Clinical trial NCT04919499
Conditions: Diabetic Retinopathy
Sponsor: Boehringer Ingelheim
Start date: 2021-07-30; Completion date: 2023-08-07
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is open to adults with diabetic macular ischemia who have received laser treatment. The main purpose of this study is to find out whether people with diabetic macular ischemia can tolerate a medicine called BI 765128.

In this study, BI 765128 is given to people for the first time.

The study has 2 parts. Part A tests 3 doses of BI 765128. Participants get either a low, medium or high dose of BI 765128 as a single injection into the eye. If participants tolerate it well, the highest dose will be used in part B.

In part B, participants are put into 2 groups randomly, which means by chance. 1 group gets BI 765128 as injection into the eye. The other group gets sham injections. 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. In this part, participants receive study treatment once every month for 3 months.

Participants in part A are in the study for about 4 months and visit the study site about 8 times.

Participants in part B are in the study for about 5 months and visit the study site about 7 times.

The doctors regularly check participants' health and take note of any unwanted effects.

Detailed description:

Arms: arm 1: Diabetic retinopathy (DR) patients with Diabetic Macular Ischemia (DMI) previously treated with panretinal photocoagulation (PRP) received one single intravitreal injection of low-dose BI 765128. arm 2: Diabetic retinopathy (DR) patients with Diabetic Macular Ischemia (DMI) previously treated with panretinal photocoagulation (PRP) received one single intravitreal injection of medium-dose BI 765128. arm 3: Diabetic retinopathy (DR) patients with Diabetic Macular Ischemia (DMI) previously treated with panretinal photocoagulation (PRP) received one single intravitreal injection of high-dose BI 765128. arm 4: Diabetic retinopathy (DR) patients with Diabetic Macular Ischemia (DMI) previously treated with panretinal photocoagulation (PRP) received 3 single intravitreal injection of high-dose BI 765128 at week 1, 4 and 8. arm 5: Diabetic retinopathy (DR) patients with Diabetic Macular Ischemia (DMI) previously treated with panretinal photocoagulation (PRP) received 3 single intravitreal sham injection at week 1, 4 and 8.
Interventions: intervention 1: BI 765128 intervention 2: Sham comparator
Intervention descriptions: intervention 1: BI 765128 intervention 2: Sham comparator

Protocol documents:
Prot_000.pdf: 




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Trial endpoints
Primary endpoints:
Part A: 
∀
Number of subjects with ocular dose limiting events (DLEs) 
from drug administration until day 8 (7 days after treatment)
Part B:
∀
Number of subjects with drug-related AEs from drug 
administration until EOS
Secondary endpoints:
Part A:
∀
Number of subjects with drug related AEs at EOS
∀
Number of subjects with any ocular AEs (eye disorders) at 
EOS
Part B:
∀
Change from baseline of the size of the FAZ in optical 
coherence tomography angiography (OCTA) at visit 5
∀
Change from baseline of the size of the FAZ in optical 
coherence tomography angiography (OCTA) at visit 6
∀
Change from baseline of the size of the FAZ in optical 
coherence tomography angiography (OCTA) at visit 7
∀
Change from baseline of BCVA at Visit 7
∀
Number of subjects with any ocular AEs (eye disorders) from 
drug administration until EOS
Trial design
This trial will consist of two parts, A and B. Part A will be non-
randomized, open-label and uncontrolled. Part B will be double-
masked, randomized and sham-controlled (ratio 2:1).
Total number of 
subjects entered
Approximately 48 subjects in total
Number of subjects on 
each treatment
Up to 18 subjects in Part A (depending on the dose escalation) and
30 subjects in Part B. In Part B subjects will be randomized to 
receive either IVT injection or sham injection.
Diagnosis
Diabetic macular ischemia (DMI) in patients previously treated with 
Panretinal photocoagulation (PRP) for diabetic retinopathy (DR)
Main in- and exclusion 
criteria
Main inclusion criteria:
Part A:
∀
Panretinal photocoagulation-treated DR patients with either 
no or inactive retinal neovascularization per investigator 
judgement in the study eye
∀
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
∀
Best-corrected VA ≤75 letters (20/32) in the study eye 


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Part B:
∀
Panretinal photocoagulation-treated DR patients with either no 
or inactive retinal neovascularization per investigator 
judgement
∀
Presence of significant DMI: Large foveal avascular zone 
(FAZ) defined as those with ≥0.5mm2 area present on OCTA. 
If FAZ is <0.5mm2 then an enlarged peri-foveal inter-capillary 
space in at least 1 quadrant will be sufficient.
∀
Best-corrected VA ≤85 letters (20/20) in the study eye 
Main exclusion criteria:
Part A:
∀
Patients receiving IVT injections for active Diabetic Macular 
Edema (DME) (anti-VEGF, steroids) and macular laser in the 
previous 3 months to screening in the study eye
∀
Subjects receiving anti-VEGF IVT injections for active DR 
in the previous 3 months to screening in the study eye
Part B:
∀
Diabetic Macular Edema (DME), defined as a CST ≥ 305μm 
for men and ≥ 290 μm for women (Optovue Angiovue) in the 
study eye
∀
Subjects receiving IVT injections for active DME (anti-
VEGF, steroids) and macular laser in the previous 3 months 
to screening in the study eye
∀
History of vitrectomy in the study eye
Test product(s)
BI 765128, solution for injection
dose
Part A: 
 mg (single doses)
Part B: The highest dose (
 mg) 
 if established as safe and 
tolerable during Part A
mode of 
administration
Intravitreal injection
Comparator product(s)
Not applicable
dose
Not applicable
mode of
administration
Not applicable
Duration of treatment
Part A: single intravitreal dose
Part B: 3 intravitreal doses at
 
Statistical methods
The main objectives of this trial will be assessed by calculating 
descriptive statistics on DLEs and drug related AEs. For the Part B 
these will be compared descriptively between the treatment groups.


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The dose escalation in the SRD part will be guided by a Bayesian
logistic regression model (BLRM) with overdose control that will be
fitted to binary toxicity outcomes. The estimates of parameters will 
be updated as data are accumulated using the BLRM.


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FLOW CHART I (PART A)
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-leadECG(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
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 subject
participation (5)
X
(1)
Could be repeated as deemed necessary at investigator´s discretion.
(2)
Single ECGs are to be recorded shortly before the PK sampling at the respective time points, (Section 5.2.5. and 
Appendix 10.1).


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(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)
(5)
Completion of subject participation also needs to be completed in the eCRF if the subject withdraws prematurely 
following assignment to dose level (Section 3.3.4)






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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART I (PART A)...................................................................................................6
FLOW CHART II (PART B)..................................................................................................8
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................14
1.
INTRODUCTION...............................................................................................18
1.1
MEDICAL BACKGROUND.............................................................................18
1.2
DRUG PROFILE................................................................................................19
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................21
1.4
BENEFIT - RISK ASSESSMENT.....................................................................21
1.4.1
Benefits.................................................................................................................21
1.4.2
Risks .....................................................................................................................22
Risks related to the Mode of Action (MoA) .........................................................22
Available data from pre-clinical toxicity studies ..................................................22
Risks related to intravitreal injection ....................................................................23
Risks related to blood sampling............................................................................23
Planned measures for monitoring the risks...........................................................23
Drug induced liver injury......................................................................................24
1.4.3
Discussion.............................................................................................................26
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................27
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........27
2.1.1
Main objectives....................................................................................................27
2.1.2
Primary endpoint(s)............................................................................................27
2.1.3
Secondary endpoint(s) ........................................................................................27
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................30
3.1
OVERALL TRIAL DESIGN.............................................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................33
3.3
SELECTION OF TRIAL POPULATION .......................................................34
3.3.1
Main diagnosis for trial entry ............................................................................34
3.3.2
Inclusion criteria .................................................................................................34
3.3.3
Exclusion criteria ................................................................................................36
3.3.4
Withdrawal of subjects from treatment or assessment...................................38
Discontinuation of trial treatment .........................................................................38
Withdrawal of consent to trial participation .........................................................38
Discontinuation of the trial by the sponsor...........................................................39


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3.3.5
Replacement of subjects .....................................................................................39
4.
TREATMENTS...................................................................................................40
4.1
INVESTIGATIONAL TREATMENTS ...........................................................40
4.1.1
Identity of the Investigational Medicinal Products..........................................40
4.1.2
Selection of doses in the trial and dose modifications......................................40
4.1.3
Method of assigning subjects to treatment groups ..........................................41
4.1.4
Drug assignment and administration of doses for each subject .....................42
4.1.5
Intravitreal Injection Technique and Sham Injection.....................................43
4.1.6
Masking and procedures for unmasking ..........................................................43
Masking.................................................................................................................43
Unmasking and breaking the code........................................................................44
4.1.7
Packaging, labelling, and re-supply...................................................................44
4.1.8
Storage conditions...............................................................................................45
4.1.9
Drug accountability.............................................................................................45
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................46
4.2.1
Other treatments and emergency procedures..................................................46
4.2.2
Restrictions ..........................................................................................................46
Restrictions regarding concomitant treatment ......................................................46
Restrictions on diet and lifestyle...........................................................................46
Contraception requirements..................................................................................46
Restrictions regarding gamete donation................................................................47
4.3
TREATMENT COMPLIANCE........................................................................47
5.
ASSESSMENTS..................................................................................................48
5.1
ASSESSMENT OF EFFICACY........................................................................48
5.2
ASSESSMENT OF SAFETY.............................................................................49
5.2.1
Dose limiting event..............................................................................................49
5.2.2
Physical examination ..........................................................................................49
5.2.3
Vital signs.............................................................................................................50
5.2.4
Safety laboratory parameters ............................................................................50
5.2.5
Electrocardiogram ..............................................................................................52
12-lead resting ECG..............................................................................................52
5.2.6
Other safety parameters.....................................................................................54
5.2.7
Assessment of adverse events.............................................................................54
Definitions of AEs ................................................................................................54
5.2.7.1.1
Adverse event........................................................................................................54
5.2.7.1.2
Serious adverse event............................................................................................54
5.2.7.1.3
AEs considered “Always Serious”........................................................................55
5.2.7.1.4
Adverse events of special interest.........................................................................55
5.2.7.1.5
Intensity (severity) of AEs....................................................................................56
5.2.7.1.6
Causal relationship of AEs....................................................................................56
Adverse event collection and reporting ................................................................57
5.2.7.2.1
AE Collection........................................................................................................57
5.2.7.2.2
AE reporting to the sponsor and timelines............................................................57
5.2.7.2.3
Pregnancy..............................................................................................................57




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8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................75
8.6
TRIAL MILESTONES.......................................................................................75
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................76
9.
REFERENCES....................................................................................................78
9.1
PUBLISHED REFERENCES............................................................................78
9.2
UNPUBLISHED REFERENCES......................................................................80
10.
APPENDICES.....................................................................................................81
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) AND ADA/NAB 
BLOOD SAMPLING (PART A AND PART B) AND AQUEOUS 
SAMPLING (PART B).......................................................................................81
10.2
BENEFIT-RISK ASSESSMENT IN CONTEXT OF COVID-19 
PANDEMIC FOR SUBJECTS PARTICIPATING IN TRIAL 1451-0001 
INVESTIGATING BI 765128............................................................................83
10.3
STATISTICAL APPENDIX..............................................................................84
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................89
11.1
GLOBAL AMENDMENT 1 ..............................................................................89
11.2
GLOBAL AMENDMENT 2 ..............................................................................92
11.3
GLOBAL AMENDMENT 3 ..............................................................................94
11.4
GLOBAL AMENDMENT 4 ..............................................................................96




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CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
DLE
Dose limiting event
DME
Diabetic macular edema
DMI
Diabetic macular ischemia
DMC
Data Monitoring Committee
DR
Diabetic Retinopathy
DRIL
Disorganisation of retinal inner layer
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EMA
European Medicines Agency
EOS
End of study
EoT
End of Treatment
EoTrial
End of Trial
EWOC
Escalation with overdose control
ETDRS
Early treatment diabetic retinopathy study
EudraCT
European Clinical Trials Database
FA
Fluorescein angiography
FAZ
Foveal avascular zone
FSH
Follicle stimulating hormone
FC
Flow Chart
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GRT
Global Randomization Team
HCG
Human chorionic gonadotropin
HR
Heart rate
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee


