest of the 
screening. In case of scheduling difficulty for certain patients, screening can be performed in one visit. If screening 
is done as one visit, fundus photography should be performed in line with other ophthalmological examinations.
(2)
See Section 5.2.5; the ECGs are to be recorded shortly before the PK sampling at the respective time points: 
Appendix 10.1
(3)
Pregnancy testing: serum pregnancy test (XS) is done at screening and on day 1 if more than a week elapsed 
between screening and day 1, and at the other visits as a reflex when urine testing (XU) is positive.
(4)
See separate flow chart for PK,
 and aqueous sampling (Appendix 10.1)
(5)
Completion of patient participation also needs to be completed if the patient withdraws prematurely following 
assignment to dose level (see Section 3.3.4)


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART I (SINGLE RISING DOSE PART) ......................................6
FLOW CHART II (MULTIPLE DOSING PART).........................................8
TABLE OF CONTENTS ................................................................................ 10
ABBREVIATIONS.......................................................................................... 14
1.
INTRODUCTION.................................................................................... 18
1.1
MEDICAL BACKGROUND............................................................................18
1.2
DRUG PROFILE...............................................................................................19
Residual Effect Period..........................................................................20
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................21
1.4
BENEFIT - RISK ASSESSMENT ...................................................................21
Benefits...................................................................................................21
Risks .......................................................................................................22
Available data from pre-clinical toxicity studies.....................24
IVT administration of BI 764524..............................24
Immunogenic response in pre-clinical studies ..........24
Risks related to intravitreal injection.......................................24
Risks related to blood sampling...............................................25
Planned measures for monitoring the risks..............................25
Drug induced liver injury.........................................................26
Discussion...............................................................................................26
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 27
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......27
Main objectives......................................................................................27
Primary endpoint..................................................................................27
Secondary endpoint ..............................................................................27
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 30
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................32
3.3
SELECTION OF TRIAL POPULATION ......................................................33
Main diagnosis for trial entry..............................................................33
Inclusion criteria...................................................................................34
Exclusion criteria ..................................................................................35


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Withdrawal of patients from treatment or assessments....................37
Withdrawal from trial treatment ..............................................37
Withdrawal of consent to trial participation ............................38
Discontinuation of the trial by the sponsor..............................38
Replacement of patients .......................................................................38
4.
TREATMENTS........................................................................................ 40
4.1
INVESTIGATIONAL TREATMENTS ..........................................................40
Identity of the Investigational Medicinal Products ...........................40
Selection of doses in the trial and dose modification .........................40
Method of assigning patients to treatment groups ............................41
Drug assignment and administration of doses for each patient .......42
Intravitreal Injection Technique and Sham Injection.......................43
Masking and procedures for unmasking............................................43
Masking ...................................................................................43
Unmasking and breaking the code...........................................44
Packaging, labelling, and re-supply ....................................................44
Storage conditions.................................................................................44
Drug accountability ..............................................................................45
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................45
Other treatments and emergency procedures....................................45
Restrictions............................................................................................45
Restrictions regarding concomitant treatment .........................45
Restrictions on diet and lifestyle..............................................46
Contraception requirements.....................................................46
Restrictions regarding gamete donation...................................46
4.3
TREATMENT COMPLIANCE.......................................................................47
5.
ASSESSMENTS....................................................................................... 48
5.1
ASSESSMENT OF EFFICACY.......................................................................48
5.2
ASSESSMENT OF SAFETY............................................................................49
Dose limiting event................................................................................49
Physical examination ............................................................................49
Vital signs...............................................................................................50
Safety laboratory parameters..............................................................50
Electrocardiogram................................................................................52
12-lead resting ECG.................................................................52
Other safety parameters.......................................................................54
Assessment of adverse events...............................................................54
Definitions of adverse events...................................................54


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Adverse event ............................................................54
Serious adverse event ................................................54
AEs considered ‘Always Serious’.............................55
Adverse events of special interest .............................55
Intensity (severity) of AEs.........................................56
Causal relationship of AEs ........................................56
Adverse event collection and reporting ...................................57
AE collection.............................................................57
AE reporting to the sponsor and timelines ................57
Pregnancy ..................................................................58
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................58
Assessment of pharmacokinetics .........................................................58
Methods of sample collection...............................................................58
Blood sampling for pharmacokinetic analysis.........................58
Pharmacokinetic - pharmacodynamic relationship...........................59
5.5
BIOBANKING ...................................................................................................60
5.6
OTHER ASSESSMENTS .................................................................................60
Pharmacogenomic evaluation..............................................................60
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................60
6.
INVESTIGATIONAL PLAN.................................................................. 61
6.1
VISIT SCHEDULE............................................................................................61
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................61
Screening and run-in period(s)............................................................61
Treatment period(s)..............................................................................62
Follow-up period and trial completion ...............................................62
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 64
7.1
STATISTICAL DESIGN – MODEL ...............................................................64
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................67
7.3
PLANNED ANALYSES....................................................................................67
Primary endpoint analyses...................................................................68
Secondary endpoint analyses ...............................................................68
Safety analyses.......................................................................................69


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Pharmacokinetic - pharmacodynamic analysis..................................70
7.4
INTERIM ANALYSES .....................................................................................71
7.5
HANDLING OF MISSING DATA ..................................................................71
Safety......................................................................................................71
Pharmacokinetics..................................................................................71
Efficacy...................................................................................................71
7.6
RANDOMISATION ..........................................................................................72
7.7
DETERMINATION OF SAMPLE SIZE ........................................................72
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 74
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ..........................................................................................................74
8.2
DATA QUALITY ASSURANCE .....................................................................75
8.3
RECORDS..........................................................................................................75
Source documents .................................................................................75
Direct access to source data and documents.......................................76
Storage period of records.....................................................................77
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................77
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY.......77
8.6
TRIAL MILESTONES .....................................................................................77
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................78
9.
REFERENCES......................................................................................... 80
9.1
PUBLISHED REFERENCES...........................................................................80
9.2
UNPUBLISHED REFERENCES.....................................................................81
10. APPENDICES .......................................................................................... 82
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) AND ADA 
BLOOD SAMPLING AND AQUEOUS SAMPLING....................................82
10.2
STATISTICAL APPENDIX.............................................................................84
10.3
BENEFIT-RISK ASSESSMENT IN CONTEXT OF COVID-19 
PANDEMIC FOR PATIENTS PARTICIPATING IN TRIAL 1436-0001 
INVESTIGATING BI 764524...........................................................................89
11. DESCRIPTION OF GLOBAL AMENDMENTS................................. 91
11.1
GLOBAL AMENDMENT 1 .............................................................................91
11.2
GLOBAL AMENDMENT 2 .............................................................................94
11.3
GLOBAL AMENDMENT 3 ...........................................................................100
11.4
GLOBAL AMENDMENT 4 ...........................................................................101
11.5
GLOBAL AMENDMENT 5 ...........................................................................103


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ABBREVIATIONS
ADCC
Antibody-dependent cellular cytotoxicity
AE
Adverse event
AESI
Adverse events of special interest
ALCOA
Attributable, legible, contemporaneous, original and accurate
AUC
Area under the curve
AUC0-∞
Area under the concentration-time curve of the analyte in serum over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUCt1-t2
Area under the concentration-time curve of the analyte in serum over the 
time interval t1 to t2
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
BA
Bioavailability
BCVA
Best corrected visual acuity
BI
Boehringer Ingelheim
BIPI
Boehringer Ingelheim Pharmaceuticals Inc.
BLRM
Bayesian logistic regression model
BP
Blood pressure
CA
Competent authority
CDC
Copper diethyldithiocabamate
CDISC
Clinical Data Interchange Standards Consortium 
CI
Confidence interval
CL/F
Apparent clearance of the analyte in serum after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in serum
CTM
Clinical Trial Manager
CRA
Clinical Research Associate
CRC
Central Reading Center
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CRO
Contract Research Organisation
CST
Central subfield thickness
CT
Clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver injury


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DLE
Dose limiting event
DME
Diabetic macular edema
DMI
Diabetic macular ischemia
DNA
Deoxyribonucleic acid
DR
Diabetic retinopathy
DRIL
Disorganisation of retinal inner layer
ECG
Electrocardiogram
EMA
European Medicines Agency
eCRF
Electronic case report form
eDC
Electronic data capture
EOS
End of study
ETDRS
Early treatment diabetic retinopathy study
EudraCT
European Clinical Trials Database
EWOC
Escalation with overdose control
F
Absolute bioavailability factor
FA
Fluorescein angiography
FAZ
Foveal avascular zone
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
gMean
Geometric mean
GMP
Good Manufacturing Practice
HCG
Human chorionic gonadotropin
HR
Heart rate
IB
ICF
Investigator’s brochure
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IOP
Intra-ocular pressure
IPD
Important protocol deviation
IQRMP
Integrated Quality and Risk Management Plan
IRB
Institutional Review Board
IRT
Interactive response technology
ISF
Investigator site file
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVT
Intravitreal


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∀z
Terminal rate constant of the analyte in serum
LPLT
Last patient last treatment
MedDRA
Medical Dictionary for Regulatory Activities
MoA
Mode of Action
MD
Multiple dosing
MRT,ex
Mean residence time of the analyte in the body, extravascular
MFD
Maximum feasible dose
NOAEL
No observed adverse effect level
OCT
Optical coherent tomography
OCTA
Optical coherent tomography angiography
OIR
Oxygen induced retinopathy
OPU
Operative unit
PD
Pharmacodynamic(s)
PDR
Proliferative diabetic retinopathy
PE
Polyethylene
PfOS
Powder for reconstitution of an oral solution
PIB
Powder in the bottle
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
PRP
Panretinal photocoagulation
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
RR
Respiratory rate
SAE
Serious adverse event
SCR
Screening
SD-OCT
Spectral domain optical coherence tomography
SMC
Safety monitoring committee
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
SUN
Standardization of Uveitis Nomenclature


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SUSAR
SVC
Suspected unexpected serious adverse reaction
Superficial vascular complex
T
Test product or treatment
t∀z,start(end)
Lower (upper) limit on time for values to be included in the calculation of 
∀z
TMF
Trial master file
t1/2
Terminal half-life of the analyte in serum
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in serum
tmax(,N)
Time from (last) dosing to the maximum measured concentration of the 
analyte in serum (after administration of N doses)
TS
Treated set
TSAP
Trial statistical analysis plan
tz
Time of last measurable concentration of the analyte in serum
ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
VA
Visual Acuity
VEGF
Vascular endothelial growth factor
WG
Working group
WOCBP
Women of childbearing potential
YAG
Yttrium aluminum garnet


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Diabetic retinopathy can cause visual loss in a number of ways. Microvascular changes due 
to hyperglycemia lead to increases in permeability, thus extravascular exudation and fluid 
accumulation in the macula (diabetic macular edema, DME). Similarly, alterations of micro-
vessels can lead to retinal non-perfusion and ischemia. The consequent dramatic increase of 
vascular endothelial growth factor (VEGF) drives the formation of retinal new vessels 
(proliferative diabetic retinopathy, PDR), that can eventually bleed, with a sudden decrease in 
vision (vitreous hemorrhage). In both conditions, VEGF plays a fundamental role, and in fact 
anti-VEGF agents are effective in improving both DME and PDR. In PDR, pan-retinal 
photocoagulation (PRP) is the current standard of care. PRP aims to destroy the ischemic 
retina, which is the major source of VEGF, thus it is effective in prevention and / or 
regression of the formation of new vessels. 
In some patients, however, even in the absence of DME, after successful treatment with PRP 
with no evidence of active new vessels, the visual acuity continues to decrease.
Some reports have suggested that a possible explanation might be the spreading of ischemia 
in the central part of the retina, the macula. In this condition, called diabetic macular ischemia 
(DMI), the retinal tissue may not receive enough nutrients leading to retinal tissue loss and 
permanent and irreversible vision loss. In DMI, anti-VEGF therapy is not effective, and 
destructive laser photocoagulation cannot be applied. 
Previously, DMI was observed and diagnosed by means of fluorescein angiography (FA) 
using an intravenous dye. It was defined as an abnormal enlargement of the physiologic 
foveal avascular zone (FAZ). In patients with diabetic retinopathy, FA might show an 
abnormal enlargement of the FAZ, which is the most common definition of DMI. Recently, 
optical coherent tomography angiography (OCTA) has emerged which can visualize the 
retinal blood vessels and hence ischemia in greater detail. OCTA is non-invasive and multiple 
levels of the capillary plexus can be visualised. OCTA is able to measure the area of the FAZ. 
Moreover, it was found that the FAZ measured by FA corresponds well with the superficial 
retinal plexus recorded by OCTA (R17-3317). For these reasons OCTA is likely to become 
the gold standard in the diagnosis and monitoring of DMI. 
There is a large list of unknowns related to DMI. Since this condition is associated with a 
progressive loss of neural tissue, it can be hypothesized that restoration of the macular 
vasculature before retinal degeneration occurs could be a key objective for these patients and 
prevent permanent vision loss. There are currently no treatments available for DMI making it 
an urgent unmet need.


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1.2
DRUG PROFILE




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1.3
RATIONALE FOR PERFORMING THE TRIAL
Diabetic macular Ischemia (DMI) is a chronic complication of diabetic retinopathy (DR) and 
can potentially lead to visual functional loss. Currently, there are no approved or effective 
treatments to prevent either onset or progression of DMI in laser-treated PDR patients.
As a transition from preclinical investigations to clinical development in this first-in human
trial, safety, tolerability and early biological response of BI 764524 will be assessed in DMI 
volunteer patients
This trial will include patients affected by DMI with significant visual loss since intravitreal
(IVT) injections in patients without the condition would not be considered ethically 
justifiable. 
This trial will consist of a single rising dose (SRD) part and a multiple dosing (MD) part. 
In the SRD part of the trial, 3 rising doses (at least 3 evaluable patients per dose cohort) are 
planned to be intravitreally administered. Within each dose cohort, all patients will receive 
the same BI 764524 dose. The next higher dose will only be administered, if the treatment in 
the preceding dose cohort was safe and showed acceptable tolerability. 
In the MD part, patients will be randomized to receive either active treatment or sham 
injection: 20 patients on active treatment and 10 patients on sham injection over a 22-week 
period. After an initial active treatment period of 12 weeks (3 injections/sham injections in 
4 weekly intervals) patients will be followed up for an additional 10 weeks without further 
injections to study the treatment effect. This might also help to guide injection frequency 
intervals in later studies.
The MD part of the trial will provide information about the early biological response of BI 
764524 by comparing the treated groups to the sham arm.
1.4
BENEFIT - RISK ASSESSMENT
Benefits
DMI is a progressive disease and patients will have irreversible retinal damage if DMI is 
present for a long time. Degeneration of retinal tissue in the macula leads to permanent visual 
impairment. There is no approved treatment for this disease. 
Even though pre-clinical data shows that BI 764524 can improve retinal vascularization, 
because of the long duration of the pathology of DMI, long-term benefit for the patients 
entered in this trial is unlikely. Their participation in this trial, however, is of major 
importance to the development of BI 764524 to determine a safe dose selection for further 
clinical trials in this pre-selected patient population.


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Because this is the First-in-human trial with BI 764524, special attention will be applied to 
ensure the highest level of safety for patients selecting the starting dose, the dose escalation 
steps and the highest dose applied (see Section 4.1.2). 
Risks
BI 764524 has not previously been tested in humans, but based on the pre-clinical toxicology 
studies, no specific adverse events are expected. Patients in this trial are exposed to risks of 
trial procedures and risks related to ophthalmic and systemic exposure to the trial medication.
Similar to other intravitreal biologic therapies, there is a risk of ocular inflammation, 
however, this is usually mild and reversible. Patients will be monitored for ocular 
inflammation and treated if deemed appropriate by the investigator. Because of the low 
dosage used in intravitreal BI 764524, the systemic exposure is expected to be very low and 
hence unlikely to have significant effect as with intravitreal anti-VEGF therapies.
In a subset of patients, an optional sampling of the aqueous humor will be performed at 
baseline and at visits 4, 6 and 7 in the MD part. This is known as an ‘anterior chamber tap’ 
and requires insertion of a 30 gauge needle into the anterior chamber of the eye under topical 
anesthesia to remove a small amount (0.1ml) of aqueous fluid. An assay will measure the 
quantity of 
 in the aqueous and the results will improve our understanding of the 
ocular PK/PD of BI 764524. 


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Table 1.4.2: 1 Overview of trial related risks
Possible or known risks of clinical 
relevance for this trial 
Summary of data, rationale for the risk 
Mitigation strategy 
Investigational Medicinal Product BI 764524
Intraocular inflammation
Immunogenic response
Drug-induced liver injury (DILI) 
IVT administration of BI 764524 in 
cynomolgus monkeys showed signs of 
intraocular inflammation (See IB 
chapter 5.3) in some animals. These 
findings had no impact on ophthalmic 
function (i.e. ERG) and was not 
associated with any histopathological 
changes and resolved during the 
recovery phase.  
No ADA response was observed in the 
13-week IVT toxicity study. However, 
because this trial is the FIH application 
of BI 764524, potential immunogenic 
response can occur
This trial is FIH application of BI 
764524, and even if the expected 
systemic exposure is anticipated to be 
low, any possible effect on liver 
function needs to be addressed
At each visit a complete 
ophthalmic examination will be 
performed to detect early signs 
of intraocular inflammation 
(see chapter 1.4.1.4)
ADA in serum will be 
evaluated at day 1 and 99 in 
SRD, and at day 1 and 85 in 
MD
Lab tests will be performed at 
each visit (except day 4 in 
SRD)
Trial procedures
Risks related to IVT injection 
Risks related to blood sampling
Clinical trials assessing efficacy and 
safety in marketed drugs administered 
via IVT injection showed a low rate of 
complications associated with IVT 
injection procedure (<0.1%, including 
endophthalmitis, traumatic cataract, 
and increased intraocular pressure). 
Because the procedure of intravitreal 
injection of BI 764524 is the same (use 
of a filter needle to extract product 
from the vial and same needle size for 
injection, 30 gauge), the expected 
adverse events related to the procedure 
are considered equal to what was 
observed with marketed drugs
Blood sampling may be accompanied 
by mild bruising and also in rare cases, 
by transient inflammation of the wall 
of the vein. In addition, in rare cases a 
nerve might be injured while inserting 
the venous catheter, potentially 
resulting in paraesthesia, reduced 
sensibility, and/or pain for an indefinite 
period.
At each visit a complete 
ophthalmic examination will be 
performed to detect early signs 
of complications. Intra-ocular 
pressure (IOP) will be 
measured at each visit.
The total volume of blood 
withdrawn during the entire 
study per patient will not 
exceed the volume of appr. 500 
mL.
Risks related to Anterior Chamber 
tap
Corneal abrasion, cataract formation, 
infection, iris and lens trauma
Only experienced physicians 
will undertake the procedure


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Available data from pre-clinical toxicity studies
IVT administration of BI 764524
Immunogenic response in pre-clinical studies
Risks related to intravitreal injection
Intravitreal injections may have potentially serious adverse events, but these are considered 
rare: clinical trials assessing efficacy and safety of EYLEA® intravitreal injections showed 
serious adverse reactions related to the injection procedure in <0.1%, including 
endophthalmitis, traumatic cataract, and increased intraocular pressure 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.pdf). Because the 
procedure of intravitreal injection of BI 764524 is the same (use of a filter needle to extract 
product from the vial and same needle size for injection, 30 gauge), the expected adverse 
events related to the procedure are considered equal to what was observed with marketed 
drugs (e.g. EYLEA®).


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BI recommends the use of material for intraocular drug delivery, which is according to 
standard medical practice. This material is not officially approved for intraocular drug 
delivery, with associated potential risks. Long-term experience as standard of medical care 
suggest a favourable risk-benefit profile. To the best of the sponsor´s knowledge there is 
currently no product on the market, which is officially approved for intravitreal drug delivery.
The needles for preparation of the drug and intravitreal injection are usually silicone oil 
coated to ease the injection of the needle through the tissue. This carries the potential risk for 
a silicone oil transfer into the vitreous with the potential risks for occurrence of side effects 
like vitreous floaters or intraocular inflammation. The overall risk for such events is based on 
long-term experience with comparable material and is considered low. However, patients 
should be made aware of this risk, as reflected in the Informed Consent Form (ICF). To the 
best of the sponsor´s knowledge there is currently no product on the market, which is 
silicone-free. The recommended syringes are silicone oil free and not considered to carry this 
risk.
The IMP handling instructions do not mandate the use of materials from certain 
manufacturers and leaves the decision to the treating investigators/sites on which materials to 
use if it meets the specifications as described in the IMP handling instructions for BI 764524.
Risks related to blood sampling
Blood sampling may be accompanied by mild bruising and also, in rare cases, by transient 
inflammation of the wall of the vein. In addition, in rare cases a nerve might be injured while 
inserting the venous catheter, potentially resulting in paraesthesia, reduced sensibility, and/or 
pain for an indefinite period.
The total volume of blood withdrawn during the entire study per patient will not exceed appr. 
500 mL. No health-related risk is expected from this blood withdrawal.
Planned measures for monitoring the risks
Patients will be evaluated with functional, imaging and systemic tests to identify any possible 
adverse event. Specifically, any signs of intraocular inflammation will be assessed by 
slitlamp examination of anterior chamber, vitreous and posterior segment of the eye, to 
identify occurrence of flare or cells in the anterior chamber, deposits of material in the 
corneal endothelium, deposits on the anterior capsule of the crystalline lens, any signs of 
vitreous haze, vitreous cells, vitreous snowbanks/snowballs, signs of intraretinal edema or 
retinal thickening, signs of perivascular inflammation e.g. vessel walls sheathing, signs of 
incipient retinitis or intraretinal haemorrhages. 
Spectral domain optical coherence tomography (SD-OCT) will be used to evaluate any 
possible occurrence of intraretinal cystic edema or perivascular reaction. The same imaging 
modality will be used to evaluate early signs of cell toxicity (e.g. increased ellipsoid zone 
disruption, granular appearance of outer retinal layers, increase in intraretinal foci 
predominantly located in the outer nuclear layers). 


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Additionally, a systemic evaluation will be performed at the time-points specified in the flow 
charts, to assess any possible systemic reaction. This will include body weight, blood 
pressure, heart rate with Electrocardiogram (ECG), full safety lab. The required assessments
will be adapted according to the pre-clinical trial results. All these evaluations will have to be 
reported immediately for evaluating any possible safety issue related to the drug or to 
inflammatory response. 
In the trial design a sentinel approach will be used in the SRD part, according to EMA and 
ICH guidelines (EMA/CHMP/SWP/28367/07 Rev.1; EMA/CHMP/ICH/731268/1998): for 
each cohort the first patient will be dosed and monitored to exclude acute AEs, before dosing 
the other patients of the same cohort (see Section 3.1). Moreover, the duration of the 
observation will reflect the expected human pharmacokinetics (PK) of BI 764524, with a 
follow-up for all patients up to 98 days, with appropriate ophthalmologic and systemic 
evaluations (see Section 3.1). 
In addition a Safety Monitoring Committee (SMC) will be established to review individual 
and aggregated safety data at regular intervals to determine the safety profile and risk/benefit 
ratio and decide on the next dose level and the next cohort size, or the appropriacy of further 
enrolment (see section 8.7).
Drug induced liver injury
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 patients´ 
safety (see also Section 5.2.7.1.4, AEs of special interest).
Discussion
Considering the data available from previous trials evaluating the same mode of action
(MoA), and data from pre-clinical studies on BI 764524, in this trial ophthalmic and systemic 
examinations are planned in all the visits. 
Blood tests and physical examination will evaluate potential changes in blood cell count and 
in any safety lab parameters, as well as in body weight and blood pressure. Ophthalmic 
physical examination will focus on the risks related to the procedure (e.g. endophthalmitis 
and retinal detachment), and the risks related to a potential immunologic response. Imaging 
and functional tests will further assess any possible signs of neurotoxicity after the 
administration of the drug.
DMI is a potentially blinding disease, with no treatment available. Given the urgent need to 
address this unmet medical need and considering the expected safety profile of BI 764524 
based on pre-clinical evaluations, it is considered acceptable to expose the patients to the trial 
risks.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
The objective of this trial is to determine the maximum feasible dose (MFD) for further 
development of BI 764524 in patients with pan retinal coagulation treated proliferative
diabetic retinopathy (PDR) patients with diabetic macular ischemia(DMI) based on the 
primary endpoint occurrence of dose limiting events (DLE) during MFD evaluation period of 
7 days (SRD) or 28 days after last administration (MD) and to investigate the safety, 
tolerability and early biological response after multiple IVT injections of BI 764524.
Primary endpoint
SRD part:
!
number of patients with dose limiting events (DLEs) from drug administration till day 
8 (7 days after treatment)
MD part:
!
number of patients with drug related adverse events (AEs) from drug administration 
till end of study (EOS)
Secondary endpoint
SRD part:
!
number of patients with drug related AEs at EOS
!
number of patients with ocular AEs (eye disorders) at EOS
MD part:
!
change from baseline of the size of the FAZ in optical coherence tomography 
angiography (OCTA) in superficial and combined vascular complex at Visit 5 
!
change from baseline of the size of the FAZ in optical coherence tomography 
angiography (OCTA) in superficial and combined vascular complex at Visit 7 
!
change from baseline of BCVA at Visit 3
!
change from baseline of BCVA at Visit 4
!
change from baseline of BCVA at Visit 5
!
change from baseline of BCVA at Visit 6
!
change from baseline of BCVA at Visit 7
!
change from baseline of Central retinal thickness (SD-OCT) at Visit 3
!
change from baseline of Central retinal thickness (SD-OCT) at Visit 4
!
change from baseline of Central retinal thickness (SD-OCT) at Visit 5
!
change from baseline of Central retinal thickness (SD-OCT) at Visit 6
!
change from baseline of Central retinal thickness (SD-OCT) at Visit 7
!
number of patients with ocular AEs (eye disorders) at EOS


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This trial will consist of an SRD part followed by an MD part. SRD part will be non-
randomized, open-label, and uncontrolled. MD part will be single-masked, randomized and 
sham-controlled.
SRD part:
In the SRD part, the starting dose is
. The other provisional dose level is
, and the 
maximum planned dose is 
. For each cohort, a single patient will be dosed on day 1, 
and the dosing investigator, coordinating investigator and 2 representatives of the sponsor 
who are involved in the trial will carefully evaluate all available systemic (i.e. physical 
examinations, safety lab parameters, ECG and AEs) and ophthalmologic (i.e. as defined in 
Section 5.2.1) safety data until day 4. If this patient neither has experienced an 
ophthalmologic nor a systemic serious adverse event, the remaining 2 patients will be dosed. 
Written minutes of this assessment are being distributed to all investigators participating in 
this trial.
For any dose-escalation cohort, at least 3 evaluable patients will be required. Each cohort will 
consist of newly enrolled patients.
A Safety Monitoring Committee (SMC, see Section 8.7) will decide on the next dose level to 
be investigated and on the size of the next cohort based on occurrence of DLEs and on 
additional information (systemic PK and patient profiles). Systemic PK data from preceding
cohorts (not from the ongoing cohort) will be available for evaluation. First SMC meeting 
will take decision based on safety data only. Refer to figure 3.1:1 (SRD) and figure 3.1:2
(MD) for a schematic representation of the dose escalation.
A Bayesian logistic regression model (BLRM), based on a weekly informative prior 
distribution, and employing the escalation with overdose control (EWOC) principle (see
Section 7) will be used for guiding the dose escalation [R13-4803]. After all patients in a 
cohort have either experienced a DLE or have been observed for at least the 7 days evaluation 
period without experiencing a DLE (I.e. 7 days after drug administration, until visit 4, will be
evaluated per patient), the BLRM will be updated with the newly accumulated data. The 
overdose risk will then be calculated for each dose, and escalation will be permitted to all 
planned doses which fulfil the EWOC criterion and the respective escalation rule.
The BLRM provides estimates for the probability of observing a DLE for each planned dose. 
Dose escalation will be permitted to the next planned dose which fulfils the EWOC criterion.
Note that this may also result in repeating the current dose level, or in going down to a lower 
dose level again.
If DLEs are observed in the first two consecutive patients of a previously untested dose level, 
subsequent enrolment to that cohort will be stopped. 




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In all patients included in the MD part of the trial, safety and early biological response will be 
studied up to 98 days after the last injection. 
Figure 3.1: 2
Schematic representation of the dosing in the MD part of the trial
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This trial is designed to confirm that the MFD can be used for further testing in phase IIb 
trials. The trial consists of separate SRD and MD parts. The SRD dose escalation part is 
included and was designed with the goal to minimize the number of patients exposed to sub-
therapeutic doses while on the other hand preserving safety and rapid dose finding. This part 
of the trial will be done in patients with DMI because IVT injections in healthy volunteers 
would not be considered appropriate. Whilst the drug may not benefit the participant directly 
during the trial, DMI is a chronic and bilateral disease. Therefore, if this trial leads to the 
approval of a treatment for DMI, the participant’s other eye as well as the eye treated in the 
study may benefit from the treatment in the future. The worse seeing eye of the participant
will be treated. As mentioned previously, risks are low but if the eye under trial treatment 
comes to harm, the impact on the patient will be less as the participants’ visual function is 
driven by the better seeing eye. Dose escalation and cohort size will be decided by the SMC, 
guided by a BLRM with overdose control. An EWOC design will increase the chance of 
treating patients at efficacious doses while reducing the risk of overdosing. The use of BLRM 
for Phase I studies has also been advocated by the European Medicines Agency (EMA) 


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guideline on small populations [R07-4856] and by the Food and Drug Administration (FDA) 
[R13-4881].
One MD cohort (3 injections in 4-weekly intervals) will be included after the SRD part. 
Patients will be randomized either to active treatment group or to sham control group (ratio 
2:1).
This part of the trial will generate additional safety data after multiple dosing and allow for 
exploration of the time course and durability of treatment effects. These data will further 
support the definition of the injection frequency and intervals in later studies.
3.3
SELECTION OF TRIAL POPULATION
This trial will recruit approximately 45 patients in total; up to 15 patients in the SRD part 
(depending on the dose escalation) and up to 30 patients in the MD part. In the MD part,
patients will be randomized to receive either IVT injection or sham injection.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all
sites at the same time once a sufficient number of patients has been screened. Investigators
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be
maintained in the Investigator Site File (ISF) at the investigational site irrespective of
whether they have been treated with investigational drug or not.
Patients who do not fulfil all eligibility criteria for a reason that later resolves and allows 
eligibility criteria to be met after the initial screening visit, can be re-screened up to one time. 
Please refer to Section 6.2.1 for further details.
If a patient is entered in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor has to be contacted immediately.
It is planned to conduct the trial in up to 3-5 countries and at approximately 20 sites.
Main diagnosis for trial entry 
Patients to be included are pan-retinal photo coagulation (PRP) treated proliferative diabetic 
retinopathy (PDR) patients with diabetic macular ischemia (DMI)
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in-and exclusion criteria.


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Inclusion criteria
Patients will only be included in the trial if they meet the following criteria:
SRD part
1. Pan-retinal photo coagulation treated PDR patients with either no or inactive retinal 
neovascularization per investigator judgement in the study eye
2. Male or female patients of age ≥18 years
3. Evidence of DMI per investigator´s judgement, defined as any degree of disruption of 
retinal vascularity in superficial and/or deep retinal plexus in OCTA
4. HbA1c of ≤ 12.0% 
5. Best-corrected Visual acuity (VA) in the non-study eye better or equal to the best-
corrected VA in the study-eye. If both eyes are eligible and have identical VA the 
investigator may select the study eye.
6. Best-corrected VA ≤55 letters (20/80) or worse for SRD
7. Women of childbearing potential (WOCBP) and men able to father a child must be 
ready and able to use two methods of contraception with at least one of them being a
highly effective methods of birth control per ICH M3 (R2) that result in a low failure 
rate of less than 1% per year when used consistently and correctly. A list of 
contraception methods meeting these criteria is provided in the patient information 
and in Section 4.2.2.3
8. Signed and dated written informed consent in accordance with ICH Harmonized 
Guideline for Good Clinical Practice (ICH GCP) and local legislation prior to 
admission to the trial
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is defined as no 
menses for 2 years without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 2 years of menorrhea, a single FSH measurement is sufficient.
MD part
1. Pan-retinal photo coagulation treated PDR patients with either no or inactive 
retinal neovascularization per investigator judgement in the study eye
2. Male or female patients of age ≥18 years
3. Presence of significant DMI: large foveal avascular zone defined as those with 
≥0.5mm2 area in superficial vascular complex (SVC) present on optical coherence 
tomography angiography. If FAZ is <0.5mm2 then enlarged peri-foveal inter-
capillary space in at least 1 quadrant will be sufficient.
4. HbA1c of ≤ 12.0% 
5. If both eyes are eligible, the investigator may select either eye to be the study eye.
6. Best-corrected VA ≤ 85 letters (20/20) or worse for MD 
7. Women of childbearing potential (WOCBP) and men able to father a child must 
be ready and able to use two methods of contraception with at least one of them 
being a highly effective methods of birth control per ICH M3 (R2) that result in a 
low failure rate of less than 1% per year when used consistently and correctly. A 
list of contraception methods meeting these criteria is provided in the patient 
information in Section 4.2.2.3