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IMP
Investigational Medicinal Product
IOP
Intra-ocular pressure
IPD
Important protocol deviation
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
IVT
Intravitreal
#z
Terminal rate constant of the analyte in plasma
LPLT
Last Patient Last Treatment
LOCF
Last observation carried forward
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MFD
Maximum feasible dose
MedDRA
Medical Dictionary for Drug Regulatory Activities
MoA
Mode of Action
MD
Multiple dosing
MRT
Mean residence time of the analyte in the body
NPDR
Non-proliferative diabetic retinopathy
NOAEL
No observed adverse effect level
Nrp1
Neuropilin 1
OCT
Optical coherent tomography
OCTA
Optical coherent tomography angiography
OPU
Operative Unit
PD
Pharmacodynamic(s) 
PDR
Proliferative diabetic retinopathy
PR
Pulse rate




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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Diabetic retinopathy (DR) can cause visual loss in a number of ways. Microvascular changes 
due to hyperglycemia lead to increases in permeability, and 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. Consequently, a dramatic 
increase of vascular endothelial growth factor (VEGF) drives the formation of retinal new 
vessels (proliferative diabetic retinopathy, PDR), which eventually bleed, and cause a sudden 
decrease in vision (vitreous hemorrhage). In both conditions, VEGF plays a fundamental role, 
and anti-VEGF agents are effective in improving both DME and DR. For patients with PDR, 
panretinal photocoagulation (PRP) is the current standard of care. Patients with severe non-
proliferative diabetic retinopathy (NPDR) and a high risk of developing PDR can also benefit 
from PRP to prevent progression of retinopathy. PRP destroys the ischemic retina, (the major 
source of VEGF), and thus prevents the formation of new vessels, or promotes their 
regression. 
In some patients, however, 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 increasing ischemia in the central part of the retina, the macula, 
as a possible explanation. 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 foveal avascular 
zone (FAZ). In patients with diabetic retinopathy, FA may show an abnormal enlargement of 
the FAZ, which is the most common definition of DMI. Recently, optical coherence
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 can measure the area of the FAZ. Moreover, the 
FAZ measured by FA corresponds well with the FAZ measured by OCTA (R17-3317). For 
these reasons OCTA is likely to become the gold standard in the diagnosis and monitoring of 
DMI. 
There are many 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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Safety Pharmacology
The core safety pharmacology function (central nervous, cardiovascular, respiratory systems)
were evaluated as part of the 4-week GLP repeat toxicity study in rats, the 13-week GLP
intravenous and intravitreal repeat toxicity studies in cynomolgus monkeys, in accordance
with the ICH S6 guidelines (R12-0027).
Overall, BI 765128 did not demonstrate any effects on neurological, cardiovascular,
and respiratory function, implicating an acceptable safety profile for Phase 1 clinical trials.
Data from clinical studies
Seven subjects have been treated in part A intravitreally with BI 765128 at the time of
finalization of CTP version 4.0. No DLEs, drug-related SAEs or Drug-related AEs were 
reported.


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For a more detailed description of the BI 765128, please refer to the current Investigator’s 
Brochure (c31489419-01).
1.3
RATIONALE FOR PERFORMING THE TRIAL
Diabetic Macular Ischemia (DMI) is a complication of diabetic retinopathy (DR) and can 
lead to vision loss. Currently, there are no approved or effective treatments to prevent either 
onset or progression of DMI in DR patients. 
As a transition from preclinical investigations to clinical development in this first-in human 
trial, the safety, tolerability, pharmacokinetics and early biological response of BI 765128 
will be investigated in volunteer subjects with DMI.
This trial will include subjects affected by DMI with significant visual loss since intravitreal 
injections in subjects without the condition would not be considered ethically justifiable. 
This trial will consist of two parts, Part A and Part B.  
In Part A of the trial, 3 rising doses (at least 3 evaluable subjects per dose cohort) are planned 
to be administered intravitreally. Within each dose cohort, all subjects will receive a single 
dose of BI 765128. The next higher dose will only be administered if the treatment in the 
preceeding dose cohort was safe and showed acceptable tolerability (see section 3.1). 
In Part B, subjects will be randomized into a single dose cohort to receive either active IVT 
injection (n=20) or sham injection (n=10) and assessed over a 20-week period. After an initial 
active treatment period of 8 weeks 
 
 subjects will be followed up for an additional 12 weeks without further injections to 
study the treatment effect. This may help guide injection frequency intervals in later studies. 
Part B will provide information about the early biological response of BI 765128 by 
comparing the treated group to the sham group.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
DMI is a progressive disease. Patients with DMI may 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 765128 can improve vascularisation of ischemic 
areas of the retina, because of the long duration of the pathology of DMI, long-term benefits 
for subjects entering this trial are unlikely. Their participation in this trial, however, is of 
major importance to the development of BI 765128, to determine a safe dose selection for 
further clinical trials in this pre-selected patient population.


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1.4.2
Risks
Subjects in this trial are exposed to risks of trial procedures and risks related to ophthalmic 
and systemic exposure to the trial medication.
Risks related to the Mode of Action (MoA)
Because this is the First-in-human trial with BI 765128, special attention will be paid to 
ensure the highest level of safety for subjects when selecting the starting dose, the dose 
escalation steps and the highest dose applied. Based on pre-clinical toxicology studies, no 
specific adverse events are expected. One eye will be selected, according to inclusion 
/exclusion criteria, as the study eye to be treated.
Similar to other intravitreal biologic therapies, there is a risk of ocular inflammation, 
however, this is usually mild and reversible. Subjects will be monitored for ocular 
inflammation and treated if deemed appropriate by the investigator. Because of the low 
dosage used in intravitreal BI 765128, the systemic exposure is expected to be very low and 
hence unlikely to have significant effect.
Available data from pre-clinical toxicity studies
Toxicology


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Risks related to intravitreal injection
Intravitreal injections have potentially serious adverse events, but these are considered rare: 
clinical trials assessing efficacy and safety of EYLEA® intravitreal injections showed serious 
adverse events related to the injection procedure, including endophthalmitis (in between 0.01 
and less than 0.1% of cases) and ocular inflammation (in between 0.1 and less than 1% of 
cases) (R20-0435). Because the procedure of intravitreal injection of BI 765128 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 
those observed with marketed drugs (e.g. EYLEA®). 
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 
suggests 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 765128.
Risks related to blood sampling
Blood sampling may be accompanied by mild bruising and 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 persubject will not exceed appr. 
500 mL. No health-related risk is expected from this blood withdrawal.
Planned measures for monitoring the risks
Subjects will be evaluated with functional, imaging and systemic tests to identify any 
possible adverse event. Specifically, signs of intraocular inflammation will be assessed by 
slitlamp examination of the anterior chamber, vitreous and posterior segment of the eye. This 
will identify flare or cells in the anterior chamber, deposits of material in the corneal 
endothelium, deposits on the anterior capsule of the crystalline lens, signs of vitreous haze, 


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vitreous cells, vitreous snowbanks/snowballs, signs of intraretinal edema or retinal thickening 
and signs of perivascular inflammation e.g. vessel walls sheathing, signs of incipient retinitis 
or intraretinal haemorrhages. 
Spectral domain optical coherence tomography (SD-OCT) will identify possible intraretinal 
cystic edema and will be used to detect 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). Clinical examination or Color Fundus 
Photoraphy will be used to identify possible perivascular reactions.
Additionally, a systemic evaluation will be performed at the timepoints specified in the flow 
charts, to assess possible systemic reactions. This will include body weight, blood pressure, 
heart rate with ECG, full safety lab. The results of these examinations will be reported 
immediately to detect possible safety issues related to the drug or to an inflammatory 
response. 
In the first dose cohort (
 mg) the first subject will be dosed and observed until Visit 6 (day 
29) to evaluate acute AEs, before dosing the second subject of the same cohort. The second 
subject will be observed until Visit 6 (day 29) before dosing the third subject of the same 
cohort. The third subject will be observed until Visit 5 (day 15) before the second dose cohort 
starts. Details of cohort 2 and cohort 3, see Section 3.1. Moreover, the duration of the 
observation will reflect the expected human pharmacokinetics (PK) of BI 765128, with a 
followup for all subjects of 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 (further details in the SMC charter). 
Drug induced liver injury
Although rare, the 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 investigations of selected liver laboratory parameters 
to ensure subjects´ safety.


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Table 1.4.2.6: 1 Overview over 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 765128
Intraocular inflammation
Immunogenic response
Drug-induced liver injury (DILI) 
IVT administration of BI 765128 in 
cynomolgus monkeys showed 
signs of intraocular inflammation 
(See IB chapter 5.3) in some 
animals. These findings in general 
had no impact on ophthalmic 
function (i.e. ERG). These are 
considered ADA responses due to 
the administration of humanized 
protein in monkeys and do not 
predict such reactions in humans.  
18 of 22 cyno monkeys showed 
ADA responses in the 13-week 
IVT toxicology study of BI765128. 
The immunogenicity of 
biotherapeutic products doesn’t 
predict the immunogenicity in 
human. Therefore, potential 
immunogenic response may or may 
not occur in human
This trial is FIH application of BI 
765128, 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)
in plasma will be 
evaluated at day 1,15,29, 57 and 99 
in Part A, and at day 1, 29, 57, 85 
and 141 in Part B
Lab tests will be performed at each 
visit (except day 4 in Part A)


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Possible or known risks of clinical 
relevance for this trial 
Summary of data, rationale for the 
risk 
Mitigation strategy 
Investigational Medicinal Product BI 765128
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 Because the procedure 
of intravitreal injection of BI 
765128 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 subject 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
1.4.3
Discussion
As this is a first in human trial, ophthalmic and systemic examinations are planned at all 
visits of the trial, despite no safety concerns being identified from pre-clinical studies
Blood tests and physical examinations 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 examinations will focus on the risks related to the procedure (e.g. endophthalmitis) 
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 765128 
based on pre-clinical evaluations, it is considered acceptable to expose the subjects to the trial 
risks.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The objective of this trial is to determine the safety and tolerability of BI 765128 in panretinal 
photocoagulation (PRP) treated diabetic retinopathy (DR) patients with diabetic macular 
ischemia (DMI), based on the primary endpoint, the occurrence of dose limiting events 
(DLE) (see Section 5.2.1) in the 7 days post administration (Part A) or the occurrence of 
drug-related AEs until EOS (Part B) and to investigate the safety, tolerability and early 
biological response after multiple IVT injections of BI 765128.
2.1.2
Primary endpoint(s)
Part A: 
∀
Number of subjects with ocular dose limiting events (DLEs) from drug administration 
until day 8 (7 days after treatment)
Part B:
∀
Number of subjects with drug related AEs from drug administration until EOS
2.1.3
Secondary endpoint(s)
Part A:
∀
Number of subjects with drug related AEs at EOS
∀
Number of subjects with any ocular AEs (eye disorders) at EOS
Part B:
∀
Change from baseline of the size of the FAZ in optical coherence tomography 
angiography (OCTA) at visit 5
∀
Change from baseline of the size of the FAZ in optical coherence tomography 
angiography (OCTA) at visit 6
∀
Change from baseline of the size of the FAZ in optical coherence tomography 
angiography (OCTA) at visit 7
∀
Change from baseline of BCVA at Visit 7
∀
Number of subjects with any ocular AEs (eye disorders) from drug administation until 
EOS