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8. Signed and dated written informed consent in accordance with ICH GCP and local 
legislation prior to admission to the trial
9. Signed and dated written informed consent for aqueous sampling (optional)
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is defined as no 
menses for 2 years without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 2 years of menorrhea, a single FSH measurement is sufficient.
Exclusion criteria
Patients will not be allowed to participate, if any of the following general criteria apply:
SRD part
1. Patients receiving IVT injections for active DME (anti-VEGF, steroids) and 
macular laser in the study eye in the previous 3 months prior to enrolment 
2. Patients receiving anti-VEGF IVT injections for active PDR in the study eye in 
the previous 3 months prior to enrolment 
3. Current or planned use of medications known to be toxic to the retina, lens or 
optic nerve (e.g. desferoximine, chloroquine/hydrochloroquine, chlorpromazine, 
phenothiazines, tamoxifen, nicotinic acid, and ethambutol)
4. Additional eye disease in the study eye that could compromise best corrected VA 
(BCVA) with visual field loss, uncontrolled glaucoma (IOP>24), age related 
macular degeneration, history of ischemic optic neuropathy or retinal vascular 
occlusion, symptomatic vitreomacular traction, or genetic disorders such as 
retinitis pigmentosa; history of high myopia > 8 diopters in the study eye. Anterior 
segment and vitreous abnormalities in the study eye that would preclude adequate 
observation with SD-OCT
5. Any intraocular surgery in the study eye within 3 months prior to screening
6. Aphakia or total absence of the posterior capsule. Yttrium aluminium garnet 
(YAG) laser capsulotomy in the study eye if performed less than 3 months prior to 
enrolment  
7. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other 
condition that, in the investigator´s opinion, makes the patient an unreliable trial 
participant)
8. Previous participation in this trial or in other trials with IVT injections 
administered within 3 months.
9. Significant disease or other medical conditions* (as determined by medical 
history, examination and clinical investigations at screening) that may, in the 
opinion of the investigator result in any of the following:
a.
Put the patient at risk because of participation in the study
b. Influence the results of the study
c.
Cause concern regarding the patient’s ability to participate in the study
10. Known hypersensitivity to any of the ingredients used in the investigational 
medicinal product (IMP) formulation, or any of the medications used
11. Active intraocular inflammation in the study eye
12. Active infectious conjunctivitis in either eye


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13. Women who are pregnant, nursing, or who plan to become pregnant while in the 
trial
*e.g. cardiac (including tachycardia), gastro-intestinal, hepatic, renal, metabolic,
dermatologic, neurological, haematological, oncological and psychiatric. Patients with
malignancy for which the patient has undergone resection, radiation or chemotherapy within past 5 years. Patients with
treated basal cell carcinoma or fully cured squamous cell carcinoma are allowed.
MD part
1. DME, defined as a CST ≥305μm for men and ≥290 μm women measured with 
Optovue OCT in the study eye
2. Patients receiving IVT injections for active DME (anti-VEGF, steroids) and macular 
laser in the study eye in the previous 3 months prior to enrolment 
3. Patients receiving anti-VEGF IVT injections for active PDR in the study eye in the 
previous 3 months prior to enrolment 
4. Heavily lasered macula in the study eye per investigator’s judgement
5. History of vitrectomy in the study eye
6. Epiretinal membrane with extended foveal contour distortion in the study eye per 
investigator’s judgement
7. Current or planned use of medications known to be toxic to the retina, lens or optic 
nerve (e.g. desferoximine, chloroquine/hydrochloroquine, chlorpromazine, 
phenothiazines, tamoxifen, nicotinic acid, and ethambutol)
8. Additional eye disease in the study eye that could compromise best corrected VA 
(BCVA) with visual field loss, uncontrolled glaucoma (IOP>24), age related macular 
degeneration history of ischemic optic neuropathy or retinal vascular occlusion, 
symptomatic vitreomacular traction, or genetic disorders such as retinitis pigmentosa; 
history of high myopia > 8 diopters in the study eye. Anterior segment and vitreous 
abnormalities in the study eye that would preclude adequate observation with SD-
OCT
9. Any intraocular surgery in the study eye within 3 months prior to screening
10. Aphakia or total absence of the posterior capsule. Yttrium aluminium garnet (YAG) 
laser capsulotomy in the study eye if performed less than 3 months prior to enrolment  
11. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other 
condition that, in the investigator´s opinion, makes the patient an unreliable trial 
participant)
12. Previous participation in this trial or in other trials with IVT injections within 3 
months
13. Significant disease or other medical conditions* (as determined by medical history, 
examination and clinical investigations at screening) that may, in the opinion of the 
investigator result in any of the following:
a.
Put the patient at risk because of participation in the study
b. Influence the results of the study
c.
Cause concern regarding the patient’s ability to participate in the study
14. Known hypersensitivity to any of the ingredients used in the IMP formulation, or any 
of the medications used
15. Active intraocular inflammation in the study eye
16. Active infectious conjunctivitis in either eye


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17. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
*e.g. cardiac (including tachycardia), gastro-intestinal, hepatic, renal, metabolic,
dermatologic, neurological, haematological, oncological and psychiatric. Patients with
malignancy for which the patient has undergone resection, radiation or chemotherapy within past 5 years. Patients with 
treated basal cell carcinoma or fully cured squamous cell carcinoma are allowed.
For study restrictions, refer to Section 4.2.2.
Withdrawal of patients from treatment or assessments
Patients 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.
Every effort should be made to keep the patients in the trial: if possible, on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to first administration of trial 
medication, as well as the explanation of the consequences of withdrawal. 
The decision to withdraw from trial treatment or from the whole trial as well as the reason 
must be documented in the patient files and Case Report Form (CRF).
Withdrawal from trial treatment
An individual patient will be withdrawn from trial treatment if:
1. The patient wants to withdraw from trial treatment, without the need to justify the 
decision
2. The patient 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 patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], other diseases or pregnancy)
5. An AE or clinically significant laboratory change or abnormality occurs that the 
investigator judge to warranting discontinuation of treatment. 
Even if the trial treatment is discontinued (MD part), the patient remains in the trial and, 
given his/her agreement, will undergo the procedures and follow up as outlined in the Flow 
Chart II and Section 6.2.3.


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Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient 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.
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-risk
assessment that could significantly affect the continuation of the trial
3. Deviation from GCP, the CTP, or the contract impairing the appropriate conduct of the 
trial.
For the following scenario further enrolment and entering into the trial will be interrupted by 
the sponsor once the sponsor becomes aware (i.e. stopping rule):
•
A single serious adverse reaction (i.e. a single serious adverse event) or two severe 
adverse reactions in two different patients (regardless of the system organ class) 
confirmed by both the investigator and sponsor as having a reasonable causal 
relationship to the IMP administration.
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
Replacement of patients
SRD part:
Patients withdrawn before visit 4 for another reason than DLE or patients who miss any visit 
from Visit 2 up to and including Visit 4 are not evaluable for the occurrence of a DLE within 
7 days after drug administration. These patients will be replaced if not decided otherwise by 
the SMC. Patients who come off study due to a DLE will not be replaced.
MD part:
If some patients 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 patients will be 
replaced. 


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A replacement patient will be assigned a unique trial patient number and will be assigned to 
the same treatment as the patient he or she replaces.




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Human dose prediction is based on the fact that the PK of BI 764524 is similar to 
in 
the rabbit and is thus expected to be similar to 
also in humans. An IVT half-life of 
 days has been described for 
(R18-2968). The minimum effective concentration 
is estimated as the upper range (about 1 nM) of the described 
 concentration in the 
vitreous for patients with DME and PDR (R17-3888, R17-3904). 
Using these values, the proposed starting dose of 
 is predicted to maintain the 
minimal efficacious vitreal concentration of 1 nM for 93 days. Doses lower than 
 are 
also expected to induce PD effects in the eye. However, the duration of the effect would be 
shorter and might not be long enough to justify a potential sufficiently long benefit to the 
patients.
The proposed escalation of the doses to 
, and 
 per eye is predicted to prolong the 
time for 
 concentrations above the estimated minimally efficacious 
concentration to 103 days and 116 days respectively. The final dose range was chosen based 
on the safety margin to the no observed adverse effect level (NOAEL), of the 13-week IVT 
study in cynomolgus monkeys. The 
 dose is expected to last only 9 days longer in the 
vitreous than the 
 dose and requires an injection volume of
 ml. Therefore, a 
decision was made to remove the 
 dose from the trial.
Table 4.1.2: 1
Provisional dose levels for escalation
Dose level
Proposed dose
Relative increment from previous 
dose
1
Starting dose
2
100%
3
150%
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria, patients will be enrolled into the SRD 
and MD part. Recruitment in the trial will start with the lowest dose group of the SRD part. 
The MD part will recruit patients only after the SRD part has been completed and safety of 
the doses has been established. 
In the SRD part, the dose is planned to be escalated in cohorts at the pre-defined provisional 
dose levels; see Table 4.1.2: 1. Intermediate or lower dose levels, depending on the number 
of DLEs observed in the study, as long as they fulfil the EWOC criterion, may be 
investigated if agreed upon between Investigator and Sponsor. At the end of each treatment 
cohort, BI will convene a meeting with the SMC members. At the dose escalation meeting, 
the clinical course for each patient in the current dose cohort will be reviewed in detail. Based 
on that and on the results of the updated BLRM, a decision on the next dose level to be tested 
is made. 


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In general, recruitment for the SRD part will be done successively for the dose groups, i.e. if 
the required number of patients for one dose group is completed and this dose is considered 
safe based on (the BLRM model and) the clinical course, the recruitment of the next higher 
dose group may be started. Therefore, the recruitment of patients for the dose groups will 
neither be influenced by the trial personnel nor by any characteristics of the patients, but only 
by temporal availability. Patients from the SRD part are not allowed to participate in the MD 
part.
The highest dose (
) if established as safe and tolerable during the SRD part will be 
used in the MD part after the SRD part has been completed. In the MD part patients will be 
randomized to receive either active treatment or sham injection according to a randomization 
plan at visit 2 via Interactive Response Technology (IRT). 20 patients on treatment and 10 on 
sham injection.
The randomization procedure is described in Section 7.6.
Drug assignment and administration of doses for each patient
BI 764524 will be administered intravitreally. “BI 764524
 for injection 
” and “Solvent for dilution of BI 764524 Solution for Injection” will be provided 
by BI. A site pharmacist (qualified person) will prepare the ready to use drug product 
according to the “Instructions to Pharmacist”. The instructions will be provided by BI and 
will be filed in the ISF. 
Table 4.1.4: 1
Planned doses and treatment schedule for the SRD part
Dose group 
(mg)
Visit 2 
Day 1
X
X
X
To determine the dose regimen for the next cohort, the available toxicity information 
(including DLEs and AEs that are not DLEs), PK, PD, as well as the recommendations from 
the BLRM will be evaluated by the SMC members at the dose decision meeting. The parties 
must reach a consensus whether further dose escalation is appropriate, or whether de-
escalation and/or expanded recruitment into particular cohorts is appropriate. Minutes from 
these meetings will be prepared and circulated to the trial team and each investigator for 
comment prior to finalization. The next dose group will only be initiated after further dose 


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escalation is considered appropriate by the SMC (see Section 4.1.2 for details on dose 
rationale and escalation concept).
Table 4.1.4: 2
Planned dose and treatment schedule for the MD part
Dose group 
(mg)
Visit 2 
Day 1
Visit 3 
Day 29
Visit 4
Day 57
Visit 5
Day 85
Visit 6
Day 113
2.5
X
X
X
Intravitreal Injection Technique and Sham Injection
IVT injections must be carried out according to medical standards and applicable guidelines 
by a qualified physician experienced in administering IVT injections. In general, adequate 
anaesthesia and asepsis, including topical broad-spectrum microbicide (e.g. povidone iodine 
applied to the periocular skin, eyelid and ocular surface) have to be ensured. Surgical hand 
disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) are 
recommended.
The MD part is designed single-masked and personnel of the trial site are masked. Therefore, 
in the MD part an unmasked injector with no other involvement in the trial will administer 
IVT/sham injections.
For a sham injection, all pre- and post-injection procedures are identical compared to IVT 
injections. For a sham injection, the hub of a syringe without a needle is pressed against the 
conjunctival surface to simulate the force of an actual injection. For sham aqueous sampling, 
all procedures are identical to aqueous sampling, the hub of a syringe without a needle is 
pressed gently against the corneal surface to simulate aqueous sampling.
Use of antibiotics in the pre-, peri-, or post-injection period is at investigator’s discretion.
After administration of BI 764524, patients will be monitored according to standard practice 
and at least for 1 hour. In this minimum post-dose observation period, systemic and ocular 
conditions will be monitored according to local practice for such procedures.
Masking and procedures for unmasking
Masking
The SRD part of the trial is open label. The MD part is designed single-masked. The 
treatments administered (active or sham injection) will be masked to patients and to the 
dedicated personnel of the trial site. For the MD part, an unmasked pharmacist (qualified 


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person) will prepare the active IVT injection and an unmasked injector with no other 
involvement in the trial will administer active/sham injections.
This single–masked design is considered acceptable because the potential bias in this type of 
study seems to be low and according to study procedures it is assured that the investigator's 
knowledge of the next treatment does not influence the decision to enter a patient.
At the sponsor site, all trial data will be handled open label. This means that trial functions of 
the sponsor are unmasked (including clinical monitor, data manager, statistician, bioanalyst, 
pharmacokineticist, pharmacometrician, drug metabolism scientist).
Within the central ECG lab, readers involved with interval measurements will be masked 
with respect to treatment, visit and demographic information collected.
If an interim safety analysis of ECG data is required, a part of the staff of the central ECG lab 
may be unmasked. 
Unmasking and breaking the code
Emergency unmasking will be available to the investigator via Interactive Response 
Technology (IRT) system. It must only be used in an emergency situation when the identity 
of the trial drug must be known by the investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. The reason for unmasking must be 
documented in the source documents and/or appropriate CRF.
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated Contract Research 
Organization (CRO). They will be packaged and labelled in accordance with the principles of 
Good Manufacturing Practice (GMP). Re-supply to the sites will be managed via an 
Interactive Response Technology (IRT) system, which will also monitor expiry dates of 
supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log with min-max recordings must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Trial 
Manager (as provided in the list of contacts) must be contacted immediately.


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Drug accountability
The investigator or designee will receive the investigational drugs from the sponsor when the 
following requirements are fulfilled:
!
Approval of the clinical trial protocol by the IRB / EC
!
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 (CA)
!
Availability of the curriculum vitae of the Principal Investigator
!
Availability of a signed and dated clinical trial protocol  
!
Availability of the proof of a medical licence for the Principal Investigator (If 
applicable)
!
Availability of FDA Form 1572 (If applicable)
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator and/or pharmacist (qualified person) and/or investigational drug storage 
manager must maintain records of the product’s delivery to the trial site, the inventory at the 
site, the use for each patient, and the return to the sponsor or warehouse / drug distribution 
centre or alternative disposal of unused products. If applicable, the sponsor or warehouse / 
drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
pharmacist (qualified person) / investigational drug storage manager will maintain records 
that document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the investigator or designee must verify that no remaining 
supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
Restrictions
Restrictions regarding concomitant treatment
Medications listed under the exclusion criteria (Section 3.3.3) are restricted during the trial.


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For the Study eye no other treatment (IVT or otherwise) is allowed during the trial.
The fellow eye can be on any on label drug. The Sponsor will not provide fellow eye 
treatment or compensate for it.
Any intravitreal treatment and use of medications known to be toxic to the retina, lens or 
optic nerve (e.g. desferoximine, chloroquine/hydrochloroquine, chlorpromazine, 
phenothiazines, tamoxifen, nicotinic acid, and ethambutol) are restricted during the trial.
Restrictions on diet and lifestyle
None
Contraception requirements
WOCBP (for the definition please refer to Section 3.3.2) and men able to father a child must 
use two medically approved methods of birth control throughout the trial (from Visit 1 until 
End of Study visit) one barrier method (condom), and one highly effective non-barrier 
method. 
Men (trial participant or partner of a trial participant) must use a condom (regardless of 
vasectomy) if their sexual partner is a WOCBP. 
WOCBP (trial participant or partner of a trial participant) must use a highly effective method 
of birth control per ICH M3 (R2) throughout the trial (from Visit 1 until EOS visit) that 
results in a low failure rate of less than 1% per year when used consistently and correctly if 
their sexual partner is a man able to father a child. 
•
Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal). 
•
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable). 
•
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS). 
•
Bilateral tubal occlusion 
Or
Patients must abstain from male-female sex if this is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, 
symptothermal, post-ovulation methods; declaration of abstinence for the duration of 
exposure to study drug; and withdrawal are not acceptable.
Restrictions regarding gamete donation
Gamete donation must not be performed from the time of the first dose of the investigational 
drug, and for at least 3 months after the last dose of the investigational drug.


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4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre. This 
is performed by a qualified physician. In the MD part the unmasked injector with no other 
involvement in the trial will administer the trial medication.
Patients 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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5.2
ASSESSMENT OF SAFETY
Dose limiting event
A DLE is defined as the occurrence of any of the following events in the study eye within the 
evaluation period (7 days after drug administration):
!
Development of sterile endophthalmitis and/or sterile inflammation of the vitreous of 
grade 3+ according to the NEI Grading of vitreous haze, and anterior chamber cells of 
3+ according to the Standardization of Uveitis Nomenclature (SUN) working group 
(WG) grading scheme (see Table 5.2.1: 1 below) and a duration of 5 or more days 
between day 1 and day 8
!
Visual loss of more than 15 letters at any given time-point
!
Persistent IOP over 30 mmHg for 3 days
!
Signs of vascular occlusion in a 1st (the main branch) or 2nd degree (the vessel after 
the first bifurcation of the main branch) retinal vessel, including peripheral retinal 
hemorrhages in the area supplied by the occluded vessel (hemorrhage of the macula 
would not be included as this is a symptom of the disease).
Table 5.2.1: 1
The SUN Working Group Grading Scheme for Anterior Chamber 
Cells (R18-1136)
Grade
Cells in Field1
0
<0
0.5+
1-5
1+
6-15
2+
16-25
3+
26-50
4+
>50
1 Field size is a 1 mm by 1 mm slit beam.
Physical examination
A complete physical examination will be performed at the time points specified in the Flow 
Chart I and Flow Chart II. It includes at a minimum general appearance, neck, lungs, 
cardiovascular system, abdomen, extremities, skin and measurement of height and body 
weight.
The results must be included in the source documents available at the site. 


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Color Fundus Photography, Slit Lamp and IOP
Seven-field or modified 4-field digital fundus photographs, slit lamp examination and IOPs
will be obtained from both eyes by a qualified person according to the imaging manual. 
This examination will be performed at the time-points defined in the Flow Chart I and Flow 
Chart II.
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart I and 
Flow Chart II, prior to blood sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. The results must be 
included in the source documents available at site.
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.4: 1. For the sampling 
time-points please see the Flow Chart I and Flow Chart II. Patients do not have to be fasted 
for the blood sampling for the safety laboratory. 
All analyses will be performed by a central laboratory, except urine pregnancy test which will 
be performed by the site staff. The respective reference ranges will be provided in the ISF. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. The central laboratory will send reports to 
the investigator. It is the responsibility of the investigator to evaluate the laboratory reports. 
Clinically relevant abnormal findings as judged by the investigator will be reported as AEs
(please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.7.1.4) and the DILI Checklist provided in the electronic 
data capture (EDC) system. The amount of blood taken from the patient concerned will be 
increased due to this additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
If blood sampling for central laboratory at the trial site is not possible, safety laboratory
analyses can be performed at a local laboratory. The results of the laboratory tests must be 
transferred to the investigator who ensures medical review and documents a clinically 
relevant safety issue as an adverse event. For minimum required safety laboratory parameters, 
see Table 5.2.4: 1.


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Table 5.2.4: 1
Safety laboratory parameters – whole blood, serum or plasma
Hematology
!
Haematocrit
!
Haemoglobin
!
MCV, MCH, RDW, MCHC
!
Red Blood Cells (RBC) / 
Erythrocytes
!
WBC / Leukocytes
!
Platelet Count / Thrombocytes
!
Differential Automatic (relative and 
absolute count): 
Neutrophils, Eosinophils, Basophils, 
Monocytes, Lymphocytes
!
HbA1c
Clinical chemistry
!
Albumin 
!
Alkaline phosphatase
- #-GT (gamma-glutamyl 
transferase) reflex test triggered by 
elevated alkaline phosphatase on 
two sequential measures
!
ALT (alanine aminotransaminase, 
SGPT)
!
AST (aspartate 
aminotransaminase, SGOT) 
!
Bicarbonate
!
Bilirubin total, fractionated if 
increased 
!
Calcium 
!
Chloride 
!
Creatinine 
!
Serum Pregnancy test*
!
Creatine kinase (CK)
!
CK-MB, troponin I (reflex tests if CK 
is elevated)
!
Lactate dehydrogenase (LDH)
!
Lipase
!
Magnesium 
!
Phosphate 
!
Potassium
!
Protein total 
!
Sodium
!
Urea (BUN)
!
LDL/HDL and total cholesterol
!
Triglycerides
!
TSH
!
Folate
*Serum pregnancy test at screening and at visit 2 as well as confirmation of positive urine pregnancy test (only for 
WOCBP)


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Table 5.2.4: 2
Safety laboratory parameters – urine
Urinalysis 
Semi quantitative
!
Nitrite
!
Protein
!
Glucose
!
Hemoglobin
!
Ketone
!
Urine pH
!
Leukocyte esterase (for 
WBC)
Human urine chorionic 
gonadotropin (HCG)*
*Pregnancy testing (HCG, urine): performed on-site, see flow chart I and flow chart II (only for WOCBP)
Electrocardiogram
12-lead resting ECG
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph at the time points given in the Flow Chart I and Flow Chart 
II. Electrode placement will be performed according to the method of Wilson, Goldberger 
and Einthoven modified by Mason and Likar (hips and shoulders instead of ankles and 
wrists). Precise electrode placement will be marked with an indelible mark on the skin to 
allow reproducible placement throughout the study.
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 patients are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after patients have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation.  The repeat ECGs are assigned to the respective 
scheduled time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. 


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Data transfer
For time points specified in the Flow Chart I and Flow Chart II, ECGs will be transferred 
electronically to the central ECG lab for evaluation.
In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded.
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
The data from the central ECG will be transferred to the sponsor.
Evaluation
Central ECG lab evaluation will be performed for all ECGs indicated in the Flow Chart I and 
Flow Chart II. For all ECGs this will include the intervals respiratory rate (RR), pulse rate 
(PR), QRS and QT measured semi-automatically. The screening ECGs will be checked for 
abnormalities.
Heart rate (HR) and the QT interval corrected for HR (QTc e.g. QTcF and QTcB) will be 
determined by the sponsor (see Trial statistical analysis plan (TSAP) for details).
All semi-automatic interval measurements in one patient will be performed on the same lead 
as far as possible. The intervals will be measured from four cardiac cycles (beats) in lead II. 
If lead II shows a flat T wave or is not measurable for any reason, lead V5 will be used, or if 
that lead is not measurable, then lead I will be used. In case of an occurrence where an 
interval cannot be measured from the same lead, a different lead will be used to measure the 
interval. This change in the lead will be noted. The lead actually used will be reported in the 
CTR.
Morphological analyses of the ECGs will be performed by a board-certified cardiologist or 
equivalent. The ECG interpretation will include an overall assessment (normal, abnormal, not 
evaluable) and findings with respect to e.g. rhythm, conduction, presence of myocardial 
infarction, ST-segment, T-wave, and presence of U-wave. Basis of the terminology used for 
the evaluation is the Clinical Data Interchange Standards Consortium (CDISC) EG standard 
findings list as specified in the data transmission agreement.
For masking arrangements see Section 4.1.5. ECG interval measurements from a particular 
patient should be performed by a single reader. For quality assurance and control of the 
measurements, a random subset of all ECGs and all ECGs meeting a set of outlier parameters 
will undergo a second review by a Quality Control Specialist. After quality control, the 
fiducial point markings will be reviewed by the cardiologist assigned to the study.
Evaluation of ECGs will comply with the ICH E14 guidance document and supplements 
[R07-4722, R16-0366] as well as the FDA requirements for annotated digital ECGs [R09-
4830].


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Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator.
Any ECG abnormalities will be monitored carefully and, if necessary, the patient will be 
removed from the trial and will receive the appropriate medical treatment. 
Other safety parameters
Not applicable
Assessment of adverse events
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation patient 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.
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 


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!
Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. 
These events should always be reported as SAEs as described in Section 5.2.7.2.
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 5.2.7.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
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 5.2.7.2.2.
The following are considered as AESIs:
!
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
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
o
Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the eDC.


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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.
All AEs meeting the criteria for a dose limiting event (DLE) as defined in Section 5.2.1 are 
defined as AESIs for this trial.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
!
The event is consistent with the known pharmacology of the drug 
!
The event is known to be caused by or attributed to the drug class
!
A plausible time to onset of the event relative to the time of drug exposure
!
Evidence that the event is reproducible when the drug is re-introduced
!
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)
!
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)
!
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)


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!
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger
!
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)
!
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
Adverse event collection and reporting
AE collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
!
From signing the informed consent onwards until the individual patient’s end of trial: 
all AEs (serious and non-serious) and all AESIs.
!
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should 
only report any occurrence of cancer and trial treatment related SAEs and trial 
treatment related AESIs of which the investigator may become aware of by any 
means of communication, e.g. phone call. Those AEs should be reported on the BI 
SAE form (see Section 5.2.7.1.1), but not on the CRF.
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process 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 send the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.


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Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the
clinical trial and has taken trial medication, the investigator must report any drug exposure
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner. 
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for 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 pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded in a CRF and used 
for determination of pharmacokinetic parameters. Planned time points for systemic 
pharmacokinetic samples are listed in Appendix 10.1.
Methods of sample collection
Blood sampling for pharmacokinetic analysis
For quantification of BI 764524 serum concentrations, approximately 3.0 mL of blood will be 
taken from a forearm vein into a serum collection tube at the time-points listed in Appendix 
10.1.
Full instructions for collection, labelling, storage and shipment of samples are provided in the
Laboratory Manual.
Samples will be stored in a freezer set at the analytical laboratory until the finalization of the 
clinical trial report (CTR). Samples may be used for further investigations (e.g. for stability 


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testing), however, only data related to the analyte and mechanism of action 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 final study report has been 
signed.
Pharmacokinetic - pharmacodynamic relationship
No formal analysis of a pharmacokinetic (PK) /pharmacodynamics (PD) relationship is 
planned. 
In order to characterize BI 764524’s serum exposure-response relationship a pharmacometric 
population PKPD analysis may be performed if data allow. The pharmacometric analysis will 
not be part of the CTR but will be provided separately.
In addition, exploratory correlation may also be made between drug concentration and AEs.




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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
For visit schedule, refer to Flow Chart I and Flow Chart II. The acceptable time windows for 
visits are given in the Flow Charts. For planned individual serum concentration sampling 
times, refer to appendix 10.1.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures and assessments to be performed at each visit are listed in the Flow Chart I, 
Flow Chart II, and in the appendix 10.1. Additional details regarding visit procedures are 
provided below.
All ophthalmic examinations will be performed in both eyes and should be performed in the 
specific order described below:
!
Before pupil dilation: BCVA assessment and 
 assessment 
!
After dilation: slit lamp examination, SD-OCT, OCT-A, colour fundus photography. 
!
At the end: ocular tonometry (for determination of IOP)
Screening and run-in period(s)
Screening Period
The screening visit does not need to be done with the patient in a fasted state. All patients 
must sign an Informed Consent consistent with ICH GCP guidelines prior to any study 
specific procedures, this includes the option that the patient signs the Informed Consent 
during an extra contact to the study site prior to the actual screening visit. The patient should 
be recorded on the enrolment log as a screened patient when Visit 1 is performed. Visit 1 is 
the beginning of the screening period. As soon as eligibility of an enrolled patient is 
confirmed, the treatment visit (Visit 2) may be performed. If the patient does not meet 
inclusion/exclusion criteria, the patient must be recorded in the eCRF as a screen failure.
Applies to the SRD part: In case of closed dose groups no further rescreening activities for a 
screened and eligible patient are required within 12 weeks after completed screening visit. If 
screening visit has been performed earlier than 28 days before randomization, an additional
visit for repeating of safety lab, vital signs, ECG and targeted physical examination has to be 
performed.
Baseline Conditions
Any pre-existing medical conditions considered as clinically relevant by the investigator, 
excluding the indication of the trial, are recorded into the appropriate eCRF. Any abnormal 


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clinical significant findings observed during ophthalmological examinations at Visit 1 need to 
be documented as Baseline Conditions.
Medical History
All clinically relevant medical history according to the investigator judgment will be captured 
in the appropriate eCRF.
IRT
All patients that are screened must be registered with IRT. If the patient results in a screen 
failure, IRT should be notified as soon as possible and within the screening period. Details of 
IRT procedures can be found in the IRT manual located in the ISF.
Re-screening
Patients who do not fulfil all eligibility criteria and are screen failed for a reason that later 
resolves and allows eligibility criteria to be met can be rescreened up to one time. For re-
screening, patient must be re-registered in IRT, which will then provide new patient number, 
and patient must sign new Informed Consent Form (ICF). Imaging of retina (SD-OCT, 
OCTA, fundus photography) does not need to be repeated at the re-screening visit if the
corresponding criteria for inclusion of the study eye were met at the initial screening visit and
the images are not older than 28 days at the re-screening visit; otherwise new images have to
be performed.
Treatment period(s)
For the SRD part, masking is not required for the IVT injection preparation or administration. 
For the MD part, IVT injection will be prepared by the unmasked pharmacist (qualified 
person).  For the MD part, an unmasked injector with no other involvement in the trial will 
administer either active or sham injection according to the treatment assigned by IRT. IVT 
injections must be carried out according to medical standards and applicable guidelines by a 
qualified physician experienced in administering IVT injections and will be done as part of 
drug administration visit procedures (Visit 2 for SRD part and Visits 2, 3 and 4 for MD part) 
after the other ophthalmologic assessments in the Flow Chart I and Flow Chart II have been 
performed (please see Section 4.1 for details). 
Follow-up period and trial completion
Patients must continue to be followed according to the visit schedule (unless they withdraw 
consent for further follow-up) in order to collect data at the end of the planned observation 
period. Unscheduled visits will be possible at the discretion of the investigator at any time for 
safety reason. The unscheduled visit may include any assessments considered necessary by 
the investigator. All unscheduled visits should be described and documented in the medical 
/source record.  The investigator may decide other treatment options during the follow-up 
period as deemed medically appropriate.


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SRD part
Visit 8/End of Study:
The Visit 8/EOS will be performed 42 days after Visit 7 (see Flow Chart I). 
The Visit 8/EOS is the final visit and the End of Study CRF has to be completed.
MD part
Visit 7/End of Study:
The Visit 7/EOS will be performed 42 days after Visit 6 (see Flow Chart II). 
The Visit 7/EOS is the final visit and the End of Study eCRF has to be completed.
Withdrawal of consent
Every effort should be made to keep the patient in the trial and undergoing the procedures 
and follow up as outlined in the Flow Charts I and II and Section 6.2.3.
If a patient is not willing to continue in the trial and wants to withdraw consent prior to the 
end of the study, Visit 7 (SRD part)/ Visit 6 (MD part) should be scheduled as soon as 
possible, and also Visit 8/EOS(SRD part)/ Visit 7/EOS(MD part) should be performed to 
assess for safety.
The End of Study eCRF has to be filled in even if patient refuses to participate to the above 
specified visits.
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2.
Patients who discontinue treatment before the end of the planned treatment period should 
undergo the EOS Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a patient’s EOS 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
This trial will consist of an SRD part followed by an MD part. The SRD part will be 
conducted non-randomized, open-label, and uncontrolled. MD part will be conducted single-
blind, randomized and sham-controlled. The main objectives of this trial will be assessed by
calculating descriptive statistics on DLEs and drug related AEs. For the MD part these will be 
compared descriptively between the treatment groups.
SRD part
The dose escalation will be guided by a Bayesian 2-parameter logistic regression model with 
overdose control [R13-4803, R13-4806]. For a given dose, the EWOC criterion is that there 
should be less than 25% risk that the true ocular DLE rate is above 0.25. 
The model is given as follows:
logit(πd) = log(α) + β*log(d/d*),
where logit(π) = log(π/(1-π)), πd represents the probability of having a DLE in the evaluation 
period at dose d, d* = 
is the reference dose, allowing for the interpretation of α as the 
odds of a DLE at dose d*, and θ = (log(α), log(β)) with α, β > 0 is the parameter vector of the 
model.
The estimated probability of a DLE at each dose level from the model will be summarized 
using the following intervals:
Target toxicity: [0.00, 0.25)
Over toxicity: [0.25, 1.00]
The BLRM-recommended dose for the next cohort is the dose level with the highest posterior 
probability of the DLE rate falling in the target interval [0.00, 0.25) among the doses 
fulfilling EWOC. Thus, it should be unlikely (< 25% posterior probability) that the DLE rate 
at that dose will exceed 0.25. However, the allowed dose increment will always be the next 
higher pre-planned dose. However, the maximum allowable dose increment for the 
subsequent cohort will be no more than 250% from the previous dose. Dose escalation will 
continue up to the
dose as long as the EWOC criterion for the next dose level is 
fulfilled. At the final dose, at least 6 treated patients are required. However, the SMC may 
decide to include additional number of patients at this dose level.