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A Safety Monitoring Committee (SMC) will be established to regularly review the data and 
to provide recommendation for the further conduct of the trial. 
After each subject has completed visit 4 follow-up assessments (7 days after drug 
administration), the dosing investigator will complete the ‘DLE Safety Review Form’ to 
summarise the key safety findings for the subject. Once completed, the site will send the form 
to the CTM and CTL. 
First 2 subjects in cohort 1 (
)
Once the first two subjects have attended visit 6 (day 29), each dosing investigator will 
complete the ‘Ocular Inflammation Review forms’.
Subsequent subjects in part A
Once the following subjects have attended visit 5 (day 15), each dosing investigator will 
complete an ‘Ocular Inflammation Review form’ to identify any ocular inflammation. Once 
completed, the site will send the form to the CTM and CTL. Once the last subjectin each
cohort has attended visit 5 (day 15), the CTL will forward the ‘DLE Safety Review Forms’  
and the ‘Ocular Inflammation Review Forms’ for that cohort to other members of the SMC to 
carefully evaluate all available systemic (i.e. physical examinations, safety lab parameters, 
ECG and AEs) and ophthalmological (i.e. as defined in section 5.2.1 of the CTP (DLEs)) 
safety data. The SMC will meet after the last subject of each dose cohort has attended visit 5.
A Bayesian logistic regression model (BLRM), based on a weakly 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 subjects 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 subject), 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 subjects of a previously untested dose level,
subsequent enrolment to that cohort will be stopped.
The MFD may be considered reached if all of the following criteria are fulfilled:
∀
Next recommended dose by the BLRM = current dose
∀
At least 12 subjects have been treated in the trial
∀
At least 6 subjects have been treated at the MFD
Part B of the study will only start if the highest dose is tolerated. Once the last subject in the 
highest dose cohort of Part A has attended visit 5 (day15) the SMC will meet and evaluate all 


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DLE data as well as available systemic and ophthalmological safety data. The decision on 
whether to proceed to Part B will be taken based on the occurrence of DLEs.
Part B:
In Part B, the highest dose will be used (
). Thirty subjects will be recruited, 2:1 ratio of 
active treatment versus sham. Subjects dosed in Part A of the trial will not be included. 
Subjects will be randomized to receive either active treatment or sham injection.
In Part B, subjects will receive three consecutive doses/sham injections over a 3-month 
period (
). All subjects included in the part B of the trial, will be observed 
for safety and efficacy for 12 weeks after the last injection. 


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This trial is designed to confirm that the highest dose of BI765128 can be used for further 
testing in phase IIb trials. The trial consists of separate parts, A and B. The SRD dose 
escalation part is included and was designed with the goal to minimize the number of subjects 
exposed to subtherapeutic doses while on the other hand preserving safety and rapid dose 
finding. This part of the trial will enrol subjects with DMI as IVT injections in healthy 
subjects would not be considered ethical. 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 subjects 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) guideline on small populations [R07-4856] and by the Food and Drug Administration 
(FDA) [R13-4881].
Part B will consist of a MD cohort 
 and will start after Part 
A. Subjects will either be randomized to the active treatment group or to a 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. This 
data will further inform the injection frequency and intervals in later studies.
An extended SMC will be established for both part A and part B. The SMC shall operate 
under the principles specified in the SMC charter. The primary objective of the SMC is to 
ensure and protect the safety and well-being of the trial subjects and to regularly review the 
trial data and provide recommendation for the further conduct of the trial (see section 8.7).


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3.3
SELECTION OF TRIAL POPULATION
This trial will recruit up to 48 subjects in total; up to 18 subjects in Part A (depending on the 
dose escalation) and 30 subjects in Part B. In Part B subjects will be randomized to receive 
either active IVT injection or sham injection.
Screening of subjects 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 subjects have been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
subjects for this trial.
A log of all subjects 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 the investigational drug or not.
Subjects who do not fulfil all eligibility criteria for a reason that later resolves allowing 
eligibility criteria to be met after the initial screening visit, can be re-screened up to one time. 
If a subject 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 3-6 countries and at approximately 50 sites.
3.3.1
Main diagnosis for trial entry
Diabetic macular ischemia (DMI) in patients previously treated with Panretinal 
photocoagulation (PRP) for diabetic retinopathy (DR)
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Part A
1. Panretinal photocoagulation-treated DR patients with either no or inactive retinal 
neovascularization per investigator judgement in the study eye
2. Male or female subjects of age ≥18 years
3. Evidence of DMI per investigator´s judgement, defined as any degree of disruption of 
retinal vascularity in OCTA
4. HbA1c of ≤ 12.0% 
5. Best-corrected VA ≤75 letters (20/32) in the study eye 
6. Best corrected VA in the non-study eye must be equal to or better than best corrected 
VA in the study eye. If both eyes are eligible (per inclusion #5) and have identical 
best corrected VA the investigator may select the study eye.
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 method 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 


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contraception methods meeting these criteria is provided in the patient information in 
Section 4.2.2.3.
8. Signed and dated written informed consent in accordance with ICH GCP Harmonized 
Guideline for Good Clinical Practice 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 amenorrhea, a single FSH measurement is insufficient.
Part B
1. Panretinal photocoagulation-treated DR patients with either no or inactive retinal 
neovascularization per investigator judgement
2. Male or female subjects of age ≥18 years
3. Presence of significant DMI: Large foveal avascular zone (FAZ) defined as those with 
≥0.5mm2 area present on OCTA. If FAZ is <0.5mm2 then an enlarged peri-foveal 
inter-capillary space in at least 1 quadrant will be sufficient.
4. HbA1c of ≤ 12.0% 
5. Best-corrected VA ≤85 letters (20/20) in the study eye 
6. If both eyes are eligible, the investigator may select either eye to be the study eye.
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 method 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.
8. Signed and dated written informed consent in accordance with ICH GCP Harmonized 
Guideline for Good Clinical Practice 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 amenorrhea, a single FSH measurement is insufficient.


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3.3.3
Exclusion criteria
Part A:
1. Subjects receiving IVT injections for active Diabetic Macular Edema (DME) (anti-
VEGF, steroids) and macular laser in the previous 3 months to screening in the study 
eye
2. Subjects receiving anti-VEGF IVT injections for active DR in the previous 3 months 
to screening in the study eye
3. Current or planned use of medications known to be toxic to the retina, lens or optic 
nerve (e.g. desferoxamine, chloroquine/hydrochloroquine, chlorpromazine, 
phenothiazines, tamoxifen, nicotinic acid, and ethambutol)
4. Additional progressive eye disease in the study eye that could compromise best 
corrected VA (BCVA), uncontrolled glaucoma (IOP>24), 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 and OCTA.
5. Any intraocular surgery in the study eye within 3 months prior to screening
6. Glaucoma tube shunts
7. Aphakia or total absence of the posterior capsule. Yttrium aluminum garnet (YAG) 
laser capsulotomy permitted, if completed more than 3 months prior to screening, in 
the study eye
8. Subjects 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 subject an unreliable trial 
subject)
9. Previous participation in this trial or in other trials with IVT injections administered 
within 3 months of screening. Subjects enrolled in trial 1436-0001 SRD part (after 
five half-lives since the last trial dose, if the participants were not discontinued from 
study due to safety reasons, and if no toxicity, adverse events or safety concerns 
related to the previous participation are present at the time of screening) and sham 
arm in the MD part may be enrolled into Part A of this trial.
10. 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) Putting the subject at risk because of participation in this study
b) Influence the results of this study
c) Cause concern regarding the subject’s ability to participate in the study
11. Known hypersensitivity to any of the ingredients used in the investigational medicinal 
product (IMP) formulation
12. Active intraocular inflammation in the study eye
13. Active infectious conjunctivitis in either eye
14. 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. Subjects with malignancy for which the subject has undergone resection, radiation or 
chemotherapy within past 5 years. Subjects with treated basal cell carcinoma or fully cured squamous cell carcinoma are 
allowed.


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Part B:
1. Diabetic Macular Edema (DME), defined as a CST ≥ 305μm for men and ≥ 290 μm
for women (Optovue Angiovue) in the study eye
2. Subjects receiving IVT injections for active DME (anti-VEGF, steroids) and macular 
laser in the previous 3 months to screening in the study eye
3. Subjects receiving anti-VEGF intravitreal IVT injections for active DR in the 
previous 3 months to screening in the study eye
4. Heavily lasered macula in the study eye per investigator judgement
5. History of vitrectomy in the study eye
6. Epiretinal membrane with extended foveal contour distortion in the study eye 
7. Current or planned use of medications known to be toxic to the retina, lens or optic 
nerve (e.g. desferoxamine, chloroquine/hydrochloroquine, chlorpromazine, 
phenothiazines, tamoxifen, nicotinic acid, and ethambutol)
8. Additional eye disease in the study eye that could compromise best corrected VA 
(BCVA). Significant visual field loss, uncontrolled glaucoma (IOP>24), clinically 
significant diabetic maculopathy, 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 and OCTA
9. Any intraocular surgery in the study eye within 3 months prior to screening
10. Glaucoma tube shunts
11. Aphakia or total absence of the posterior capsule. Yttrium aluminum garnet (YAG) 
laser capsulotomy permitted, if completed more than 3 months prior to screening) in 
the study eye
12. Subjects 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 subject an unreliable trial 
subject)
13. Previous participation in this trial or in other trials with IVT injections administered
within 3 months of screening. Subjects enrolled in the sham arm of the MD part of 
trial 1436-0001 may be enrolled into Part B of this trial.
14. 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 subject at risk because of participation in the study
b. Influence the results of the study
c.
Cause concern regarding the subject’s ability to participate in the study
15. Known hypersensitivity to any of the ingredients used in the IMP formulation
16. Active intraocular inflammation in the study eye
17. Active infectious conjunctivitis in either eye
18. 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. Subjects with malignancy for which the subject has undergone resection, radiation or 
chemotherapy within past 5 years. Subjects with treated basal cell carcinoma or fully cured squamous cell carcinoma are 
allowed.


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3.3.4
Withdrawal of subjects from treatment or assessment
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the subjects in the trial: if possible, on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful subject selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment and first 
administration of trial medication, as well as the explanation of the consequences of 
withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the subject files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see sections 5.2.7.1 and 5.2.7.2).
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the 
decision. 
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing 
or able to adhere to the trial requirements in the future. 
3. The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment.
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).An AE or clinically significant 
laboratory change or abnormality occurs that the investigator judge to warranting 
discontinuation of treatment 
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the 
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all subjects 
or take any other appropriate action to guarantee the safety of the trial subjects. 
Even if the trial treatment is discontinued (Part B), the subjects remain in the trial and, given 
their agreement, will undergo the procedures for early treatment discontinuation and follow-
up as outlined in the Flow Chart II and section 6.2.3.
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a subject wants to withdraw consent, the investigator should be involved in the discussion 
with the subject and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued
follow-up after trial treatment discontinuation, please see section 3.3.4.1.


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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 the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see section 3.3.4.1.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
For the following scenario further enrolment and entering in part A and further treatments in 
part B 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 subjects (regardless of the system organ class) 
confirmed by both the investigator and sponsor as having a reasonable causal 
relationship to the IMP administration.
If the trial stops because one of the stopping rules is triggered, then the trial re-start will only 
be possible after regulatory authority approval via a substantial amendment.
Further follow up of subjects affected will occur as described in section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects 
Part A:
Subjects withdrawn before visit 4 for another reason than DLE or subjects 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 subjects will be replaced if not decided otherwise by 
the SMC. Subjects who come off study due to a DLE will not be replaced.
Part B:
If some subjects do not complete the trial, the Clinical Trial Leader together with the Trial
Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. A replacement subject will be assigned a unique trial subject number and will be 
assigned to the same treatment as the subject he or she replaces.






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detail. Based on that and on the results of the updated BLRM, a decision on the next dose 
level to be tested is made.
In general, recruitment for Part A will be done successively for the dose groups, i.e. if the 
required number of subjects 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 subjects for the dose groups will 
neither be influenced by the trial personnel nor by any characteristics of the subjects, but only 
by temporal availability. Subjects from the Part A are not allowed to participate in Part B.
The highest dose (
), if established as safe and tolerable during Part A will be used in 
Part B after Part A has been completed. If the highest dose (
) is not considered safe 
and tolerable Part B will not commence. In Part B subjects will be randomized to receive 
either active IVT treatment or sham injection according to a randomization plan at visit 2 via 
Interactive Response Technology (IRT). 20 subjects will receive IVT treatment and 10 will 
receive sham injection.
The randomization procedure is described in Section 7.5.
4.1.4
Drug assignment and administration of doses for each subject
BI 765128 will be administered intravitreally. “BI 765128 solution for injection 
” 
and “Solvent for dilution of BI 765128 Solution for Injection” will be provided by BI. Site 
personnel who are qualified to prepare IVT injections will prepare the drug product according 
to the ‘Handling and Preparation Guidelines’. 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 Part A
Dose group 
(mg)
Visit 2 
Day 1
Visit 3 
Day 4
Visit 4
Day 8
Visit 5
Day 15
Visit 6
Day 29
Visit 7
Day 57
To determine the dose regimen for the next cohort, the available information (including DLEs 
and AEs that are not DLEs) 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 escalation is 
considered appropriate by the SMC (see Section 4.1.2 for details on dose rationale and 
escalation concept). 