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MD part
The size of the FAZ of deep retinal plexus is associated with visual loss. Measuring FAZ by 
OCTA is highly reproducible. The assumed treatment effect of BI 764524 (reduction in the 
area of FAZ) as compared with sham treatment after 3 months of treatment is 10%). Showing 
this reduction in size of FAZ is believed to be clinically relevant.
Only 1 dose fulfilling the EWOC criterion would be used for the MD study after completion 
of the SRD part. 
The highest dose is usually limited by DLE in SRD or the maximum dose possible in the 
intravitreal injectable volume.
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in this study.
Any confidence intervals computed are to be interpreted in the perspective of the exploratory 
character of the study; i.e., confidence intervals are considered as interval estimates for 
effects.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:
!
Treated set (TS): The treated set includes all patients who were randomized and 
treated with at least one dose of study drug (either treatment with BI 764524 or 
Sham).
! Pharmacokinetic parameter analysis set (PKS): This set includes all patients in the 
treated set (TS) who provide at least one PK endpoint that was not excluded due to a 
protocol violation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a patient will be 
included in the PKS, even if he/she contributes only one PK parameter value for one 
period to the statistical assessment.
For the analysis the patients will be assigned to the treatment they actually received.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation
(IPD) categories will be suggested in the Integrated Quality and Risk Management Plan 
(IQRMP), IPDs will be identified no later than in the Report Planning Meeting, and the IPD
categories will be updated as needed.


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Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for drug BI 764524 and Sham-injection
will be calculated according to the relevant Standard operating procedure (SOP) of the 
Sponsor (001-MCS-36-472). 
Serum concentration data and parameters of a patient will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a patient’s data will be documented in the CTR.
Relevant protocol violations may be
!
Incorrect trial medication administered, i.e. the patient received at least one dose of 
trial medication the patient was not assigned to
!
Incorrect dose of trial medication taken
!
Use of restricted medications
Serum concentrations and/or parameters of a patient will be considered as non-evaluable, if 
for example
!
Missing samples/concentration data at important phases of PK disposition curve.
Serum concentration data and parameters of a patient which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report
(that is to the same number of decimal places provided in the bioanalytical report).
Primary endpoint analyses
The primary endpoint as specified in Section 2.1.2 will be derived according to BI standards.
The primary endpoints will be analyzed on the TS. DLEs and drug related AES will be 
summarized by means of frequency tables. 
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be summarized by means of descriptive 
statistics (at least n, mean, standard deviation, median, minimum and maximum) for 
continuous variables or frequency tables for categorical variables. The change from baseline 
(in mm2) of FAZ will be analysed using a generalized mixed linear model (for details refer to 
the TSAP).
Analyses regarding safety and efficacy will be performed on the TS.


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In addition for the Central retinal thickness and BCVA descriptive statistics will be computed 
to describe the empirical distributions and descriptive p-values will be calculated with 
appropriate statistical tests. The endpoint Central retinal thickness will be analyzed in the 
same way as the endpoint FAZ. The endpoint BCVA will be analyzed using a generalized 
linear model.
Safety analyses
Safety will be assessed as defined by the endpoints listed in Section 2.1.2 and 2.2.2 based on 
the treated set (TS). Safety analyses will be descriptive in nature and will be based on BI 
standards. 
For all analyses the treatment actually administered (= treatment at onset) to the patient will 
be used (any deviations from the randomized treatment will be discussed in the minutes of 
the Report Planning Meeting).
Treatments will be compared in a descriptive way. The sham group in the safety evaluation 
will consist of all patients treated with sham injection, regardless of the dose group in which 
they were treated. The test treatment groups will be compared to the sham group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.


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Measurements (such as ECGs, vital signs, or laboratory parameters) or AEs will be assigned 
to treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment-emergent AEs). 
Therefore, measurements planned, or AEs recorded prior to first intake of trial medication 
will be assigned to the screening period. For BI 764524 the residual effect period (REP) after 
IVT administration is not known. Therefore, all AEs with an onset between start of treatment 
and the respective EOS visit will be assigned to the on-treatment period for evaluation. These 
assignments including the corresponding time intervals will be defined in detail in the TSAP. 
Note that AEs occurring after the last per protocol contact but entered before database lock 
will be reported to Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (called analysing treatments) may be defined in the 
TSAP in order to provide summary statistics for other than above periods, such as combined 
treatments, on-treatment totals, or periods without treatment effects (such as screening and 
post-study intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.7.1) 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 and frequency tables will be 
provided for the number of patients within and outside the reference range. Values outside 
the reference range as well as possibly clinically significant values will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline. 
The ECG variables QT, HR, QTcF, QTcB, PR, QRS, and RR obtained from the centralised 
evaluation of 12-lead ECG recordings will be the basis for the derivation of quantitative and 
categorical ECG endpoints. These endpoints and their analyses will be described in the 
TSAP.
Pharmacokinetic - pharmacodynamic analysis
In order to characterize BI 764524’s exposure-response relationship, a pharmacometric
population PKPD analysis may be performed. The pharmacometric analysis will not be part 
of the CTR but will be provided separately.




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7.6
RANDOMISATION
SRD part
Patients within a cohort receive the same trial medication, therefore no randomization for 
treatment assignment is performed.
MD part
Patients will be randomized in a 2:1 ratio (BI 764524: Sham injection).
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 patient replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
SRD part
No formal statistical power calculations to determine sample size were performed for this
explorative study. A Bayesian logistic regression model (BLRM) was used for guiding the 
dose escalation process (see Section 3.1 for details). For the SRD part, a minimum of 3 
patients and a maximum of 15 patients will be expected for this trial based on the number of 
dose levels/cohorts that are tested (for details regarding the BLRM assumptions refer to 
appendix 10.2). Fewer patients might be needed based on the recommendation of the SMC. 
However, the actual number of patients will depend on the number of dose cohorts tested. 
Based on the simulation study to evaluate operating characteristics of the BLRM, about 15
evaluable patients are expected to be treated in the dose escalation part for the model to have 
reasonable operating characteristics relating to its MFD recommendation.
MD part
In the publication Samara et al. [R17-3318] estimates for FAZ means and standard deviations 
(SD) were derived. The worst case was for PDR patients with mean deep FAZ of 0.766 mm2. 
The standard deviation of FAZ ranged from 0.112 mm2 to 0.3402 mm2 for disease categories 
from control to PDR. It is assumed that intra-individual variability is much lower than the 
inter-individual SD from Samara et al. because of the high correlation of the baseline and the 
FAZ values after treatment. Taking into account the high correlation, a SD of FAZ of 
seems to be reasonable to be used in calculation of risk probabilities
With 20 patients in the BI 764524 2.5 mg arm and 10 patients in the sham arm, there is a 
likelihood of 
of observing a treatment effect larger than 
(a reduction of 
 


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mm2) and a likelihood of 
 of observing a treatment effect smaller than 
(a reduction 
of
) when the assumed mean treatment difference is
. Assuming a mean 
treatment difference of 
there is a likelihood of 
observing a treatment effect larger 
than
 and a likelihood of 
 of observing a treatment effect smaller than 
.


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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 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 patient’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients 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.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the responsible IRB / IEC and CA according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to a patient’s participation in the trial, written informed consent must be obtained from 
each patient (or the patient’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 patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient 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 patient 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 patients will be provided by the sponsor. See Section 4.1.6.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.9.
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial patient 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.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Before providing any copy of patients’ source documents to the sponsor, the investigator 
must ensure that all patient identifiers (e.g., patient’s name, initials, address, phone number,


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and social security number) have properly been removed or redacted to ensure patient
confidentiality.
If the patient is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the patient file.
For the CRF, data must be derived from source documents, (some of the data will be reported 
in IRT and transferred to the CRF) for example:
!
Patient identification: sex, year of birth (in accordance with local laws and 
regulations)
!
Patient participation in the trial (substance, trial number, patient number, date patient
was informed)
!
Dates of patient’s visits, including dispensing of trial medication
!
Medical history (including trial indication and concomitant diseases, if applicable)
!
Medication history
!
AEs and outcome events (onset date [mandatory], and end date [if available])
!
SAEs (onset date [mandatory], and end date [if available])
!
Concomitant therapy (start date, changes)
!
Completion of patient’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)
!
Prior to allocation of a patient 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 patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the patient eligible for the clinical trial.
Originals or copies of laboratory results and other imaging or testing results (with proper 
documented medical evaluation (in validated electronic format, if available) will be 
electronically transferred and uploaded into the trial database
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.


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Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’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.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Completed”). 
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of suspected unexpected 
serious adverse reactions (SUSARs) occurring with the trial medication until 30 days after 
LPLT at their site. 
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.


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Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / CA in each participating EU member state will be notified about the trial 
milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI). 
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
An extended SMC will be established for both SRD and MD parts. The SMC shall operate 
under the principles specified in the SMC charter. The primary responsibility of the SMC is 
to ensure and protect the safety and well-being of the patients participating in the trial. The 
primary objectives of the SMC are to make a joint decision on dose escalation in the SRD 
part and on the transfer to the MD part after the SRD part has been completed. 
The SMC will decide on the next dose level to be investigated based on occurrence of DLEs 
(see section 5.2.1) and on additional information (systemic pharmacokinetics [PK] and 
patient profiles). 
During the trial the SMC will monitor the trial for possible harmful effects of the test 
treatment, make an assessment as to the conduct of the trial, evaluate the accrued data in 
order to recommend whether the trial should continue as planned, continue with modification
or stop the trial (e.g. for safety concerns or ethical reasons). 
In its assessment and recommendations the SMC should always consider trial 
integrity/conduct issues (e.g. accrual, withdrawal rates, important protocol violations, 
relevant quality findings and non-compliances, missing data and censoring) and also consider 
factors external to the trial when relevant new information becomes available, such as 
scientific or therapeutic developments that may have an impact on the safety and well-being 
of the patients or on the ethics of the trial. 
The SMC is a multidisciplinary group composed of the co-ordinating investigator, 
participating investigators (as deemed necessary) with treated patients in the cohort that will 


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be evaluated in the meeting (SRD part only), members of the BI trial team and two experts 
independent from the BI trial / project team in the field of ophthalmology. The SMC 
members have been selected for their expertise in these areas, their knowledge of the 
management of patients with DMI and their experience in clinical trials and SMC activities.
Details of the SMC responsibilities and procedures are described in the SMC charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. 
The investigators will have access to the BI web portal Clinergize to facilitate document 
exchange and maintain electronic ISF. 
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CTMs), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done 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.
A central laboratory, central ECG, central ophthalmologic reading centre and an IRT vendor 
will be used in this trial. Details will be provided in corresponding manuals, available in the 
ISF.
Analyses of BI 764524 concentrations in serum will be performed at a qualified analytical 
laboratory or at another Contract Research Organization (CRO) with given authorisation by 
BI.




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R16-0366
E14 Implementation Working Group
ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs: questions & 
answers (R3) (current version dated 10 December 2015).
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/E
fficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2016); 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (2015)
R13-4803
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the 
Bayesian approach to phase I cancer trials. Stat Med 2008. 27:2420-2439
R13-4806
Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose
escalation with overdose control. Stat Med 1998. 17:1103-1120
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Corporate SOP: Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics. Current version
C27076166-01    BI 764524 Investigator’s Brochure, Current Version


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10.
APPENDICES
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) AND ADA BLOOD 
SAMPLING AND AQUEOUS SAMPLING
Table 10.1: 1 Time schedule for PK and 
 sampling (SRD part)
Course
Visit
Day/
Week
Planned Time
Planned 
Time [h]
PK BI 
764524
1
V2
1
Before drug 
administration 
of BI 764524*
-0:30
X
X
V2
1
Drug 
administration
0:00
V2
1
30 min after 
drug 
administration*
00:30
X
V3
4
(+/- 1 
day)
3 days after 
drug 
administration
72:00
X
V4
8
(+/- 2
day)/
Week 1
1 week after 
drug 
administration
168:00
X
V5
15
(+/- 2 
day)/
Week 2
2 weeks after 
drug 
administration
336:00
X
X
V6
29
(+/- 3
day)/
Week 4
4 weeks after 
drug 
administration
672:00
X
X
V7
57
(+/- 7
day)/
Week 8
8 weeks after 
drug 
administration
1344:00
X
EOS
V8
99
(+/- 7 
day)/
Week 14
12 weeks after 
drug 
administration
2016:00
X
X**
* A time window of +/-15 min for sample drawing is allowed.
**If there is 
 occurrence a further follow-up will be conducted.


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Table 10.1: 2 Time schedule for PK and
 blood sampling (MD part)
Course
Visit
Day/
Week
Planned Time
Planned 
Time [h]
PK 
BI 764524
1
V2
1*
Before drug 
administration 
of BI 764524
-0:30
X
X
V2
1
First Drug 
administration
0:00
V3
29
(+/- 3 
day)*/
Week 4
4 weeks after 
first drug 
administration; 
predose to 2nd
drug 
administration
671:30
X
X
V3
29(+/- 3 
day)/
Week 4
Second Drug 
administration
672:00
V4
57
(+/- 3 
day)*/
Week 8
8 weeks after 
first drug 
administration; 
predose to 3rd
drug 
administration
1343:30
X
V4
57
(+/- 3 
day)/
Week 8
Third Drug 
administration
1344:00
Follow 
Up 
Period
V5
85
(+/- 7
day)/
Week 12
12 weeks after 
first drug 
administration
2016:00
X
X**
Follow
Up 
Period
V6
113
(+/- 7 
day)/
Week 16
16 weeks after 
first drug 
administration
2688:00
X
Follow
Up 
Period
V7
155
(+/- 7 
day)/
Week 22
22 weeks after 
first drug 
administration
3360:00
X
*A time window of 30 mins to 2 hrs before dosing is allowed for sample drawing. PK and 
samples must be taken before next drug administration; no window afterwards.
**If there is 
 occurrence a further follow-up will be conducted.


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Table 10.1: 3 Time schedule for optional Aqueous sampling (MD part)
Trial Periods
Visit
Day
Time Point 
Optional Aqueous 
sampling
Treatment 
2
1
Just before drug 
administration
X*
3
29
(±3)
4
57
(±3)
Just before drug 
administration
X*
Follow-up
5
85
(±7)
Follow-up
6
113
(±7)
Any time during 
the visit
X*
EOS
7
155
(±7)
Any time during 
the visit
X*
* Optional aqueous samples are collected immediately before drug administration at Visits 2 and 4. At visits 6 and 7, when 
no drug is administered, the aqueous samples can be collected at any time during the visit.
10.2
STATISTICAL APPENDIX
A BLRM with overdose control will be used to guide dose escalation in this study. The 
BLRM is introduced in Section 7.1, which also specifies the prior for the model. After 
patients in each cohort have completed the evaluation period of 7 days, the prior distribution 
will be updated through Gibbs sampling procedures with the accumulated DLE data from the 
evaluation period. Posterior probabilities for the rate of DLEs will be summarized from the 
BLRM. Selection of the next dose will be based on these probabilities as well as on other 
safety and laboratory data.
The purpose of this statistical appendix is to present performance metrics (operating 
characteristics) that illustrate the precision of the design in estimating the MFD (see 
Section 3.1) under various dose-toxicity relationships through computer simulation. These 
results are summarized in Table 10.2: 3. In addition, recommendations of the next dose level
by the BLRM with overdose control principle are provided under various hypothetical 
outcome scenarios in early cohorts, to show how it facilitates on-study dose-escalation
decisions (see Table 10.2: 1). For simplicity reasons, a cohort size of 3 patients who are all 
evaluable is assumed. 
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.2: 1. These scenarios reflect potential on-
study data constellations and related escalation as allowed by the model and the planned dose 
groups. It is assumed that each cohort has exactly three patients who are all evaluable. For 
each scenario, the probability of overdose for the current dose, as well as the next potential 
dose and related probabilities of target dosing and over-dosing are shown (probability of 
over-dosing: P(OD), probability of target dosing: P(TD).






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!
Scenario 4: low-toxicity scenario
!
Scenario 5: non-logistic dose-toxicity scenario
!
Scenario 6: low-toxicity followed by high-toxicity
Table 10.2: 2 
Assumed true dose-toxicity scenarios
Scenario
Dose (mg)
1: Prior Med
P(DLE)
0.014
0.024
0.054
0.112
2: Prior Mean
0.086
0.106
0.153
0.224
3: High Tox
0.150
0.200
0.280
0.350
4: Low Tox
0.001
0.005
0.010
0.100
5: Non-Logistic
0.050
0.010
0.200
0.500
6: Low-High
0.010
0.050
0.400
0.600
For each of these scenarios, 1000 trials were simulated. Each cohort consisted of 3 patients 
and dose escalation complied with the following rule:
Escalate to the maximum dose which satisfies the overdose criterion and is ≤ 500% 
increase from the current dose. 
The MFD was considered reached if at least 6 patients have been evaluated at a dose level 
which is the model’s recommendation for the next dose cohort. The maximum allowed 
patient number for each trial was chosen as 24.
It was then assessed how often a dose was declared as MFD with true DLE rate in the 
targeted or in the overdosing range. Furthermore, the average, minimum and maximum 
number of patients per trial and the average number of DLEs per trial are reported. Results 
are shown in Table 10.2: 3.


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Table 10.2: 3
Simulated operating characteristics
Scenario
Max. allowed    # 
Patients
% of trials declaring a MFD
with true DLE rate in
% of 
stopped 
trials*
# Patients
# DLEs
[
)
target dosing
[
]
overdosing
Mean (Min-
Max)
Mean
(Min-
Max)
1
15
94.1 
0.0 
5.9 
11.8 (3-15) 
0.39 (0-3) 
2
15
65.4 
0.0 
34.6 
9.1 (3-15) 
1.10 (0-4) 
3
15
23.8 
13.6 
62.6 
8.5 (3-15) 
1.88 (0-6) 
4
15
100 
0 
0 
9.2 (9-15) 
0.06 (0-1) 
5
15
67.9 
0 
32.1 
10.7 (3-15) 
1.16 (0-4) 
6
15
47.9 
20.3 
31.8 
13.1 (3-15) 
2.01 (0-5) 
* The stopped trials include early stopped trials (stopped due to too much toxicity), as well as trials that stopped because the 
maximum allowed patient number was reached before an MFD was found.
In scenario 1, which reflects the case that the true dose-toxicity is aligned with prior medians,
94.1% of the simulated trials declared a dose as MFD with true DLE rate in the targeted 
toxicity range. Note that 5.9% of the simulated trials stopped either because there was no 
MFD determined after 15 patients had been observed (1.4 %) or because of too high toxicity 
for the planned doses (4.5 %). This latter is mostly due to the cases that 1 DLE is observed 
out of 3 patients at the starting dose of 
. In reality, this situation would rarely happen 
as the safety profile of starting dose is expected to be good. 
In scenario 2, the assumed dose toxicities are higher than in scenario 1. This results in a 
higher percentage of early stopped trials (about 34.6 %). In this case, about 65.4 % of the 
trials would end with an estimated MFD within the targeted toxicity range, and 27.7 % in the 
overdosing range.
In Scenario 3 (high-toxicity scenario), only 23.8% of the trials declared a dose as MFD with 
true DLE rate in the targeted toxicity range. In 13.6% of the trials, the estimated MFD was in 
the overdosing range. Scenario 4 (low-toxicity scenario) shows the best results, i.e. the lowest 
number of stopped trials and a high number of trials with estimated MFD in the target range, 
as would be expected. 
Scenarios 5 and 6 showed reasonable operating characteristics, given the quite large 
deviations of the assumed true dose-toxicity curve from the assumptions underlying the 
BLRM. 
The mean patient numbers ranged from 8.5 patients (Scenario 3) to 13.1 patients (Scenario 
6 ), and the maximum number of patients was 18. Therefore, the patient numbers are as 
expected and increase when moving away from the high-toxicity scenario.
Overall, by reviewing the metrics presented in table 10.2: 3, it can be seen that the model is 
generally conservative due to the overdose control criteria. In all scenarios, except for the 


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high-toxicity case (scenario 3) the probabilities of recommending a dose with true DLE rate 
being at least 25%, P(DLE ≥ 25%), as MFD are much smaller than the probabilities of 
recommending a dose with true P(DLE) < 25% as MFD.
R version 3.5.1 was used for data scenarios and simulations.
10.3
BENEFIT-RISK ASSESSMENT IN CONTEXT OF COVID-19 
PANDEMIC FOR PATIENTS PARTICIPATING IN TRIAL 1436-0001 
INVESTIGATING BI 764524
STUDY POPULATION
As per the Centers for Disease Control and prevention (CDC), people with serious chronic 
medical conditions, including diabetes and heart disease, might be at higher risk for severe 
illness from COVID-19. 
BENEFITS AND RISKS CONCLUSIONS AND RECOMMENDATIONS
Currently, there is no evidence that based on the pharmacological mechanism and existing 
non-clinical data BI764524 either may affect the immune system or increase the risk of 
progression of COVID-19 infection. BI 764524 is administered intravitreally using standard 
aseptic technique. 
The low dosage of BI764524 means the systemic exposure is expected to be very low.
Therefore, no change on the Benefit-Risk assessment of the compound in the context of the 
COVID-19 pandemic is foreseen.
The current study population is potentially at higher risk of COVID-19 infection due to 
background or concomitant diseases. Enrolment will start when the local situation allows, and 
appropriate risk mitigation measures (e.g. use of Personal Protective Equipment) will be 
implemented in line with local instructions and recommendations 
The investigators will take the totality of information related to each single patient and the 
local COVID-19 situation into consideration when performing the individual benefit-risk 
assessment on a case-by-case basis. Considering all aspects, the investigator will decide upon 
each patient’s (continued) participation in the trial. BI as the sponsor, where required, will 
support the investigator in their decision finding. It is acknowledged that the investigator may 
decide to implement protocol deviations where this protects the safety, wellbeing and/or is in 
the best interest of the patient.  
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
In situations where an individual patient is unable or unwilling to attend a clinic visit, the 
investigator must assess the risk-benefit for the individual patient and may decide to perform 
a visit remotely if this is in the best interest of the patient and if agreed with the sponsor. 


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All COVID-19 related deviations from the original schedule of visits and procedures will be 
documented and the implications considered for the analysis of the trial data. 
No trial specific SARS-CoV-2 testing will be performed. Testing will be performed in line 
with local standard procedures. In case of a confirmed infection appropriate measures e.g. for 
monitoring and quarantine will be implemented.






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observation period, systemic and ocular conditions 
will be monitored according to local practice for 
such procedures.
Rationale for change
Clarification
Section to be changed
4.2.2.1
Description of change
For restrictions regarding concomitant treatment the 
following sentence was added: For the Study eye no 
other treatment (IVT or otherwise) is allowed 
during the trial.
The fellow eye can be on any on label drug. 
Sponsor will not provide fellow eye treatment or 
compensate for it.
Rationale for change
Clarification
Section to be changed
4.2.2.4
Description of change
Following sentence was added: Gamete donation 
must not be performed from the time of the first 
dose of the investigational drug, and for at least 3 
months after the last dose of the investigational 
drug.
Rationale for change
Clarification
Section to be changed
5.2.1.
Description of change
The dose-limiting event
grading for sterile endophthalmitis and/or sterile 
inflammation of the vitreous has been reduced from 
Grade 4 to Grade 3.
SUN Working group grading scheme for measuring 
anterior chamber cells was revised: `0`represents no 
cells
Rationale for change
Authority feedback
Section to be changed
5.2.5 
Description of change
Wording of triplicate ECG was removed since 
ECGs will be recorded only as single ECGs.
Rationale for change
Clarification
Section to be changed
6.2.1.
Description of change
The following sentence was corrected to align with 
the 28 days screening period: If screening visit has
been performed earlier than 28 days before
randomization, an additional visit for repeating of 
safety lab, vital signs, ECG and targeted physical 
examination has to be performed.
Rationale for change
Clarification
Section to be changed
9.1.
Description of change
Update of the Published References – R17-3318 
added
Rationale for change
Update
Section to be changed
Flow chart, abbreviations, 2.2, 5.1, 5.7, 6.2, 9.2


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Description of change
Spelling mistakes corrected: 
, pregnancy 
test footnote (MD flowchart), BI764524
Rationale for change
Correction
Section to be changed
Appendix 10.2 
Description of change
Benefit-Risk Assessment in context of COVID-19 
pandemic for patients participating in trial 1436-
0001 investigating BI 764524
Rationale for change
Clarification
11.2
GLOBAL AMENDMENT 2
Date of amendment
28 Sep 2021
EudraCT number
EU number
2019-004432-28 
BI Trial number
1436-0001
BI Investigational Medicinal 
Product(s)
BI 764524
Title of protocol
A First-in Human trial to study safety and 
tolerability of single rising intravitreal dOses (open 
label, non-randomized, uncontrolled) and in 
addition the early biological response of multiple 
intravitReal dosing (single-masked, raNdomized, 
sham-controlled) of BI 764524 in panretinaL
photocoagulation (PRP) treated proLiferative 
diabetic retinopathy (PDR) patients with diabetic 
macular ischemia (DMI) – the HORNBILL Study
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Synopsis, 2.1.3
Description of change
The following secondary endpoint was added:
!
change from baseline of the size of the FAZ 
in optical coherence tomography 
angiography (OCTA) in superficial and 
combined vascular complex at Visit 5 (week 
12).
Rationale for change
This timepoint (visit 5) is used for interim analysis.
Section to be changed
Synopsis, 2.1.3, 2.2.2
Description of change
“Change from baseline of the size of the FAZ in 
OCTA in superficial and deep retinal plexus” was 
revised to 
“Change from baseline of the size of the FAZ in 
OCTA in superficial and combined vascular 
complex”


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Rationale for change
Change in the terminology of the classification. No 
change in the actual measurements.
Section to be changed
Abbreviations
Description of change
Deletion of unnecessary abbreviations and 
replacement of plasma to serum in PK relevant 
abbreviations
Rationale for change
Correction
Section to be changed
1.2
Description of change
Information of the treated patients was added.
Rationale for change
Update: availability of new study data
Section to be changed
1.3
Description of change
The following sentence was revised as follows:
“The next higher dose will only be administered to 
the next cohort, if the treatment in the preceding 
dose cohort was safe and showed acceptable 
tolerability.”
Rationale for change
Correction
Section to be changed
1.4.2, 1.4.2.1.2, 2.2.2, 5.3.4, 6.1, 7.3, 8.7
Description of change
Word “plasma” was replaced with “serum”.
Rationale for change
Correction: serum 
 and PK samples will be 
collected and analysed.
Section to be changed
1.4.2.2
Description of change
Risks related to IVT injection regarding the use of 
material for intraocular drug delivery was updated.
Rationale for change
Following release of a caution statement by Becton 
Dickinson (BD), who supply materials for use in
this trial, a risk-benefit evaluation and associated 
mitigation steps was performed and incorporated 
into the trial protocol.
Section to be changed


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Description of change
 
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
3.1
Description of change
The following sentences were revised as follows: 
The MD part of the study would only start if the 
highest dose 2 doses (i.e. 
is are
tolerated.
The highest dose (e.g.
) if established as safe 
and tolerable during the SRD part will be used in 
the MD part after the SRD part has been completed.
Rationale for change
Clarification that if the highest dose (
) is not 
considered safe and tolerable, MD part will not 
commence.
Section to be changed
Section 3.1; Figure 3.1:1
Description of change
Figure was corrected to reflect that the maximum 
feasible dose is considered as reached if at least 6 
patients have been evaluated at a dose level which 
is the model´s recommendation for the next dose 
cohort.




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vitreous grade 3+ according to standardization of
Uveitis Nomenclature (SUN) working group (WG)
grading scheme for anterior chamber cells (see
Table 5.2.1: 1 below) and a duration of 5 or more
days between day 1 and day 8”
was replaced with the sentence:
Development of sterile endophthalmitis
and/or sterile inflammation of the vitreous of grade
3+ according to the NEI Grading of vitreous haze,
and anterior chamber cells of 3+ according to the
Standardization of Uveitis Nomenclature (SUN)
working group (WG) grading scheme (see Table
5.2.1: 1 below) and a duration of 5 or more days
between day 1 and day 8
Rationale for change
Correction: the SUN only assesses inflammation in 
the anterior chamber, the NEI Grading of vitreous 
haze assesses inflammation in the vitreous.
Rationale for change
Clarification
Section to be changed
5.2.4
Description of change
Option to use local lab for safety lab analysis was 
added if blood sampling for central lab at the trial 
site is not possible.
Rationale for change
Clarification
Section to be changed
5.3.2.1
Description of change
The following sentence was revised as follows:
Samples may be used for further methodological 
investigations (e.g. for stability testing), however, 
only data related to the analyte and
mechanism of action will be generated by these 
additional investigations. The study samples will be 
discarded after completion of the additional 
investigations but not later than 5 years upon after 
the final study report has been signed.
Rationale for change
Correction
Section to be changed
5.4
Description of change
The following revisions were made: If feasible, BI 
764524 levels in aqueous humor samples might 
also be determined. In total, four aqueous samples 
collections are planned in the multiple dosing part 
of the trial.
Samples may be used for further investigations (e.g. 
measurements of BI 764524).
Rationale for change
Clarification
Section to be changed
6.2.2


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Description of change
The following sentence was removed: “An 
additional tonometry will be performed after IVT
injection to monitor IOP.”
Rationale for change
Clarification: no additional tonometry required.
Section to be changed
7.1
Description of change
The following sentence was removed; “Further 
analyses of these endpoints comprise the power 
model for assessment of dose proportionality” and 
correction of some typos in the priors of the blrm 
and a typo in the table “Summary of prior 
distribution”.
Rationale for change
Interpretation of the results of the power model for 
dose proportionality is challenging with maximum 
of 3 patients in 2 cohorts. Correction of typos.
Section to be changed
7.3.2
Description of change
Sentence was corrected: Analyses regarding safety 
and efficacy will be performed on the TS, analysis 
regarding PK will be performed on the PKS.
Rationale for change
Correction: all PK parameters are further endpoints
Section to be changed
Description of change
Rationale for change
Section to be changed
7.4
Description of change
As an interim analysis, a “Fast track” analysis of the 
MD part for analyses of the efficacy endpoint was 
added. Clarification of the final analysis was added.
Rationale for change
Interim analysis was included for early project 
planning. Final analysis was defined for 
completeness.
Section to be changed
7.5.2
Description of change
Reference to the BI SOP (001-MCS-36-472) was 
deleted.
Rationale for change
Correction
Section to be changed
8
Description of change
Wording applicable for Germany was deleted.
Rationale for change
Germany will not participate in the trial.
Section to be changed
8.7
Description of change
“As deemed necessary” was added in brackets after 
participating investigator to clarify the role of the 
participating investigator in the SMC meetings.
Rationale for change
Clarification
Section to be changed
10.1


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Description of change
Separate table (10.1:3) was created for aqueous 
sampling.
Rationale for change
Clarification
11.3
GLOBAL AMENDMENT 3
Date of amendment
17 Jan 2022
EudraCT number
EU number
2019-004432-28 
BI Trial number
1436-0001
BI Investigational Medicinal 
Product(s)
BI 764524
Title of protocol
A First-in Human trial to study safety and 
tolerability of single rising intravitreal dOses (open 
label, non-randomized, uncontrolled) and in 
addition the early biological response of multiple 
intravitReal dosing (single-masked, raNdomized, 
sham-controlled) of BI 764524 in panretinaL
photocoagulation (PRP) treated proLiferative 
diabetic retinopathy (PDR) patients with diabetic 
macular ischemia (DMI) – the HORNBILL Study
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
3.3.2
Description of change
MD part: Inclusion criteria#5 was revised as 
follows:
Best-corrected VA in the non-study eye better or 
equal to the best corrected VA in the study eye. If 
both eyes are eligible and have identical VA, the 
investigator may select the study eye.
If both eyes are eligible, the investigator may 
select either eye to be the study eye.
Rationale for change
The available data from the SRD part indicates that 
BI 764524 single IVT injections are well tolerated, 
and the benefit/risk ratio remains positive in 
subjects with DMI up to 
. As BI764524 
has proved safe in the SRD part, risks are low for 
the treated eye.
Section to be changed
3.3.2


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Description of change
MD part: Exclusion criteria#7 removed:
Clinically significant disorganisation of retinal 
inner layer (DRIL) in the study eye
Rationale for change
To broaden the patient population.
11.4
GLOBAL AMENDMENT 4
Date of amendment
20 Apr 2022
EudraCT number
EU number
2019-004432-28 
BI Trial number
1436-0001
BI Investigational Medicinal 
Product(s)
BI 764524
Title of protocol
A First-in Human trial to study safety and 
tolerability of single rising intravitreal dOses (open 
label, non-randomized, uncontrolled) and in 
addition the early biological response of multiple 
intravitReal dosing (single-masked, raNdomized, 
sham-controlled) of BI 764524 in panretinaL
photocoagulation (PRP) treated proLiferative 
diabetic retinopathy (PDR) patients with diabetic 
macular ischemia (DMI) – the HORNBILL Study
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Synopsis; Flow Chart I and II
Description of change
“including weight” included in brackets next to 
Physical examination
Rationale for change
Clarification in flow chart to indicate that weight is 
part of Physical examination.
Section to be changed
1.2
Description of change
The following sentence was revised as follows: 
Although no systemic adverse events were observed 
in the IVT pre-clinical study, at each the time-
points specified in the flow charts, patients will be 
evaluated with systemic evaluation, including body 
weight, blood pressure, pulse rate, and laboratory 
tests.
Rationale for change
Clarification
Section to be changed
1.4.2.4
Description of change
The following sentence was revised as follows: 
Additionally, a systemic evaluation will be 
performed at each the time-points specified in the 


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flow charts, to assess any possible systemic 
reaction.
Rationale for change
Clarification
Section to be changed
3.3, 6.2.1
Description of change
The following sentences were revised:
Section 3.3: Patients who do not fulfil all eligibility 
criteria for a reason that later resolves and allows 
eligibility criteria to be met within a 12 week period
after the initial screening visit, can be re-screened 
up to one time.
Section 6.2.1: Patients who do not fulfil all 
eligibility criteria and are screen failed for a 
reason that later resolves and allows eligibility 
criteria to be met within a 12 week period after 
initial screening visit, can be rescreened up to one 
time. For re-screening, patient must be re-registered 
in IRT, which will then provide new patient 
number, and patient must sign new Informed 
Consent Form (ICF).
Rationale for change
To remove the time restriction for rescreening of 
patients and allow patients beyond 12 weeks from 
date of initial screening to be rescreened once.
Section to be changed
6.2.1
Description of change
Revision as follows: 
Applies to the SRD part: In case of closed dose 
groups no further rescreening activities for a 
screened and eligible patient are required within 12 
weeks after completed screening visit.
Rationale for change
Clarification to indicate that closed dose groups 
apply to the SRD part only.
Section to be changed
Table 10.1:2
Description of changes
Footnote in the table was revised as follows:
*A time window of 30 mins to 2 hrs before dosing 
is allowed+/ 15 min for sample drawing is allowed 
here. PK and 
samples must be taken before 
next drug administration; no window afterwards.
Rationale for change
To allow broader time window for PK and 
 
samples before dosing.