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Table 4.1.4: 2 Planned dose and treatment schedule for the Part B
Dose group 
(mg)
Visit 2 
Day 1
Visit 3 
Day 29
Visit 4
Day 57
Visit 5
Day 85
Visit 6
Day 113
4.1.5
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) to be 
used in accordance with local standards and regulations.
Part B is designed double-masked and personnel of the trial site are masked. Therefore, in 
Part B, 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 765128, subjects will be monitored according to standard local
practice. In this minimum post-dose observation period, systemic and ocular conditions will 
be monitored according to local practice for such procedures.
4.1.6
Masking and procedures for unmasking
Masking
Part A of the trial is open label. Part B is designed double-masked. The treatments 
administered (active or sham injection) will be masked to subjects and to the dedicated 
personnel of the trial site. The table below summarizes the masking level of individual 
functions in Part B of the trial.


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Table 4.1.6.1:1
Overview about masking status of trial role and functions in Part B
Role/function
Timing of Unmasking / receiving access to the 
treatment information (including rationale)
Subjects
Masked until data ready for final analysis.
Investigator/Site staff
Masked until data ready for final analysis.
Pharmacist*
Unmasked during trial conduct. 
Injector**
Unmasked during trial conduct
Sponsor (incl. clinical 
trial/project team) SMC and 
database
Unmasked descriptive analyses will be performed on the 
subjects in the database during the trial conduct (see 
Section 7.3.7). The release of the treatment information 
at the individual time points will be documented 
accordingly.
Bioanalytical Staff
Unmasked as requested for analysis of bioanalytical 
samples.
* Unmasked independent pharmacist (qualified person) with no other involvement in the trial will prepare the active IVT 
injection
** Unmasked independent injector with no other involvement in the trial will administer active/sham injections.
Within the central ECG lab, readers involved with interval measurements will be masked 
with respect to treatment, visit and demographic information collected. During the time a 
role/function is masked, the treatment information is kept restricted by the global 
Randomization Team (gRT) per Sponsor Standard Operating Procedure (SOP).
Unmasking and breaking the code
Emergency unmasking will be available to the investigator via IRT. It must only be used in 
an emergency situation when the identity of the trial drug must be known to the investigator 
in order to provide appropriate medical treatment or otherwise assure safety of trial subjects. 
The reason for unmasking must be documented in the source documents and/or appropriate 
CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to
access the randomization code for individual subjects during trial conduct. The access to the
code will only be given to authorised Pharmacovigilance representatives for processing in the
PV database system and not be shared further.
4.1.7
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated 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 IRT system, which will also 
monitor expiry dates of supplies available at the sites.


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For details of packaging and the description of the label, refer to the ISF.
4.1.8
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation. 
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate CRA (as provided in the list of contacts) must be contacted immediately.
4.1.9
Drug accountability
The investigator or designee will receive the investigational drugs delivered by 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,
∀
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 license 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 or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the 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 (part A) assigned to the investigational medicinal product and 
trial subjects. The investigator or designee will maintain records that document adequately 
that the subjects were provided the doses specified by the Clinical Trial Protocol (CTP) and 
reconcile all investigational medicinal products received from the sponsor. At the time of 
return to the sponsor and/or appointed CRO, the investigator or designee must verify that all 
unused or partially used drug supplies have been returned by the clinical trial subject and that 
no remaining supplies are in the investigator’s possession.


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
Medications listed under the exclusion criteria (Section 3.3.3) are restricted during the trial.
For the Study eye no other treatment (IVT or otherwise) is allowed during the trial.
The fellow eye can be treated with 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. desferoxamine, 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 subject or partner of a trial subject) must use a condom (regardless of vasectomy) 
if their sexual partner is a WOCBP. 
WOCBP (trial subject or partner of a trial subject) 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 


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Or
Subjects must abstain from male-female sex if this is defined as being in line with the 
preferred and usual lifestyle of the subject. 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.
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.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the eCRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
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. All ophthalmologic examinations will be performed on both 
eyes, as described below.
Centrally collected ophthalmological data (color fundus photography, SD-OCT, OCTA) will 
be transferred from the Central Reading Center (CRC) to the sponsor’s database. The local 
measurement data (BCVA, Slit lamp, IOP, LLBCVA) will be transferred to the appropriate 
eCRFs and will remain at the study sites as source documents.
If clinically significant worsening is observed in the assessments of efficacy during the study, 
it will be reported as AE in the eCRF (please also refer to Section 5.2.7).
SD-OCT/OCT-Angiography
The retinal layers and their thickness can be visualized and measured by SD-OCT. The 
assessment will be performed by a qualified person, and only specified OCT equipment will 
be used. OCTA is a non-invasive imaging technique that provides high-resolution volumetric 
blood flow information without the use of dye. The assessment is also performed by a 
qualified person, and only specified device(s) will be used. 
OCT and OCTA images will be sent to an independent CRC for evaluation. A detailed 
manual for OCTand OCTA image acquisition and data transmission will be provided.
Visual Acuity measured by ETDRS letter charts
BCVA will be measured using the early treatment diabetic retinopathy study (ETDRS) VA 
chart. The BCVA score is the number of letters read correctly by the subject. The assessment 
will be performed by a trained person under specified conditions regarding examination room 
and equipment.


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5.2
ASSESSMENT OF SAFETY
5.2.1
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 (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.
5.2.2
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. 
Measurement of height and body weight will be performed at the time points specified in the 
flowchart.
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 or ultrawide field imaging, will be 
obtained from both eyes by a qualified person according to the imaging manual. Slit lamp 
examination and IOPs will be performed by a qualified person.
This examination will be performed at the time-points defined in the Flow Chart I and Flow 
Chart II.
5.2.3
Vital signs
Vital signs will be evaluated at the time points specified in the flowchart, 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 the site.
5.2.4
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.
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. 
Subjects do not have to be fasted for the blood sampling for the safety laboratory. 
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 adverse events (please refer to section 5.2.7).
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 eDC system.
The amount of blood taken from the subject 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 lab at the trial site is not possible, safety lab analyses can be 
performed at a local lab. The results of the lab 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 lab parameters, please 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 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
∀
Blood
∀
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)
5.2.5
Electrocardiogram
12-lead resting ECG
Recording
Single 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 subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled 
for the same time 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 subject 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 centrally 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) ECG standard findings list as specified in the data transmission
agreement.
For masking arrangements see Section 4.1.6. ECG interval measurements from a particular 
subject 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 subject will be 
removed from the trial and will receive the appropriate medical treatment. 
5.2.6
Other safety parameters
Not applicable.
5.2.7
Assessment of adverse events
Definitions of AEs 
5.2.7.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the eCRF 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 exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.7.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation or prolongation of existing hospitalisation
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement 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 


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room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
5.2.7.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of 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. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described 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 drug and must be reported as 
described in 5.2.7.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.2.7.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.7.2.2.
The following are considered as AESIs:
∀
DLE
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.
∀
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
o
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2 
fold ULN measured in the same blood draw sample, or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the 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 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.


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5.2.7.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.2.7.1.6
Causal relationship of AEs
Medical judgement 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).
∀
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.


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Adverse event collection and reporting
5.2.7.2.1
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
(the End of Study (EOS) visit): all AEs (serious and non-serious) and all AESIs.
∀
After the individual subject’s end of trial: 
the investigator does not need to actively monitor the subject 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 5.2.7.2.2), but not on the CRF.
5.2.7.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific contact details will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and 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 subject’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
5.2.7.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has received trial medication, the investigator must report any drug 
exposure during pregnancy in a trial subject 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 subject 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 Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).




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be assessed in the study eye at times indicated in the Flow Chart II. If feasible BI 765128 
levels in 
samples might be determined. In total, four 
 
collections are planned in the multiple dosing part of the trial.
Full instructions for collection, labelling, storage and shipment of samples are provided in the
Laboratory Manual.
Additionally, if feasible proteins affected by the drug’s mode of action might be determined 
in serum samples. 
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an intravitreally administered drug and are widely 
used in clinical trials. Within the ophthalmologic examinations, colour fundus photography, 
slit lamp IOP and SD-OCT are considered standard, whereas OCTA is of exploratory nature. 
The pharmacokinetic parameters and measurements outlined in Section 5.3 are generally used 
assessments of drug exposure. 


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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 plasma 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, OCTA, colour fundus photography. 
∀
At the end: ocular tonometry (for determination of IOP)
6.2.1
Screening and run-in period(s)
Screening Period
The screening visit does not need to be done with the subject in a fasted state. All subjects 
must sign an Informed Consent consistent with ICH GCP guidelines prior to any study 
specific procedures. This includes the option that the subject signs the Informed Consent 
during an extra contact to the study site prior to the actual screening visit. The subject should 
be recorded on the enrolment log as a screened subject when Visit 1 is performed. Visit 1 is 
the beginning of the screening period. As soon as eligibility of an enrolled subject is 
confirmed, the treatment visit (Visit 2) may be performed. If the subject does not meet 
inclusion/exclusion criteria, the subject must be recorded in the eCRF as a screen failure.
Applies to part A: In case of closed dose groups no further rescreening activities for a 
screened and eligible subject 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 
clinically significant findings observed during ophthalmological examinations at Visit 1 need 
to be documented as Baseline Conditions.


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Medical History
All clinically relevant medical history according to the investigator judgment will be captured 
in the appropriate eCRF.
IRT
All subjects that are screened must be registered with IRT. If the subject 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
Subjects 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, subject must be registered in IRT, which will then provide a new subject number, 
and the subject 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 
if the images are not older than 28 days at the re-screening visit; otherwise, new images have 
to be performed.
6.2.2
Treatment period(s)
For Part A, masking is not required for the IVT injection preparation or administration. For 
Part B, IVT injection will be prepared by the unmasked pharmacist/qualified person (Section 
4.1.6). In addition, an unmasked injector (Section 4.1.6) 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 Part A and Visits 2, 3 and 4 for Part B) 
after the other ophthalmologic assessments in the Flow Chart I and Flow Chart II have been 
performed (please see Section 4.1 for details). 
6.2.3
Follow-up period and trial completion
Subjects 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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Part A
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 eCRF has to be completed.
Part B
Visit 7/End of Study:
The Visit 7/EOS will be performed 28 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 subject 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 subject is not willing to continue in the trial and wants to withdraw consent prior to the 
end of the study, Visit 7 (Part A)/ Visit 6 (Part B) should be scheduled as soon as possible, 
and also Visit 8/EOS(Part A)/ Visit 7/EOS(Part B) should be performed to assess for safety.
The End of Study eCRF has to be filled in even if subject 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.
Subjects 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 subject’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
The objective of this trial is to determine the safety and tolerability of BI 765128 in panretinal 
photocoagulation (PRP) treated diabetic retinopathy (DR) patients with diabetic macular 
ischemia (DMI), based on the primary endpoint, the occurrence of dose limiting events 
(DLE) (see Section 5.2.1) in the 7 days post administration (Part A) or the occurrence of 
drug-related AEs until EOS (Part B).The safety, tolerability and early biological response 
after multiple IVT injections of BI 765128 will also be investigated.
7.1
STATISTICAL DESIGN – MODEL
This trial will consist of a Part A followed by a Part B. The Part A will be conducted non-
randomized, open-label, and uncontrolled. Part B will be conducted double-masked 
randomized and sham-controlled.
Part A:
The dose escalation will be guided by a Bayesian 2-parameter logistic regression model with 
overdose control [R13-4803, R13-4806]. 
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* = 
mg 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 highest dose level with posterior 
probability of the DLE rate falling in the target interval [0.00, 0.25) among the doses 
fulfilling EWOC. Thus, applying the EWOC criterion 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 subjects are 
required. However, the SMC may decide to include additional number of subjects at this dose 
level.