 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Technical Version Number:
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Meaning of Signature  
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SAP_001.pdf: 
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TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c33215538-03
BI Trial No.:
1436-0001
Title:
A First-in Human trial to study safety and tolerability of single 
rising intravitreal dOses (open label, non-randomized, 
uncontrolled) and in addition the early biological response of 
multiple intravitReal dosing (single-masked, raNdomized, sham-
controlled) of BI 764524 in panretinaLphotocoagulation (PRP)
treated proLiferative diabetic retinopathy (PDR) patients with 
diabetic macular ischemia (DMI) – the HORNBILL Study.
Investigational
Product(s):
(including Protocol Amendments No 1-5 [c29487972-06])
BI 764524
Responsible trial 
statistician(s):
Date of statistical 
analysis plan:
25 MAY 2023
Version:
3
Page 1 of 34
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................4
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................8
5.
ENDPOINTS(S).....................................................................................................8
5.1
PRIMARY ENDPOINT(S)...................................................................................9
5.2
SECONDARY ENDPOINT(S).............................................................................9
5.2.1
Key secondary endpoint(s) ...................................................................................9
5.2.2
Secondary endpoint(s)...........................................................................................9
5.3
FURTHER ENDPOINT(S) ................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS...........................................................13
6.1
TREATMENT(S) ................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................15
6.3
SUBJECT SETS ANALYSED ...........................................................................15
6.5
POOLING OF CENTRES..................................................................................17
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................17
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................18
7.
PLANNED ANALYSIS ......................................................................................20
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........22
7.2
CONCOMITANT DISEASES AND MEDICATION......................................22
7.3
TREATMENT COMPLIANCE ........................................................................22
7.4
PRIMARY ENDPOINT(S).................................................................................22
7.4.1
Primary analysis of the primary endpoint(s)....................................................22
7.5
SECONDARY ENDPOINT(S)...........................................................................23
7.5.1
Key secondary endpoint(s) .................................................................................23
7.5.2
(Other) Secondary endpoint(s)...........................................................................24
7.5.3
Interim analysis ...................................................................................................25
7.7
EXTENT OF EXPOSURE .................................................................................27
7.8
SAFETY ANALYSIS..........................................................................................27
7.8.1
Adverse Events ....................................................................................................27
7.8.2
Laboratory data...................................................................................................29
7.8.3
Vital signs.............................................................................................................30
7.8.4
ECG ......................................................................................................................30
7.8.5
Others ...................................................................................................................30
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............31


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9.
REFERENCES ....................................................................................................31
11.
HISTORY TABLE..............................................................................................34


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis – SRD part....................................14
Table 6.1: 2
Treatments and labels used in the analysis – MD part .....................................14
Table 6.3: 1
Subject sets analysed ........................................................................................17
Table 6.7: 1
Time window assignment of efficacy, safety lab, pk and vital signs 
measurements to visits for statistical analysis of the MD Part.........................19
Table 6.7: 2
Time window assignment 12 lead ECG measurements to visits for statistical 
analysis of the MD Part ....................................................................................19
Table 6.7: 3
Time window assignment physical examination measurements to visits for 
statistical analysis of the MD Part ....................................................................20
Table 11: 1
History table .....................................................................................................34
2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
AE
Adverse Events
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC0-tz
Area under the concentration-time curve of the analyte in serum over the 
time interval from 0 to the last quantifiable drug concentration
AUC0-∞
Area under the concentration-time curve of the analyte in serum over the 
time interval from 0 extrapolated to infinity
BCVA
Best Corrected Visual Acuity
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
BMI
Body mass index
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in serum
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic Coefficient of Variation
CVC
Combined Vascular Complex
DBLM
Database Lock Meeting


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Term
Definition / description
DILI
Drug induced liver injury
DLE
Dose Limiting Event
DVC
Deep Vascular Complex
ECG
Electrocardiogram
EOS
End of Study
ES
Enrolled set
FAZ
Foveal Avascular Zone
FTR
Full Thickness Retina
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
HR
Heart Rate
IPD
Important Protocol Deviation
IVT
intravitreal
LLT
Lower Level Term
IQRMP
Integrated Quality and Risk Management Plan
Max
Maximum
MedDRA
Medical Dictionary for Drug Regulatory Activities
MD
Multiple Dose
Min
Minimum
N
Number non-missing observations
OCT
Optical Coherence Tomography
OCTA
Optical Coherence Tomography Angiography
P10
10th percentile
P90
90th percentile
PK
Pharmacokinetic
PKS
PK parameter analysis set
Q1
1st quartile
Q3
3rd quartile
QRS
Combination of the Q, R, and S waves in electrocardiogram


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Term
Definition / description
QT
Time between start of the Q-wave and the end of the T-wave in an
electrocardiogram
QTcB
QT interval corrected for heart rate using the method of Bazett
QTcF
QT interval corrected for heart rate using the method of Fridericia
RAGe
Report Appendix Generator system
REP
Residual Effect Period
SD
Standard Deviation
SRD
Single Rising Dose
SVC
Superficial Vascular Complex
tmax
Time from dosing to maximum measured concentration of the analyte in 
serum
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
VEGF
Vascular Endothelial Growth Factor
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomization.
Study data (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 8.1 or higher, 
) or SAS Version 9.4 (or later 
version).
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).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP. 
For a more accurate reflection of the data, the term 'combined vascular complex' (CVC) for 
FAZ-related parameters has been renamed as 'full thickness retina' (FTR). For the MD part, 
the main assessment for FAZ parameters in FTR was changed to a manual grading of the 
3mm OCTA scans i.e., the MD part endpoints related to FAZ area in FTR mentioned in the 
CTP are considered to be based on manually graded data for 3mm scan size. If an OCTA 
measurement is done for a specific scan size, this will be indicated in the endpoint label.
For other OCTA endpoints where a measurement was not performed for a specific scan size, 
it will be deemed that the measurement was made primarily based on a 6mm scan size and if 
this was not possible then otherwise taken from a 3mm scan size.
 
 
 
 
 
 
 
 
 
Sensitivity statistical analysis of the efficacy endpoints using LOCF will not be performed as 
the handling of missing data is taken into account within the MMRM approach
5.
ENDPOINTS(S)
The pharmacokinetic and pharmacodynamic parameters listed in Section 2.2 of the CTP for 
drug BI 764524 will be calculated according to relevant BI internal procedure.


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5.1
PRIMARY ENDPOINT(S)
Section 2.1.2 of the CTP:
SRD part:
∀
Number of patients with dose limiting events (DLEs) from drug administration till day 
8 (7 days after treatment). 
For definition of DLEs, refer to Section 7.4.
MD part:
∀
number of patients with drug related adverse events (AEs) from drug administration 
till end of study (EOS)
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoint(s)
Section 2.1.3 of the CTP:
SRD part:
∀
number of patients with drug related AEs at EOS
∀
number of patients with ocular AEs (eye disorders) at EOS
MD part:
∀
change from baseline of the size of the FAZ area in optical coherence tomography 
angiography (OCTA) in superficial vascular complex and full thickness retina at Visit 
5.
∀
change from baseline of the size of the FAZ area in optical coherence tomography 
angiography (OCTA) in superficial vascular complex and full thickness retina at Visit 
7.
∀
change from baseline of BCVA at Visit 3
∀
change from baseline of BCVA at Visit 4
∀
change from baseline of BCVA at Visit 5
∀
change from baseline of BCVA at Visit 6
∀
change from baseline of BCVA at Visit 7
∀
change from baseline of Central retinal thickness (SD-OCT) at Visit 3
∀
change from baseline of Central retinal thickness (SD-OCT) at Visit 4
∀
change from baseline of Central retinal thickness (SD-OCT) at Visit 5
∀
change from baseline of Central retinal thickness (SD-OCT) at Visit 6
∀
change from baseline of Central retinal thickness (SD-OCT) at Visit 7
∀
number of patients with ocular AEs (eye disorders) at EOS
Note that the above FAZ area in FTR is understood to be the FAZ area in FTR for the 3mm 
scan size, manually graded.


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5.3
FURTHER ENDPOINT(S)


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Concise summary of efficacy endpoints to be described in CTR:
SRD Part
FAZ area in superficial vascular complex
FAZ area in full thickness retina
BCVA
Central Retinal Thickness


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on treatments to be administered, assignment of treatment groups, 
selection of doses, refer to CTP Sections 3 and 4. 
The trial will consist of an SRD part followed by an MD part. The SRD part will be 
conducted open-label, non-randomized, and uncontrolled, whereas the MD part will be single-
masked, randomized and sham-controlled.
It was planned to assign up to 45 patients in total, up to 15 in the SRD part in (3 sequential 
dose groups comprising at least 3 patients each) and 30 in the MD part (20 patients on 
BI 764524 and 10 patients on sham injection). 
With recruitment completed, the actual numbers enrolled are 12 patients in the SRD part and 
32 in the MRD part (3 patients discontinued and were replaced).
For details of dosage and formulation see Tables 6.1:1 and 6.1:2 below.


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Table 6.1: 1
Treatments and labels used in the analysis – SRD part
Dose 
group
Treatment
Description
Short label
1
D
BI 764524 
 SRD
BI 
 SRD
2
E
BI 764524 
 SRD
BI 
 SRD
3
F
BI 764524 
 SRD
BI 
 SRD
Table 6.1: 2
Treatments and labels used in the analysis – MD part
Dose 
group
Treatment
Descriptive
Short label
1
A
BI 764524 
g
BI 
 MD
2
S
Sham injection
Sham MD
Section 7.3.4 of the CTP: 
For BI 764524 the residual effect period (REP) after IVT administration is not known. 
Therefore, all AEs with an onset between start of treatment and the respective EOS visit will 
be assigned to the on-treatment period for evaluation.
The following separate study phases will be defined for the analyses of AEs:
∀
Screening (ranging from 0:00h (midnight) on the day of informed consent until the 
first administration time of BI 764524)
∀
On treatment
o
BI treatment (separately for each treatment, ranging from the time of first 
administration of BI 764524 until 0:00h (midnight) on the day after trial 
completion date)
The following AE displays will be provided in the report:
Section 15.3 (presented separately for SRD and MD part) and Appendix 16.1.13.1.8 (for 
ClinicalTrials.gov and EudraCT) of the CTR displays:
In these displays, the -on- treatment phase will be analysed (labelled with the short label of 
the study treatment). Screening will not be included in this analysis. 
The following totals will be provided in section 16.1.13.1.8 in addition:
∀
a total over all on-treatment phases ("Total")
∀
a total over all on-treatment phases in the SRD part ("Total - SRD part")
∀
a total over all on-treatment phases in the MD part ("Total - MD part")
∀
a total over all on-treatment phases involving BI 764524 ("BI Total")


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∀
a total over all on-treatment phases involving BI 764524 in the SRD part ("BI Total –
SRD part")
∀
a total over all on-treatment phases involving BI 764524 in the MD part ("BI Total –
MD part")
In Section 15.4 and Appendix 16.2 (Listings) of the CTR displays, the screening period will 
be included and no totals will be provided.
Tables of vital signs and laboratory values will present results for the above mentioned on 
treatment phase.
For detailed information on the handling of the treatments refer to the Technical TSAP ADS 
(analysis data set) plan and the Analysis Data Reviewers guide.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated patients.
Section 7.3 of the CTP:
Important protocol deviation (IPD) categories will be suggested in the Integrated Quality and 
Risk Management Plan (IQRMP), IPDs will be identified no later than in the Report Planning 
Meeting, and the IPD categories will be updated as needed.
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting and database lock meeting
(RPM/DBLM). At latest at this meeting, all manual deviations identified at the sites by the 
CRAs and deviations too complex to program will be reviewed by the trial team to decide 
which are considered important. For definition of important protocol deviations (iPD), and for 
the process of identification of these, refer to the Boehringer Ingelheim (BI) SOP " Identify 
and Manage Important Protocol Deviations Deviations (iPD)" (3).
If any iPDs are identified, they are to be summarised into categories and will be captured in
an accompanying Excel spreadsheet (DV sheet), where the categories which are considered to 
be iPDs in this trial are defined (4). The decision on the exclusion of subjects with iPDs from 
population sets will be documented in the decision log. 
The iPDs will be summarised and listed.
6.3
SUBJECT SETS ANALYSED
Enrolled set (ES):
This subject set includes all patients who were enrolled in the study regardless of whether 
they were treated or not. The ES is used for the disposition tables / listings and the disclosure 
tables for enrolment.


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Section 7.3 of the CTP:
Treated set (TS)
The treated set includes all patients who were randomized and treated with at least one dose 
of study drug (either treatment with BI 764524 or Sham).
Biomarkers
Section 7.3.3.2 of the CTP:
 
Biomarker set (BMS):
Biomarker data and parameters of a patient will be included in the statistical biomarker (BM) 
analyses if they are not flagged for exclusion due to a protocol deviation relevant to the 
evaluation of biomarkers (to be decided no later than in the Report Planning Meeting) or due 
to non-evaluability.


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Exclusion of a patient’s data will be documented in the CTR.
Biomarker data and parameters of a patient which is flagged for exclusion will be reported 
with its individual values but will not be included in the statistical analyses.
Table 6.3: 1
Subject sets analysed
Class of endpoint
ES
TS
PKS
BMS
Primary endpoints 
X
Analysis of PK endpoints
X
Analysis of PD endpoints/biomarkers
X
Other secondary and further endpoints 
X
Safety parameter
X
Demographic/baseline parameter
X
Important protocol deviations
X
Disposition/Disclosure (enrolment)
X
6.5
POOLING OF CENTRES
Due to the limited number of patients, all patients will be pooled without using different 
weights for centres.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
Imputation might be necessary for AE dates in the safety evaluation. Missing or incomplete 
AE dates are imputed according to BI standards (see BI-KMED-BDS-HTG-0035 (7)).
Missing time at unscheduled ocular assessment performed on the day of administration are 
regarded as on treatment. The missing time will be imputed and set to 23:59 at the day of 
administration.
Missing data and outliers of PK data are handled according to BI standards.
Missing baseline laboratory values will be imputed by the respective values from screening.


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If single cardiac cycles of an ECG (out of the generally four) are missing, the arithmetic mean 
for this single ECG will be computed with the reduced (1, 2 or 3) number of cardiac cycles.
If replicate ECG recordings are missing, the arithmetic means per time point will be computed 
with the reduced number (1 or 2) of recordings.
For the classification of the on-treatment QTc/QT intervals into “no new onset” / “new onset” 
categories, a missing value is obtained only in case that
(i)
all on-treatment values are missing and
(ii)
the baseline value is less than or equal to 500 msec, or missing.
If condition (i) is fulfilled but the baseline value is greater than 500 msec, this case will be 
categorized as ‘no new onset’. If baseline is missing and the maximum on treatment 
QTc interval is greater than 450 msec (or 500 msec for QT interval, respectively), this is 
classified as a ‘new onset’ in the respective category. If baseline is missing and the maximum 
QTc interval is less than or equal to 450 msec (or 500 msec for QT interval, respectively), this 
will be categorized as ‘no new onset’. If baseline is missing, a QTc/QT interval > 500 msec at 
any time on treatment will be a notable finding.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before first administration of trial 
medication (= value at V2, in case no actual time is given in data).
Section 5.1 of the CTP:
For the endpoints, baseline is defined as the value at Visit 2; if not measured at Visit 2 then 
baseline is the value at Visit 1.
This rule will also apply to the additional endpoint, 
.
Section 6.1 of the CTP:
For visit schedule, refer to Flow Chart I and Flow Chart II. The acceptable time windows for 
visits are given in the Flow Charts. For planned individual serum concentration sampling
times, refer to appendix 10.1.
SRD Part:
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.
MD Part:
Analysis of AE data, potentially clinically significant abnormal laboratory values, 
concomitant medication or non-drug therapies, as well as use of rescue therapy will not be 
based on visits. Therefore, no assignment to time windows will be necessary for such data.
All other safety and efficacy measurements will be assigned to visits based on extended time 
windows around the planned visit dates, defined relative to the day of first trial treatment 
(which is scheduled for Visit 2). These extended time windows are defined in Table 6.7: 1, 
Table 6.7: 2, and Table 6.7: 3.