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Since a Bayesian approach is applied, a prior distribution f(θ) for the unknown parameter 
vector θ needs to be specified. This prior distribution will be specified as a mixture of three 
multivariate normal distributions, i.e.
f(θ) = a1f1(θ) + a2f2(θ) + a3f3(θ)
with ai, i = 1, 2, 3 the prior mixture weights (a1+ a2+ a3 = 1), and fi(θ) = MVN(μi, Σi), the 
multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, where 
Σ = 
	
,
 , ,		
 , ,		
	
,		
.
Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.
For the current study, no relevant information in the form of human data is available, since no 
study in a comparable population has been conducted. Therefore, the three mixture 
components were established as follows:
1.
A weakly informative prior was derived reflecting the a priori assumption that the 
median DLE rate at the starting dose of 
 would equal 0.02, and the median DLE 
rate at the maximum dose of 
would equal 0.1. This yields μ1 = (-2.197, 0.052). 
The standard deviations were set such that medium uncertainty about the parameter 
means is reflected, and the correlation was set to 0, thus yielding σ1,11 = 1.2, σ1,22 = 1.5
and ρ1 = 0, respectively. The prior weight a1 for the first component was chosen as 0.9.
2.
A high-toxicity weakly informative prior was derived reflecting the case that the 
compound would be much more toxic than expected. For this prior component, it was 
assumed that the median DLE rate at the starting dose of 
 would equal 0.1, and the 
median DLE rate at 
would equal 0.3. These assumptions yield μ2
=(-0.847, -0.176) . The standard deviations and correlations were such that large
uncertainty about the parameter means is reflected, and the correlation was set to 0, thus 
yielding σ2,11 = 2, σ2,22 = 1 and ρ2 = 0, respectively. The prior weight a2 for the second 
component was chosen as 0.05.
3.
A low-toxicity weakly informative prior was derived reflecting the case that the 
compound would be much less toxic than expected. For this prior component, it was 
assumed that the median DLE rate at the starting dose of 
 would equal 0.001, and 
the median DLE at 
would equal 0.01. These assumptions yield μ3 =(-4.595, 
0.362) . The standard deviations and correlations were set to σ3,11 = 2, σ3,22 = 1. The 
correlation was set to 0, i.e. ρ3 = 0. The prior weight a3 for the third component was 
chosen as 0.05.
A summary of the prior distribution is provided in Table 7.1: 1. Additionally, the prior 
probabilities of DLEs at different doses, as well as the corresponding probability of targeted 
and overdosing, are shown in Table 7.1: 2. Graphically, the prior medians with 
accompanying 95% credible intervals are shown in Figure 7.1: 1. As can be seen from both 
Table 7.1: 2 and Figure 7.1: 1, the prior medians of the DLE probabilities are in line with the 
prior medians derived from the weakly informative prior, and the uncertainty around the 
medians is realtively large, showing the medium amount of information this prior provides. 
This is also supported by the prior sample size, i.e. the information contained in the prior. 
This is approximately equal to 3.7 subjects. A detailed evaluation of the model using 
hypothetical data scenarios and operating characteristics is provided in Appendix 10.3.




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The prior may be updated once the trial has started in case new data that can be used will be 
available. Only subjects for which the occurrence of DLEs within the evaluation period can 
be evaluated will be considered. The prior that is used for each BLRM analysis for the SMC 
meetings will be documented in the SMC minutes, the prior used for the final analysis will be 
documented in the TSAP in case a different prior than described above will be used.
The MFD may be considered reached if all of the following criteria are fulfilled:
∀
Next recommended dose by the BLRM = current dose
∀
At least 12 subjects have been treated in the trial.
∀
At least 6 subjects have been treated at the MFD.
Part B: 
The size of the foveal avascular zone (FAZ) is associated with visual loss. Measuring FAZ by 
OCTA is highly reproducible. The assumed treatment effect of BI 765128 (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, the highest dose, of Part A will be used for Part B, the MD study. The highest 
dose is usually limited by the maximum dose possible in the IVT injectable volume.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No confirmatory testing is performed and hence no null and alternative hypotheses are 
defined. 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. A discussion of the sample size is provided in Section 7.6.
7.3
PLANNED ANALYSES
7.3.1
Subject analysis sets
The main analysis populations are defined below. In the TSAP, further analysis data sets may 
be defined. Subjects will be analysed according to the assigned treatment, unless otherwise 
specified. 
Important protocol deviations (IPD) categories will be defined in the IPD specificatioin 
document. IPDs will be identified no later than in the Report Planning Meeting, and the iPD 
categories will be updated as needed. The handling of subjects with iPDs will be described in 
the TSAP.
Treated set (TS)
For part A the treated set includes all subjects who were treated with at least one dose of 
study drug.


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For part B the treated set includes all subjects who were randomized and treated with at least 
one dose of study drug (either treatment with BI 765128 or Sham).
7.3.2
Primary endpoint analyses
Part A:
The primary safety endpoint “Number of subjects with ocular (in the study eye) DLEs from 
drug administration till day 7” will be analysed descriptively, based on the TS.
Part B:
The primary safety endpoint “Number of subjects with drug-related AEs from drug 
administration until EOS” will be analysed descriptively, based on the TS.


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7.3.3
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). The endpoint Central retinal thickness (μm) will be analyzed in the same way as 
the endpoint FAZ. In addition, the BCVA will be analyzed using a generalized linear model.
Analyses regarding safety and efficacy will be performed on the TS.
7.3.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. For BI 765128, 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 
ontreatment period for evaluation. The safety analysis will be performed by planned dose 
group.
All treated subjects will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the
EOS. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
For all analyses the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomized treatment will be discussed in the minutes of 
the Report Planning Meeting).
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.


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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 (See 
section 5.2.7.2.1).
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of subjects with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
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).
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.
7.3.6
Other Analyses
In order to characterize BI 765128’s exposure-response relationship, a pharmacometric
population PKPD analysis may be performed. Furthermore, if data allow, a pharmacometric 
analysis will be conducted to estimate vitreal concentrations. The pharmacometric analysis 
will not be part of the CTR but will be provided separately.
7.3.7
Interim Analyses
No interim analysis is planned.
The sponsor will continuously monitor the safety. 


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Part A
The dose escalation design of the Part A foresees that the sponsor and the SMC perform 
regular safety evaluations, the SMC will meet after the last subject of each dose cohort has 
attended Visit 5 (section 3.1) These evaluations will be unmasked to dose.
Part B
The sponsor and the SMC perform one safety evaluation, the SMC will meet after 50% of the 
subjects were randomized and finished Visit 5. This analysis will involve descriptive and 
graphical presentation of primary, secondary and further endpoints. These evaluations will be 
unmasked to dose.
In addition, a fast track analysis will be performed after the final subject of Part B has 
attended Visit 6 (i.e. approximately 8 weeks after receiving the final dose).
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
Missing baseline laboratory values will be imputed by the respective values from the
screening visit. No other imputations will be performed on missing data although every effort
will be made to obtain complete information on all AEs, with particular emphasis on
potential DLEs.
7.4.3
Efficacy
All data will be analyzed and presented without any form of imputation. For the statistical 
sensitivity analysis missing values will be imputed using LOCF.
7.5
RANDOMISATION
Part A
Subjects within a cohort receive the same trial medication, therefore no randomization for 
treatment assignment is performed.


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Part B
Subjects will be randomized in a 2:1 ratio (BI 765128: Sham injection).
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomization list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
The randomization list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
Part A:
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
subjects and a maximum of 18 subjects 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 10.3). Fewer subjects might be needed based on the recommendation of the SMC.
However, the actual number of subjects will depend on the number of dose cohorts tested.
Based on the simulation study to evaluate operating characteristics of the BLRM, about 15
evaluable subjects are expected to be treated in the dose escalation part for the model to have
reasonable operating characteristics relating to its MFD recommendation.
Part B:
In the publication Samara et al. [R17-3318] estimates for FAZ means and standard deviations 
(SD) were derived. The worst case was for PDR subjects 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 0.1 
mm2 seems to be reasonable to be used in calculation of risk probabilities. With 20 subjects 
in the BI 765128
 arm and 10 subjects in the sham arm, there is a likelihood of 81.7% 
of observing a treatment effect larger than 6% (a reduction of 0.0462 mm2) and a likelihood 
of 10.2% of observing a treatment effect smaller than 4% (a reduction of 0.0308mm2) when 
the assumed mean treatment difference is10%. Assuming a mean treatment difference of 0% 
there is a likelihood of 12.3% observing a treatment effect larger than 6% and a likelihood of 
78.7% of observing a treatment effect smaller than 4%.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014 and other relevant regulations. Investigators and site 
staff must adhere to these principles. Deviation from the protocol, the principles of ICH GCP 
or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the subject.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
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 respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to subject participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.”
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. See section 4.1.6.2 for rules 
about emergency code breaks. For drug accountability, refer to section 4.1.9.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. 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 subject 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 subject, documented 
in their medical records, would be acceptable.
Before sending or uploading those copies, the investigator must ensure that all subject
identifiers (e.g. subject’s name, initials, address, phone number, social security number) have 
properly been removed or redacted from any copy of the subjects’ source documents.


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If the subject is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the subject file.
For the CRF, data must be derived from source documents, for example:
∀
Subject identification: gender, year of birth (in accordance with local laws and 
regulations)
∀
Subject participation in the trial (substance, trial number, subject number, date subject
was informed)
∀
Dates of subject’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
Adverse events and outcome events (onset date (mandatory), and end date (if available))
∀
Serious adverse events (onset date (mandatory), and end date (if available))
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)
∀
Completion of subject’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
∀
Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial subject meets 
all inclusion criteria and does not meet any exclusion criteria. The absence of records 
(either medical records, verbal documented feedback of the subject or testing conducted 
specific for a protocol) to support inclusion/exclusion criteria does not make the subject
eligible for the clinical trial.
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.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.


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8.3.3
Storage period of records
Trial site(s):
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 subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Not applicable.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial
(“Last Patient Completed”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
subject in the whole trial is administered the last dose of trial treatment (as scheduled per 


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protocol or prematurely). Individual investigators will be notified of 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.
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 subjects 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 subject
(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 part A and part B. The SMC shall operate 
under the principles specified in the SMC charter. The primary objective of the SMC is to to 
ensure and protect the safety and well-being of the trial subjects and to regularly review the 
trial data and provide recommendation for the further conduct of the trial. 
The SMC is a multidisciplinary group composed of the co-ordinating investigator, 
participating investigators (as deemed necessary) with treated subjects in the cohort that will 
be evaluated in the meeting (Part A 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 subjects 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 access documents 
provided by the sponsor.


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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 (CT 
Managers), 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 by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
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 765128 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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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R17-3317
Botto de Borros Garcia JM, Toledo Lima T, Noguera Louzada R, 
Thome Rassi A, Cruvinel Isaac DL, Avila M 
Title: Diabetic macular ischemia diagnosis: comparison between 
optical coherence tomography angiography and fluorescein 
angiography. Source: J Ophthalmol 2016; 2016; 3989310 
R17-2540
Committee for Medicinal Products for Human Use (CHMP): guideline 
on immunogenicity assessment of biotechnology-derived therapeutic 
proteins: draft (24 September 2015, EMEA/CHMP/BMWP/
14327/2006 rev. 1). Source: http://www.ema.europa.eu/docs/
en_GB/document_library/Scientific_guideline/2015/1 0/
WC500194507.pdf (access date: 17 July 2017); London: European 
Medicines Agency (EMA); 2015.
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European Medicines Agency (EMA). Committee for medicinal 
products for human use (CHMP): ICH guideline S6 (R1) - preclinical 
safety evaluation of biotechnology-derived pharmaceuticals: step 5 
(June 2011, EMA/CHMP/ICH/731268/1998). Source: 
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London: European Medicines Agency (EMA); 2011.
R20-4303
Wakshull E, Quarmby V, Mahler HC, Rivers H, Jere D, Ramos M, et al 
Title: Advancements in understanding immunogenicity of 
biotherapeutics in the intraocular space. Source: AAPS J 2017; 19(6); 
1656-1668
R20-0435
Eylea (aflibercept) injection, for intravitreal use (Regeneron 
Pharmaceuticals) (U. S. prescribing information, revised: 5/2019).
Source: https://www.accessdata.fda.gov/drugsatfda_docs/label/
2019/125387s061lbl.pdf (access date: 10 February 2020); 2019.
R07-4856
European Medicines Agency (EMEA). Committee for Medicinal 
Products for Human Use (CHMP): guideline on clinical trials in small 
populations (London, 27 July 2006, doc. ref.
CHMP/EWP/83561/2005). London: EMEA 2006


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Hutton-Smith LA, Gaffney EA, Byrne HM, Maini PK, Schwab D, 
Mazer NA; A mechanistic model of the intravitreal pharmacokinetics 
of large molecules and the pharmacodynamic suppression of ocular 
vascular endothelial growth factor levels by ranibizumab in patients 
with neovascular age-related macular degeneration. Mol Pharm 13, 
2941 – 2950 (2016)
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Cerani A, Tetreault N, Menard C, Lapalme E, Patel C, Sitaras N, et al;
Neuron-derived 
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permeability in diabetic retinopathy via neuropilin-1. Cell Metab 18, 
505 - 518 (2013)
R13-4881
FDA's critical path initiative (page last updated: 12/28/2012). 
cm076689.htm (access date: 8 November 2013); Silver Spring: U.S.
Food and Drug Administration 2012
R13-4803
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the 
Bayesian approach to phase I cancer trials. Stat Med 2008. 27:2420-
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Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient 
dose escalation with overdose control. Stat Med 1998. 17:1103-1120
R18-1136 
Trusko B, Thorne J, Jabs D, Belfort R, Dick A, Gangaputra S, et al,
Standardization of Uveitis Nomenclature (SUN) Project. The
Standardization of Uveitis Nomenclature (SUN) Project: development
of a clinical evidence base utilizing informatics tools and techniques. 
Methods Inf Med 2013. 52(3):259-265
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc 
intervalprolongation and proarrhythmic potential for non-
antiarrhythmic drugs. Rockville: U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER) (2005)
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/Guideli
nes/Efficacy/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)
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 
2005).


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R17-3318
Samara WA, Shahlaee A, Adam MK, Khan MA, Chiang A, Maguire 
JI, et al, Quantification of diabetic macular ischemia using optical 
coherence tomography angiography and its relationship with visual 
acuity. Ophthalmology. Rochester 124 (2), 235 - 244 (2017)
9.2
UNPUBLISHED REFERENCES
c31489419-01
BI 765128 Investigators’s Brochure, Current Version
001-MCS-36-472
Corporate SOP: Standards and processes for analyses performed within
Clinical Pharmacokinetics/Pharmacodynamics. Current version


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10.
APPENDICES
10.1




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10.2
BENEFIT-RISK ASSESSMENT IN CONTEXT OF COVID-19 
PANDEMIC FOR SUBJECTS PARTICIPATING IN TRIAL 1451-0001 
INVESTIGATING BI 765128
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 BI 765128 either may affect the immune system or increase the risk of 
progression of COVID-19 infection. BI 765128 is administered intravitreally using standard 
aseptic technique. 
The low dosage of BI 765128 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. Enrollment 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 subject 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 subject’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 subject.  
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
In situations where an individual subject is unable or unwilling to attend a clinic visit, the 
investigator must assess the risk-benefit for the individual subject and may decide to perform 
a visit remotely if this is in the best interest of the subject and if agreed with the sponsor. 
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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Scenario
# Pat.
# DLE
19
6
6
6
1
1
0
20
6
6
6
1
1
1
21
6
6
6
1
1
2
*Non of the pre-specified dose levels is fulfilling the EWOC criterion
# No higher dose level specified
Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model by illustrating 
the precision of the design in estimating the MFD. Under an assumed true dose-toxicity 
curve, metrics such as the probability of recommending a dose with true DLE rate in the 
target interval can be approximated via simulation. Table 10.3: 2 describes 5 assumed true 
dose-toxicity scenarios which were used to assess the operating characteristics of the model. 
These scenarios reflect a wide range of possible cases as follows:
∀
Scenario 1: aligned with prior means
∀
Scenario 2: high-toxicity scenario
∀
Scenario 3: low-toxicity scenario
∀
Scenario 4: very high toxicity scenario
∀
Scenario 5: low-toxicity followed by high-toxicity
Table 10.3: 2 
Assumed true dose-toxicity scenarios
Scenario
1: Prior Mean
P(DLE)
0.054
0.073
0.153
0.364
2: High Tox
0.154
0.173
0.243
0.464
3: Low Tox
0.005
0.007
0.053
0.264
4: Very high Tox
0.245
0.353
0.564
0.689
5: Low-High
0.005
0.007
0.243
0.464
The dose level 5 was added for technical reasons, since for simulations at least one dose with assumed true DLE rate in each 
toxicity interval was required 




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Scenario 4 (very-high-toxicity scenario) shows the worst results, i.e. the highest number of 
stopped trials (66.8 %) and a low number of trials with estimated MFD (15.1 %) in the target 
range, as would be expected. 
Scenarios 5 (low-high toxicity scenario) shows the best results, i.e. the lowest number of 
stopped trials (0.1 %) and a highest number of trials with estimated MFD (99.9 %) in the 
target range.
The mean subject numbers ranged from 9.3 subjects (Scenario 3) to 11.8 subjects (Scenario 
5), and the maximum number of subjects was 27.
Overall, by reviewing the metrics presented in Table 10.3: 3, it can be seen that the model is 
generally conservative due to the overdose control criteria. In all scenarios, except for the 
very-high-toxicity case (scenario 4) 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 4.0.2 and Jags version 4.3.0 was used for data scenarios and simulations.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
02 Jun 2021
EudraCT number
EU number
2020-005425-87
BI Trial number
1451-0001
BI Investigational Medicinal 
Product(s)
BI 765128
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 doses (double-masked, RandomIzed, 
sham-controlleD) of BI 765128 in panretinal 
photocoaGulation (PRP) treated diabetic 
rEtinopathy (DR) patients with diabetic macular 
ischemia (DMI) – the PARTRIDGE Study
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Abbreviations
Description of change
Nrp1 – Neuropilin 1 was added
Rationale for change
Clarification
Section to be changed
1.4.2.5, 3.1
Description of change
In part A the interval between dosing of subjects 
was extended.
Rationale for change
Authority feedback
Section to be changed
1.3
Description of change
Correction of the following sentence: The next 
higher dose will only be administered to the next 
cohort if the treatment in the preceeding dose cohort
was safe and showed acceptable tolerability (see 
section 3.1).
Rationale for change
Clarification
Section to be changed
1.4.2.1
Description of change
The following sentence was deleted: There are no 
previous trials testing Neuropilin-1 inhibitors in 
humans.
Rationale for change
Correction
Section to be changed
1.4.2.3
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 


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this trial, a risk-benefit evaluation and associated 
mitigation steps was performed and incorporated 
into the trial protocol.
Section to be changed
Description of change
Rationale for change
Section to be changed
3.1, 7.1, 10.3
Description of change
The required number of subjects was corrected 
from 9 to 12 to the definition when the MFD may 
be considered reached.
Rationale for change
Correction
Section to be changed
3.3.3
Description of change
Exclusion criteria number 9 (part A) was revised to 
indicate that subjects enrolled in trial 1436-0001 
SRD part may be enrolled into part A of this trial 
only after five half-lifes since the last trial dose, if 
the participants were not discontinued from study 
due to safety reasons, and if no toxicity, adverse 
events or safety concerns related to the previous 
participation are present at the time of screening
Rationale for change
Authority feedback
Section to be changed
3.3.4.3
Description of change
The following sentence was added to clarify the re-
start of the trial in case one of the stopping rules is 
triggered: “If the trial stops because one of the 
stopping rules is triggered, then the trial re-start will 
only be possible after regulatory authority approval 
via a substantial amendment.”
Rationale for change
Authority feedback
Section to be changed
Section 3.1; Figure 3.1:2
Description of change
Word “safe” was removed from Figure 3.1:2 to be 
consistent with the statement on page 40 that Part B 
will not commence if the highest dose (
) is 
not considered safe and tolerable in Part A.


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Rationale for change
Clarification
Section to be changed
Section 4.1.1; Table 4.1.1:2 Posology
Description of change
Reference to diluent in Part B was removed.
Rationale for change
Correction
Section to be changed
4.1.2
Description of change
The following sentence was revised as follows:
The proposed escalation of the doses to 
 and 
 per eye is predicted to prolong the time for 
IVT antibody concentrations above the estimated 
minimally efficacious concentration, potentially 
allowing for longer dosing intervals. The starting 
dose and dose escalation were chosen based on the 
safety margin to the highest tested dose level 
 
mg/eye) that did not result in adverse effects 
directly attributed to BI 765128no observed
adverse effect level (NOAEL), in the 13-week IVT 
toxicology study in cynomolgous monkeys.
Rationale for change
Correction
Section to be changed
4.2.2.3
Description of change
Word “condom” was added in brackets to the 
following sentence as an acceptable barrier method:
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. 
Rationale for change
Clarification
Section to be changed
5.2.1
Description of change
DLE definition was revised to include the following 
event: 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)
Rationale for change
Authority feedback
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
Description of change
Correction of the following sentence: The samples 
may be used for further methodological 


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11.2
GLOBAL AMENDMENT 2
investigations e.g. 
, to characterize 
 response or to address Health authority 
questions regarding the results/methodology; 
however, only data related to the analyte, and anti-
drug antibodies, and mechanism of action will be 
generated by these additional investigations.
Rationale for change
Clarification
Section to be changed
Description of change
Rationale for change
Section to be changed
5.4
Description of change
The following sentences were added: “If feasible BI 
765128 levels in 
samples might be 
determined”
“Additionally, if feasible proteins affected by the 
drug’s mode of action might be determined in 
serum samples”
Rationale for change
Clarification of additional measurements
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
10.3
Description of change
The following sentence was corrected: The 
maximum allowed subject number for each trial 
was chosen as 1827.
Rationale for change
Correction
Date of amendment
18 Jan 2022
EudraCT number
EU number
2020-005425-87
BI Trial number
1451-0001
BI Investigational Medicinal 
Product(s)
BI 765128
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 


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intravitreal doses (double-masked, RandomIzed, 
sham-controlleD) of BI 765128 in panretinal 
photocoaGulation (PRP) treated diabetic 
rEtinopathy (DR) patients with diabetic macular 
ischemia (DMI) – the PARTRIDGE Study
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Synopsis, 3.3.2
Description of change
Part A, inclusion criteria # 5: BCVA was revised 
from ≤65 to 75 letters (20/50 to 20/32) in the study 
eye.
Part B, inclusion criteria #5: BCVA was revised 
from ≤80 to 85 letters (20/25 to 20/20) in the study 
eye.
Rationale for change
To include a broader patient population on the 
study.
Section to be changed
3.3.2
Description of change
Part B, inclusion criteria 6 was revised:
“Best-corrected VA in the non-study eye must be 
equal to or better than best-corrected VA in the 
studyeye. If both eyes are eligible (per inclusion #5) 
and have identical best corrected VA, the 
investigator may select the study eye.” was replaced 
with “If both eyes are eligible, the investigator 
may select either eye to be the study eye.”
Rationale for change
Part B of the trial will only start if the highest dose 
is tolerated in part A. Once BI765128 has proved 
safe in part A, risks are low for the treated eye.
Section to be changed
Synopsis, 3.3.3
Description of change
Part A:
Exclusion criteria#1: restriction of IVT injections 
for active DME (anti-VEGF, steroids) and macular 
laser decreased from 6 months to 3 months
Exclusion criteria #2: restriction of anti-VEGF IVT 
injections for active DR decreased from 6 months to 
3 months 
Part B:
Exclusion criteria#2: restriction of IVT injections 
for active DME (anti-VEGF, steroids) and macular 
laser decreased from 6 months to 3 months
Exclusion criteria#3: restriction of anti-VEGF IVT 
injections for active DR decreased from 6 months to 
3 months 


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11.3
GLOBAL AMENDMENT 3
Rationale for change
To include a broader patient population 
participation on the study. Decreasing the 
restriction of the previous treatments from 6 months 
to 3 months is not expected to impact the results.
Date of amendment
15 Jun 2022
EudraCT number
EU number
2020-005425-87
BI Trial number
1451-0001
BI Investigational Medicinal 
Product(s)
BI 765128
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 doses (double-masked, RandomIzed, 
sham-controlleD) of BI 765128 in panretinal 
photocoaGulation (PRP) treated diabetic 
rEtinopathy (DR) patients with diabetic macular 
ischemia (DMI) – the PARTRIDGE 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
Synopsis; Flow Chart II, Tables 10.2:1 and 10.1:2
Description of change
Footnote in the Flowchart was revised as follows:
See separate flow chart for 
, 
 sampling
(Table 10.1: 2). PK samples during Visits 2, 3, & 4
should be taken within 30 min to 2hrs before drug 
administration.  
Tables: Time Point was revised as follows: Just
Within 2 hrs before drug administration*.
Footnote was deleted: * A time window of +/ 15 
min for sample drawing is allowed.
Rationale for change
To allow broader time window for 
 
samples before dosing.