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Only one observation per time window will be selected for statistical analysis at a particular 
visit – the value which is closest to the protocol planned visit day will be selected, except for 
safety lab where the worst scenario is chosen. If there are two observations which have the 
same difference in days to the planned day, the later value will be selected. 
For 
, the worst case scenario will be used (i.e. highest value will be taken) if more than 
one measurement is made in the same time window.
Section 5.2.5.1 of the CTP:
Central ECG lab evaluation will be performed for all ECGs indicated in the Flow Chart I and
Flow Chart II. For all ECGs this will include the intervals RR, PR, QRS and QT measured 
semi-automatically. The screening ECGs will be checked for abnormalities.
The baseline value of an ECG variable is defined as the mean of the ECG measurements prior 
to drug administration.
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.
Table 6.7: 1
Time window assignment of efficacy, safety lab, pk and vital signs 
measurements to visits for statistical analysis of the MD Part
Time window [days]
Visit 
number 
(CTP)
Visit label 
(analysis)
Planned 
Day
Window 
per CTP
Start 
(extended)
End 
(extended)
V2
Baseline 
1
± 0
NA
1
V3
Week 4
29
± 3
2
43
V4
Week 8
57
± 3
44
71
V5
Week 12
85
± 7
72
99
V6
Week 16
113
± 7
100
134
V7
Week 22/EoS
155
+7
135
End of Trial 
visit date
Days are counted relative to the day of first treatment, which is defined as Day 1.
Table 6.7: 2
Time window assignment 12 lead ECG measurements to visits for statistical 
analysis of the MD Part
Time window [days]
Visit 
number 
(CTP)
Visit label 
(analysis)
Planned 
Day
Window 
per CTP
Start 
(extended)
End 
(extended)
V2
Baseline 
1
± 0
NA
1


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Time window [days]
Visit 
number 
(CTP)
Visit label 
(analysis)
Planned 
Day
Window 
per CTP
Start 
(extended)
End 
(extended)
V3
Week 4
29
± 3
2
43
V4
Week 8
57
± 3
44
71
V5
Week 12
85
± 7
72
End of Trial 
visit date
Days are counted relative to the day of first treatment, which is defined as Day 1.
Table 6.7: 3
Time window assignment physical examination measurements to visits for 
statistical analysis of the MD Part
Time window [days]
Visit 
number 
(CTP)
Visit label 
(analysis)
Planned 
Day
Window 
per CTP
Start 
(extended)
End 
(extended)
V1
Baseline
… -1
NA
NA
1
V5
Week 12
85
± 7
2
End of Trial 
visit date
Days are counted relative to the day of first treatment, which is defined as Day 1.
7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be presented in Sections 15.1 to 15.4 of the CTR 
and in Appendix 16.1.13.1.
The prior specified in the CTP, Section 7.1 will be used in all BLRM evaluations.
The format of the listings and tables will follow the BI standards (see BI-KMED-BDS-HTG-
0045 (8)) with the exception of those generated for PK-calculations (6).
The individual values of all patients will be listed, sorted by treatment group, patient number, 
and visit. 
The listings will be included in Appendix 16.2 of the CTR.
The data of the last screening attempt of re-screened patients will be considered. In case a 
value from the last screening attempt of re-screened patients is missing this value will be 
imputed with the previous screening value.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 


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Min
minimum 
Median
median 
Max
maximum
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment group. Percentages will be rounded to one decimal place and will be based on all 
patients in the respective subject set whether they have non-missing values or not. The 
category 'missing' will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS. 
The data will be summarized by treatment group and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only frequency tables are planned for this section of the report, based on the TS.
Summaries will be presented for concomitant therapies ongoing at baseline and separately for 
those newly onset after first drug intake. Use of non-drug therapies will also be summarized.
Concomitant diseases and non-drug therapies will be coded using the latest version of the 
coding system of the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
Medications will be coded using the latest version of the World Health Organization Drug 
Dictionary (WHO-DD). The coding version number will be displayed as a footnote in the 
respective output.
The diagnoses and medications and non-drug therapies will be listed. Patients without any 
concomitant diagnoses or concomitant therapies should be marked with a “No” in the 
respective column.
The relevance of the concomitant therapies to the evaluation of PK, efficacy and safety data 
will be decided no later than at the RPM/DBLM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP:
Compliance will be assured by administration of all trial medication in the study centre. This 
is performed by a qualified physician. In the MD part the unmasked injector with no other 
involvement in the trial will administer the trial medication.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM/DBLM (see Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint(s)
SRD part:


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Section 5.2.1 of the CTP:
A DLE is defined as the occurrence of any of the following events in the study eye within the 
evaluation period (7 days after drug administration):
∀
Development of sterile endophthalmitis and/or sterile inflammation of the vitreous 
grade 3+ according to the NEI Grading of vitreous haze, and anterior chamber cells 
of 3+ according to standardization of Uveitis Nomenclature (SUN) working group 
(WG) grading scheme for anterior chamber cells (see Table 5.2.1: 1 below) and a 
duration of 5 or more days between day 1 and day 8
∀
Visual loss of more than 15 letters at any given time-point
∀
∀
Signs of vascular occlusion in a 1st (the main branch) or 2nd degree (the vessel after 
the first bifurcation of the main branch) retinal vessel, including peripheral retinal 
hemorrhages in the area supplied by the occluded vessel (hemorrhage of the macula 
would not be included as this is a symptom of the disease).
Section 5.2.7.1.4 of the CTP:
All AEs meeting the criteria for a dose limiting event (DLE) as defined in Section 5.2.1 are
defined as AESIs for this trial.
Descriptive statistics (number and percentage of patients with DLEs) will be provided by dose 
group and in total.
MD part:
Descriptive statistics (number and percentage of patients with drug-related AEs) will be 
provided, based on the TS.
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.


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7.5.2
(Other) Secondary endpoint(s)
Section 7.3.2 of the CTP:
The secondary endpoints (refer to Section 5.2.2) will be summarized by means of descriptive 
statistics (at least n, mean, standard deviation, median, minimum and maximum) for 
continuous variables or frequency tables for categorical variables.
Analyses regarding safety and efficacy will be performed on the TS.
The change from baseline in FAZ area (separately for the superficial vascular complex and 
full thickness retina) over time will be analysed via a restricted maximum likelihood (REML) 
based approach using a mixed model with repeated measurements (MMRM) . 
The model will include the fixed, categorical effects of treatment at each visit and the fixed 
continuous effects of baseline at each visit. Visit will be treated as the repeated measure with 
an unstructured covariance structure used to model the within-patient measurements.
The statistical model will be as follows
jjk = j i + 
jk + ij
ij ~ Z (, ) .
yijk = response variable (as change from baseline) for subject i at visit j receiving treatment k,
i= the baseline measurement of subject i, i=1,2,…
j= coefficient of baseline effect at visit j

jk= the effect of treatment k at visit j, j=1,…,Z and k = 1, ..,Y ,
eij = the random error associated with the jth visit of the ith subject. Errors are independent 
between subjects.
 = an unstructured covariance matrix
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. Least-squares means per treatment and for the treatment difference 
will be provided by time point, and in addition corresponding two-sided 95% confidence 
intervals and p-values will be presented.
In the event of non-convergence, the following methods will be attempted (in order) to 
overcome it:
1. Add the ‘singular=1e-10’ option in the model statement – This raises the threshold at 
which columns are declared linearly dependent (from typically 1e-12). 
2. Set ‘maxiter=100’ in the Proc Mixed statement – This increases the number of 
convergence iterations used from a default of 50.


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3. Set ‘scoring=4’ to specify use of the Fisher scoring algorithm in the first 4 iterations. 
4. Include the statement ‘performance nothread’ – this removes multi-threading from the 
calculations.
5. Should none of the previous methods work, the covariance matrix will be changed 
from unstructured to Toeplitz with heterogeneous variances (TOEPH). Should this 
also not converge, a standard Toeplitz matrix (TOEP) will be fitted. Finally, if 
convergence still does not occur, then an order-1 autoregressive matrix (AR(1)) will 
be fitted.
The analysis will be performed on the TS. The above analysis is to be repeated for the below 
endpoints:
i.
The change from baseline in Central Retinal thickness over time.
ii.
The change from baseline in BCVA over time.
iii.
The change from baseline in FAZ area 3mm scan size in full thickness retina over 
time.
The focus in the CTR will be on the manually graded 3mm scan size FAZ FTR parameters, as 
such the pre-existing manually corrected FAZ FTR parameters (not assessed by scan size) 
will be placed in Appendix 16.1.13.1 and will not be described in the CTR.
For all continuous longitudinal secondary endpoints, time profiles of mean (±SD) absolute 
values and mean (±SD) changes from baseline by treatment group as well as individual time 
profiles (absolute values and changes from baseline) per treatment group will be provided for 
the study eye / fellow eye in addition.
7.5.3
Interim analysis
Section 7.4 of the CTP:
For this trial, a “Fast track” analysis of the MD part is planned at Visit 6 (Week 16). After all
data of the above-mentioned time point are available, a snapshot of the database will be 
taken.
This snapshot will be used for performing the Fast track analysis.
For the fast track analysis, the change from baseline in FAZ area 3mm scan size in full 
thickness retina over time will be analysed using the MMRM described in Section 7.5.2, with 
the restriction that only visits up to Visit 6 (Week 16) are included in the model.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each patient.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
If not stated otherwise, the safety results will be sorted by treatment group. 
The safety data for treated patients who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
Per the European Union (EU) Regulation 536/2014 (Annex V, Point 4) (14), the following
information will be included in Appendix 16.1.13.1 of CTR:
∀
number of subjects included by country
∀
number of subjects inside (member states) and outside the EU (third countries)
∀
frequency of serious drug-related AEs by treatment, primary system organ class and
preferred term.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in “Analysis and Presentation of Adverse Event Data from Clinical Trials – Display 
Template” [BI-KMED-BDS-HTG-0041] (9).
Unless otherwise specified, 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.


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For analysis multiple AE occurrence data on the eCRF will be collapsed into an AE provided 
that all of the following applies:
∀
All AE attributes are identical (lower level term (LLT), intensity, action taken, therapy 
required, seriousness, reason for seriousness, relationship, outcome, AE of special 
interest (AESI))
∀
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
two occurrences is given if the second occurrence started within one hour after end of 
the first occurrence)
Section 5.2.7.1.4 of the CTP: The following are considered as AESIs:
∀
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
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
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN 
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
eDC. 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. All AEs meeting the criteria for a 
dose limiting event (DLE) as defined in Section 5.2.1 are defined as AESIs for this 
trial.
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. 
Section 5.2.7.1.4 of the CTP: For BI 764524 the residual effect period (REP) after IVT 
administration is not known. Therefore, all AEs with an onset between start of  treatment and 
the respective EOS visit will be assigned to the on-treatment period for evaluation.
According to ICH E3 (11), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at the RPM/DBLM at the latest.
An overall summary of AEs (including number of patients with any AE, DLEs, drug related 
AEs, ocular AEs, AESIs, serious AEs and drug related serious AEs) will be presented. 


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The frequency of patients with AEs will be summarized by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for patients with other 
significant AEs according to ICH E3 (11), for patients with serious AEs, for patients with 
drug-related AEs, for patients with drug related serious adverse events for patients with 
AESIs, for patients with ocular AEs, and for patients with ocular AEs in the study eye.
The SOC and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of patients with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:
∀
Adverse Events per arm for disclosure on EudraCT
∀
Non-serious Adverse Events for disclosure on EudraCT
∀
Serious Adverse Events for disclosure on EudraCT
For all ocular adverse events, ocular symptoms will be listed in addition.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
[BI-KMED-BDS-HTG-0042] (12).
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possible 
clinically significant will be flagged in the data listings. 
To support analyses of liver related adverse drug effects, the frequency of patients with AST
and/or ALT ≥ 3xULN combined with a total bilirubin ≥ 2xULN, and the frequency of patients 
with AST and/or ALT ≥ 10xULN, will be displayed. This analysis will be based on
standardized laboratory values. A graphical analysis of the ALT and total bilirubin during the
on-treatment period will also be performed; the so called eDISH plot. In the graph, for each
subject, the peak total bilirubin is presented as a fold increase over the ULN against the peak
ALT as a fold increase over the ULN, on a log10 scale. The measurements displayed or total
bilirubin and ALT may, or may not, occur on the same date. Two reference lines, 2xULN for
total bilirubin and 3xULN for ALT, are drawn onto the graph in order to divide the plane into
four quadrants. Normal cases are in the lower left quadrant, potential DILI cases are in the
upper right quadrant (Hy’s Law quadrant), while the lower right quadrant is known as the
Temple’s corollary range (ALT ≥ 3xULN and total bilirubin < 2xULN).
Clinically relevant findings in laboratory data will be reported as adverse events if judged 
clinically relevant by the investigator, and will be analysed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significant 
abnormal or not (at the RPM/DBLM at the latest).


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Descriptive statistics of laboratory data including change from baseline will be calculated by 
visit based on the worst value of the patient at that visit.
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure, pulse rate and body weight).
7.8.4
ECG
Continuous safety ECG monitoring (by investigator)
Clinically relevant abnormal findings will be reported as adverse events.
No separate listing or analysis of continuous ECG monitoring will be prepared.
12-lead ECG
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during the 
trial) if judged clinically relevant by the investigator.  
All evaluations of ECG data will be based on the TS.
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR only listings will be provided. Occurrences of notable findings will be flagged.
Comments regarding the ECGs will be listed.
Categorical endpoints
For the categorical endpoints, frequency tables will be provided.
For all patients with any notable finding in ECG intervals, a separate listing will be created as 
end-of-text display (based on the same display template as in Appendix 16.2), and the 
corresponding time profiles will be shown.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the changes from 
baseline over time of QTcF, QT, HR, PR and QRS. The time profiles of mean and SD for the 
changes from baseline on treatment will be displayed graphically by treatment.
7.8.5
Others
Physical examination
Physical examination findings, including general appearance, neck, lungs, cardiovascular 
system, abdomen, extremities, and skin will be reported as relevant medical history/baseline 


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condition (i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. 
No separate listing or analysis of physical examination findings will be prepared.
Ophthalmologic data
 will be analysed descriptively by time point, treatment group and in total. 
Shift tables from baseline in SUN grading for anterior chamber cells, in other slit lamp 
examinations and in Diabetic Retinopathy Severity Scale will be presented by time point, 
treatment group and in total.
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.
9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMED.
3.
BI-VQD-12045_40-413: "Identify and Manage Important Protocol Deviations (iPD) ", 
current version, KMED.
4.
BI-KMED-BDS-TMP-0059: “iPD specification document (sdtm-dv-domain-
specification)”, template, current version; KMED.
5.
BI-KMED-COPS-OTH-0101: “Integrated Quality and Risk Management Plan”, current 
version; KMED.
6.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies”, current version; KMED.
7.
BI-KMED-BDS-HTG-0035: "Handling of Missing and Incomplete AE Dates", current 
version; KMED.
8.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project
Summaries”, current version; KMED.
9.
BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
10.
 


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11. 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
12. BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; KMED.
13. Ring A. Statistical models for heart rate correction of the QT interval. Stat Med 2010 
[R10-2920]
14. REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF 
THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, 
and repealing Directive 2001/20/EC, European Commission webpage.
15. REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE 
COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and 
repealing Directive 2001/20/EC, European Commission webpage.


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Boehringer Ingelheim
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c33215538-03
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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 
10-MAY-22
None
This is the final TSAP 
2
25-APR-23
Section 
2, 4, 
5.2.2, 
5.3, 
7.5.2, 
7.5.3, 
7.6, 
7.8.4, 9, 
10.1
Updated the secondary and further 
endpoints and their analysis. Removed 
Interim analysis description; Reduction 
of ECG analyses descriptions, 
implemented protocol amendment 
updates, additional endpoints were 
added which are not available in the 
protocol, 
3
25-MAY-23
Section  
4, 6.7,  
7.5.2, 
7.5.3  
BCVA analysis updated to only include 
all patients, Fast Track Analysis reduced 
to only FAZ 3mm FTR, Rule introduced 
to how to deal with more than one 
 
measurement in the same time window. 
Time windows corrected and aligned 
with ADS plan. 


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