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Section to be changed
1.2.
Description of change
Data from clinical studies updated
Rationale for change
Update
Section to be changed
1.4.2.2
Description of change
The following sentence was revised as follows: 
Although no systemic adverse events were observed 
in the pre-clinical studies, at each time-point, 
subjects will undergo systemic evaluation as 
specified in the flow charts, including body 
weight, blood pressure, pulse rate, ECG and 
laboratory tests.
Rationale for change
Clarification
Section to be changed
1.4.2.5
Description of change
The following sentence was revised as follows: 
Additionally, a systemic evaluation will be 
performed at each the timepoints specified in the 
flow charts, to assess possible systemic reactions.
Rationale for change
Clarification
Section to be changed
3.3, 6.2.1
Description of change
The following sentences were revised:
Section 3.3: Subjects 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: Subjects 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, subject must be registered in 
IRT, which will then provide a new subject number, 
and the subject 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 if the images are not older than 
28 days at the re-screening visit; otherwise new 
images have to be performed.
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
3.3


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11.4
GLOBAL AMENDMENT 4
Description of change
Update of the amounts of planned countries and 
sites
Rationale for change
Update
Section to be changed
3.3.3
Description of change
Part B: Exclusion criteria#7 removed: Clinically 
significant disorganisation of retinal inner layer 
(DRIL) in the study eye
Rationale for change
To broaden the subject population
Section to be changed
3.3.3
Decsription of change
Part B: Exclusion criteria 13 revised as follows:
Previous participation in this trial or in other trials 
with IVT injections administered within 3 months 
of screening. Subjects enrolled in the sham arm of 
the MD part of trial 1436-0001 may be enrolled into 
Part B of this trial.
Rationale for change
Clarification
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 Part A only.
Section to be changed
7.3.7
Description of change
Revision as follows:
A preliminary analysis of 
 
and 
provided as individual values and 
geometric means of each cohort per dose level may 
be performed, if feasible.
Rationale for change
Clarification that in addition to PK parameters also 
a preliminary analysis of 
 may be performed. 
Date of amendment
16 Mar 2023
EudraCT number
EU number
2020-005425-87
BI Trial number
1451-0001
BI Investigational Medicinal 
Product(s)
BI 765128
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 




 
 
 
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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Meaning of Signature  
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SAP_001.pdf: 




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Date: 07 SEP 2023, Version 2.0
7.9
OTHER ANALYSIS...........................................................................................35
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............36
9.
REFERENCES....................................................................................................37
11.
HISTORY TABLE..............................................................................................41


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................17
Table 6.4: 1
Subject sets analysed........................................................................................21
Table 6.7: 1
Time window assignment of efficacy, safety lab,
, vital signs and weight 
measurements to visits for statistical analysis of the SRD Part .......................23
Table 6.7: 2
Time window assignment of 12 lead ECG measurements to visits for 
statistical analysis of the SRD Part ..................................................................23
Table 6.7: 3
Time window assignment of efficacy, safety lab, 
 and vital signs 
measurements to visits for statistical analysis of the MD Part.........................23
Table 6.7: 4
Time window assignment of 12 lead ECG measurements to visits for 
statistical analysis of the MD Part....................................................................24
Table 6.7: 5
Time window assignment of physical examination measurements (weight) 
to visits for statistical analysis of the MD Part.................................................24
Table 11: 1
History table .....................................................................................................41




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Term
Definition / description
DLE
Dose limiting event
DRIL
Disorganisation of retinal inner layer
DRSS
Diabetic retinopathy severity scale
ECGPCS
ECG Pharmacokinetic Concentration Set
EDMS
Electronic documentation management system
EOS
End of Study
ES
Enrolled set
ETDRS
Early treatment diabetic retinopathy study
FAZ
Foveal avascular zone
gCV
Geometric coefficient of variation
gMean
Geometric mean
IOP
Intra-ocular pressure
IVT
Intravitreal
LLBCVA
Low luminance best corrected visual acuity
LOCF
Last observation carried forward
Max
Maximum
MD
Multiple dosing
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model for repeated measures
Min
Minimum
N
Number of non-missing observations
NEI
National Eye Institute
Nobs
Number of observations
OCTA
Optical coherent tomography angiography
P10
10th percentile
P90
90th percentile
PT
Preferred term
Q1
1st quartile
Q3
3rd quartile








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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP:
Part A: 
!
Number of subjects with ocular dose limiting events (DLEs) from drug administration 
until day 8 (7 days after treatment)
Part B:
!
Number of subjects with drug related AEs from drug administration until EOS (end of 
study)
Dose limiting events were defined in the CTP as the following ocular events:
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 of 
grade 3+ according to the NEI (National Eye Institute) Grading of vitreous haze, and 
anterior chamber cells of 3+ according to the Standardization of Uveitis 
Nomenclature (SUN) working group grading scheme (see CTP Table 5.2.1: 1) 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)


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5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 2.1.3 of the CTP:
Part A:
!
Number of subjects with drug related AEs at EOS
!
Number of subjects with any ocular AEs (eye disorders) at EOS
Part B:
!
Change from baseline of the size of the FAZ (Foveal Avascular Zone) in optical 
coherence tomography angiography (OCTA) at visit 5
!
Change from baseline of the size of the FAZ in optical coherence tomography 
angiography (OCTA) at visit 6
!
Change from baseline of the size of the FAZ in optical coherence tomography 
angiography (OCTA) at visit 7
!
Change from baseline of BCVA (Best Corrected Visual Acuity) at Visit 7
!
Number of subjects with any ocular AEs (eye disorders) from drug administration 
until EOS


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5.4
OTHER VARIABLES
Section 5.2.2 of the CTP:
A complete physical examination will be performed at the time points specified in the CTP 
Flow Charts. It includes at a minimum general appearance, neck, lungs, cardiovascular 
system, abdomen, extremities. 
Measurement of height and body weight will be performed at the time points specified in the 
CTP flowchart.
Age [years] will be determined as the difference between year of informed consent and year 
of birth.
BMI will be calculated as weight [kg] / (0.01 * height [cm])2.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment groups 
and selection of doses, please see CTP, Sections 3 and 4.
This phase I/IIa trial in patients with diabetic macular ischemia consists of 2 parts, a single-
rising dose (SRD) part and a multiple dose (MD) part: 
The single-rising dose part (Part A) of the trial with 3 dose groups is designed as non-
randomized, open-label and uncontrolled. Each dose group consists of at least 3 evaluable 
patients, the highest dose groups consists of 6 patients.
The multiple dose part (Part B) is designed as double-masked, randomized and sham-
controlled. Thirty patients will be recruited, in a 2:1 ratio of active treatment versus sham.
Patients receive three administrations of trial medication 
.
For both parts, one eye will be selected, according to inclusion /exclusion criteria, as the study 
eye to be treated.
For details of dosage and formulation see Table 6.1: 1:
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
Section 7.3.5 of the CTP: 
For BI 765128, 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 safety analysis will be performed 
by planned dose group.


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The following study phases will be defined for the analysis of adverse events (AEs):
!
Screening (ranging from 0:00h on day of informed consent until first administration 
of study medication (BI/Sham))
!
On treatment (ranging from the first time of administration of BI or Sham until 0:00h 
on the day after trial termination date)
Section 7.3.5 of the CTP: 
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.
The following AE displays will be provided in the report:
In Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT) of the CTR 
displays, the on treatment phase will be analysed (labelled with the short label of the study 
treatment). The screening phase will not be included in this analysis.
In Appendix 16.1.13.1.8, parts will be combined and not displayed separately. 
The following totals will be provided in addition for Section 15.3.
! a total over all on treatment phases (“Total”)
In Section 15.4 and Appendix 16.2 (Listings) of the CTR displays, the screening period will 
additionally be included and no totals will be provided.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewers guide.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all subjects enrolled 
(i.e. signed informed consent available) who did not fail during screening. 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 (RPM)/ database lock meeting 
(DBLM). At this meeting, it will be decided whether a discrepant data point can be used or 
whether it must be corrected in the clinical database. For definition of important protocol 
deviations (iPD), and for the process of identification of these, refer to the Boehringer 
Ingelheim (BI) SOP "Identify and Manage Important Protocol Deviations (iPD)" (2).
Important protocol deviation (iPD) categories are pre-specified in the iPD specification file 
(DV domain). 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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If any iPDs are identified, they are to be summarised into categories and will be captured in 
the iPD specification file (DV domain) and in the decision log. Both documents will be stored 
within the TMF in EDMS.
The iPDs will be summarized and listed in the CTR.
6.3
INTERCURRENT EVENTS
For the following intercurrent events in the MD part, the hypothetical strategy as defined in 
ICH E9(R1) (13) will be applied for all ophthalmological efficacy endpoints (see Table 5.3: 
1), i.e. data obtained after the intercurrent event will be censored and not included in the 
statistical analyses:
!
Treatment discontinuation
!
Administration of any anti-VEGF treatment in study eye or any intravitreal/intraocular 
steroid treatment other than the randomised treatment, if administration occurred 
during the trial
Censoring will be applied to all efficacy endpoints of the study eye. The start date of 
censoring is 28 days after treatment discontinuation or 1 day after start of a relevant 
concomitant medication (see definition above) in the study eye, whatever occurs first.    
6.4
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 table / listing and the disclosure 
tables for enrolment.
Section 7.3 of the CTP:
Treated set (TS)
For part A the treated set includes all subjects who were treated with at least one dose of 
study drug.
For part B the treated set includes all subjects who were randomized and treated with at least 
one dose of study drug (either treatment with BI 765128 or Sham).
Analyses regarding safety and efficacy will be performed on the TS. For ophthalmological 
efficacy analysis, intercurrent events have to be taken into account respectively (see Section 
6.3). For FAZ area, a supplementary analysis including all available data irrespective of 
intercurrent events (i.e. following the treatment policy approach as defined in ICH E9(R1)) 
will be performed in addition. The analysis population for the outputs of this analysis will be 
labelled “TS (supplementary analysis including data after intercurrent events)”.


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Section 7.3 of the CTP:




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Missing or incomplete AE dates are imputed according to BI standards (see BI-KMED-BDS-
HTG-0035) (3).
Missing data and outliers of PK data are handled according to BI standards (see BI-KMED-
TMCP-HTG-0025 (4) and BI-KMED-TMCP-MAN-0014 (5).
ECG analysis
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, the handling of missing values is described in Additional Section 10.1.2.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
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.
Baseline is defined as the last measurement before first administration of trial medication.
Section 6.1 of the CTP:
The acceptable time windows for visits are given in the CTP Flow Charts. For planned 
individual serum concentration sampling times, refer to CTP appendix 10.1.
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 to 
Table 6.7: 5.
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 and 
 where the worst scenario is chosen (i.e. for IOP the highest value will be 
taken). If there are two observations which have the same difference in days to the planned 
day, the later value will be selected. If there is more than one IOP measurement being the 
worst value within a time window, the value collected closer to the planned day will be 
selected. 


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Table 6.7: 1
Time window assignment of efficacy, safety lab, 
, vital signs and weight 
measurements to visits for statistical analysis of the SRD Part
Time window [days]
Visit 
(CTP)
Week
Visit label 
(analysis)
Planned 
Day
Window 
per CTP
Start 
(extended)
End 
(extended)
V2
Baseline 
Baseline 
1
± 0
NA
1
V3*
Day 4 (FU)
4
± 1
2
6
V4*
Week 1
Day 8 (FU)
8
± 2
7
11
V5
Week 2
Day 15 (FU)
15
± 2
12
22
V6
Week 4
Day 29 (FU)
29
± 3
23
43
V7
Week 8
Day 57 (FU)
57
± 7
44
78
V8
Week 14/EOS
Day 99 (EOS)
99
± 7
79
End of Trial 
visit date
* Safety lab is not scheduled for Day 4. Consequently, the time window for Day 8 is [2, 11], the other time 
windows remain the same.
Table 6.7: 2
Time window assignment of 12 lead ECG measurements to visits for statistical 
analysis of the SRD Part
Time window [days]
Visit 
(CTP)
Week
Visit label 
(analysis)
Planned 
Day
Window 
per CTP
Start 
(extended)
End 
(extended)
V2
Baseline 
Baseline 
1
± 0
NA
1
V3
Day 4 (FU)
4
± 1
2
16
V6
Week 4
Day 29 (FU)
29
± 3
17
43
V7
Week 8
Day 57 (FU)
57
± 7
44
78
V8
Week 14/EOS
Day 99 (EOS)
99
± 7
79
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 of efficacy, safety lab, 
 and vital signs 
measurements to visits for statistical analysis of the MD Part
Time window [days]
Visit 
(CTP)
Week
Visit label 
(analysis)
Planned 
Day
Window 
per CTP
Start 
(extended)
End 
(extended)
V2
Baseline 
Baseline 
1
± 0
NA
1
V3
Week 4
Day 29
29
± 3
2
43
V4
Week 8
Day 57
57
± 3
44
71


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Time window [days]
Visit 
(CTP)
Week
Visit label 
(analysis)
Planned 
Day
Window 
per CTP
Start 
(extended)
End 
(extended)
V5
Week 12
Day 85 (FU)
85
± 7
72
99
V6
Week 16
Day 113 (FU)
113
± 7
100
127
V7
Week 20/EOS
Day 141 (EOS)
141
± 7
128
End of Trial 
visit date
Table 6.7: 4
Time window assignment of 12 lead ECG measurements to visits for statistical 
analysis of the MD Part
Time window [days]
Visit 
(CTP)
Week
Visit label 
(analysis)
Planned 
Day
Window 
per CTP
Start 
(extended)
End 
(extended)
V2
Baseline 
Baseline 
1
± 0
NA
1
V3
Week 4
Day 29
29
± 3
2
43
V4
Week 8
Day 57
57
± 3
44
71
V5
Week 12
Day 85 (FU)
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: 5
Time window assignment of physical examination measurements (weight) to 
visits for statistical analysis of the MD Part
Time window [days]
Visit 
(CTP)
Week
Visit label 
(analysis)
Planned 
Day
Window 
per CTP
Start 
(extended)
End 
(extended)
V2
Baseline 
Baseline 
-28 to -3
NA
NA
1
V5
Week 12
Day 85 (FU)
85
± 7
2
End of Trial 
visit date
Days are counted relative to the day of first treatment, which is defined as Day 1.
Section 5.2.5.1 of the CTP:
Central ECG lab evaluation will be performed for all ECGs indicated in the CTP Flow Chart 
I and CTP 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.
At all time points mentioned in the CTP Flow Charts, single ECGs will be recorded shortly 
before the PK sampling at the respective time points, and will be transferred to the central 
ECG lab.




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For analyte concentrations and PK parameters, the following descriptive statistics will 
additionally be calculated:
Tabulations of frequencies for categorical data will include all possible categories available in 
the CRF and will display the number of observations in a category, as well as the percentage 
(%). Percentages will be rounded to one decimal place and will be based on all subjects in the 
respective subject set whether they have non-missing values or not. The category 'missing' 
will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in 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 summarised by treatment group and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output. If a concomitant medication has multiple Anatomical 
Therapeutic Chemical (ATC) codes, it is presented with all ATC codes.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies will be marked with a “No” in the respective column.
An additional table/listing will be provided for previous ophthalmic interventional therapies.
Separate tables will be provided for concomitant medication before start of treatment and 
with new onset after start of treatment.
The relevance of the concomitant therapies to the evaluation of PK and efficacy endpoints 
will be decided no later than at the RPM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the trial centre under supervision of the investigating physician or a designee. The 
measured serum concentrations and urinary excretion of trial medication will provide 
additional confirmation of compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM (cf. TSAP Section 6.2) and described in the CTR.


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7.4
PRIMARY OBJECTIVE ANALYSIS
7.4.1
Main analysis 
SRD part:
The primary endpoint ‘number of subjects with DLEs from drug administration till day 7’ 
will be analysed descriptively (see Section 7.8 for details).
MD part:
Refer to TSAP Section 7.8 for a description of the analysis of the primary endpoint 
(treatment-emergent drug-related AEs).
7.5
SECONDARY OBJECTIVE ANALYSIS
7.5.1
Key secondary objective analysis
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary objective analysis
Section 7.3.3 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.
Model-based analyses will be performed for all ophthalmological efficacy endpoints of the 
MD part that were defined as secondary endpoints, i.e. FAZ area and BCVA. These analyses 
will only be done for the study eye and not for the fellow eye.


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The change from baseline in the respective secondary endpoint 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.
The following SAS code can be used to fit the model:
PROC MIXED DATA=indata CL METHOD=REML;
CLASS subject treat visit;
MODEL endpoint = baseline treat visit treat*visit baseline*visit/ DDFM=KR 
CL 
ALPHA=0.1;
REPEATED visit / SUBJECT=subject TYPE=UN;
LSMEANS treat*visit/ DIFF CL ALPHA=0.1 SLICE=visit;
RUN;
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). 


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2. Set ‘maxiter=100’ in the Proc Mixed statement – This increases the number of 
convergence iterations used from a default of 50.
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.
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.
Furthermore, for the ophthalmological secondary endpoints, time profiles of 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. For the secondary endpoint FAZ area, these figures will be presented for absolute and 
percent changes whereas plots of the other secondary endpoint BCVA will only comprise 
absolute changes.
7.5.3
Interim analysis
Section 7.3.7 of the CTP:
In addition, a fast track analysis of Part B will be performed after the final subject of Part B 
has attended Visit 6 (i.e. approximately 8 weeks after receiving the final dose).
For the fast track analysis, the analyses on FAZ area (3mm) will be presented.




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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
The safety data for treated subjects who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse Events
AEs will usually be coded with the most recent version of MedDRA. The version to be used 
will be specified in RPM. The coding version number will be displayed as a footnote in the 
respective outputs.
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. BI 
standards as presented in “Analysis and Presentation of Adverse Event Data from Clinical 
Trials – Display Template” [BI-KMED-BDS-HTG-0041] (9) and [BI-KMED-BDS-HTG-
0066] (10) will be applied. 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to ‘screening’ and ‘on treatment’ phases as defined in Section 6.1. 
AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
According to the clinical study protocol, adverse events of special interest (AESI) will be 
analysed:
Section 5.2.7.1.4 of the CTP:
The following are considered as AESIs:
!
DLE
All AEs meeting the criteria for a dose limiting event (DLE) as defined in CTP Section
5.2.1 are defined as AESIs for this trial.
!
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
o
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2 
fold ULN measured in the same blood draw sample, or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
According to ICH E3 (11), in addition to Deaths and Serious Adverse Events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced
or interrupted).
An overall summary of AEs will be presented. The frequency of subjects with AEs will be 
summarised by treatment, primary system organ class (SOC) and preferred term (PT). 
Separate tables will be provided for subjects with


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-
serious AEs,
-
drug-related AEs, 
-
drug-related serious AEs,
-
ocular AEs,
-
ocular AEs in the study eye,
-
DLEs during study, 
-
DLEs during primary DLE evaluation period of 7 days (for SRD part only), 
-
AESIs,
-
drug-related AESIs,
-
other significant AEs,
-
procedure related AEs. 
In addition, the frequency of subjects with AEs will be summarised by treatment, worst 
intensity, primary system organ class (SOC) and preferred term (PT).
The SOC and PTs will be sorted by frequency (within SOC).
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT, additional information not included in a
standard AE analysis will be performed. The following three entries will be created:
!
Adverse Events per arm for disclosure on EudraCT
!
Non-serious Adverse Events for disclosure on EudraCT
!
Serious Adverse Events for disclosure on EudraCT.
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). 
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
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 possibly 
clinically significant will be flagged in the data listings. A frequency table including the 
number of subjects with possibly clinically significant abnormal laboratory values by 
treatment group and in total will be provided by laboratory parameter. The analysis of 
possibly clinically significant abnormal values will be based on converted/standardised 
values.


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A frequency table including subjects with elevated liver enzymes (potential DILI cases) will 
be provided in addition to support analyses of liver related adverse drug effects. In this 
analysis, 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 baseline conditions (at 
screening) or as AEs (during the trial) 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 significantly 
abnormal or not (at the RPM at the latest). 
Descriptive statistics of laboratory data including change from baseline will be calculated by 
planned time point based on the worst value of the subject at that planned time point (or 
assigned to that planned time point).
7.8.3
Vital signs
For vital signs (blood pressure and pulse rate), descriptive statistics including change from 
baseline will be calculated by treatment group. In the listings the difference from baseline will 
also be displayed.
Body weight will be analysed analogously to blood pressure and pulse rate.
Clinically relevant findings will be reported as baseline conditions (at screening) or as AEs 
(during the trial) if judged clinically relevant by the investigator, and will be analysed as such.


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7.9
OTHER ANALYSIS
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such.
No separate listing or analysis of physical examination findings will be prepared.


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8.
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.


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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-VQD-12045_40-413: "Identify and Manage Important Protocol Deviations (iPD) ", 
current version, Group “Clinical Operations”, KMED
3.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version, Group “Biostatistics & Data Sciences”, KMED.
4.
BI-KMED-TMCP-HTG-0025: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version, Group “Translational 
Medicine Clinical Pharmacology”, KMED.
5.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version, Group “Translational 
Medicine Clinical Pharmacology”, KMED.
6.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project
Summaries”, current version, Group “Biostatistics & Data Sciences”, KMED.
7.
BI-KMED-TMCP-OTH-0003: “Graphs and Tables for Clinical Pharmacokinetics and 
Pharmacodynamic Noncompartmental Analyses”, current version, Group “Translational 
Medicine Clinical Pharmacology”, KMED.
8.
BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version, Group “Translational Medicine Clinical Pharmacology”, 
KMED.
9.
BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version, Group “Biostatistics & Data 
Sciences”, KMED.
10. BI-KMED-BDS-HTG-0066: “Analysis and Presentation of AE data from clinical trials”, 
current version, Group “Biostatistics & Data Sciences”, KMED.
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, EMA webpage.
12. BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version, Group “Biostatistics & Data Sciences”, KMED.
13. CHMP/ICH/436221/2017: " ICH E9 (R1) addendum on estimands and sensitivity 
analysis in clinical trials to the guideline on statistical principles for clinical trials”, 
current version.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1.0
30-AUG-23
None
This is the final TSAP.
2.0
07-SEP-23
6.3, 7
Extension of the definition of 
“intercurrent events” in section 6.3,
two minor wording changes at p.25 in 
section 7.