Clinical trial NCT03861234
Conditions: Wet Macular Degeneration
Sponsor: Boehringer Ingelheim
Start date: 2019-06-27; Completion date: 2023-11-01
Enrollment: 43 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a study in people with an eye disease called wet age-related macular degeneration (wAMD). The purpose of the study is to find out how well different doses of a medicine called BI 836880 are tolerated.

People can participate if they are at least 55 years old and if they have new blood vessels in their eyes despite treatment (anti-VEGF therapies). The study has 2 parts. In the first part, people get only 1 dose of BI 836880. This part takes 6 weeks. In the second part, people get 3 times the same dose of BI 836880. This part takes 6 months. BI 836880 is injected into the eye. During the entire study doctors regularly check the health of the participants.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None
Interventions: intervention 1: BI 836880
Intervention descriptions: intervention 1: Solution for Intravitreal (IVT) injection

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 October 2016
Clinical Trial Protocol
TITLE PAGE
Document Number: c17360540-08
EudraCT No.:
EU Trial No:
2017-001221-40
BI Trial No.:
1336-0007
BI Investigational 
Product(s):
BI 836880
Title:
Safety, tolerability and pharmacodynamics of single rising 
intravitreal and multiple rising intravitreal doses of BI 836880 in 
patients with wAMD (open label, non-randomized, uncontrolled).
Lay Title:
A study to test different doses of BI 836880 in patients with an 
eye disease called wet age-related macular degeneration (wAMD)
Clinical Phase:
I/IIa
Trial Clinical Monitor:
Phone 
 Fax 
Coordinating 
Investigator:
Phone
, Fax 
Status:
Final Protocol
(Revised Protocol (based on global amendment No. 7))
Version and Date:
Version: 8.0
Date: 28 Sep 2022
Page 1 of 113
Proprietary confidential information.
2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Finished product name
NA
Active ingredient name: BI 836880
Protocol date
05 Nov 2018
Revision date
28 Sep 2022
Trial number
1336-0007
Title of trial:
Safety, tolerability and pharmacodynamics of single rising 
intravitreal and multiple rising intravitreal doses of BI 836880 in 
patients with wAMD (open label, non-randomized, uncontrolled).
Coordinating 
Investigator
Phone 
, Fax 
Trial site(s):
Multi-centre trial
Clinical phase:
I/IIa
Objective(s):
To investigate the safety, tolerability, and pharmacodynamics of 
single and multiple intravitreal doses of BI 836880
Methodology:
Open label, uncontrolled, non-randomized trial of BI 836880 
administered intravitreally as single dose in the single rising dose 
(SRD) part and as multiple doses in the multiple rising dose (MRD) 
part.
Number of patients 
entered: 
Approximately 42; 15 in the SRD part and approximately 27 in the 
MRD part
Number of patients on 
each treatment:
SRD part: 15, in different dose groups
MRD part: 11 patients in dose group 1 (cohort 1); approximately 
16 patients in dose group 2 (4 patients from cohort 2, 12 patients 
from cohort 3).
Diagnosis:
Treatment-resistant wet age-related macular degeneration (wAMD)
in SRD part and MRD cohort 1; treatment-naïve wAMD for MRD 
cohort 2; patients within 3 years of initial wAMD diagnosis for 
MRD cohort 3.
Main in- and exclusion 
criteria
Inclusion: SRD and MRD cohort 1: Men and women over the age of 
55 with active choroidal neovascularization (CNV) secondary to 
wAMD despite prior anti-VEGF therapies; for MRD cohort 1 only: 
central subfield retinal thickness (CSFT) > 300 microns.
For MRD cohort 2: Men and women over the age of 55 with 
treatment-naïve CNV secondary to AMD.


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For MRD cohort 3: Men and women over the age of 55 with active 
CNV secondary to wAMD that require frequent intravitreal (IVT) 
treatment (28 to 56 days between treatments) with ranibizumab, 
aflibercept, or bevacizumab for standard of care for at least 6 
months, with the last IVT administration between 4-8 weeks before 
the first study drug administration.
Exclusion: Additional eye disease in the study eye that could 
compromise best corrected visual acuity.
For MRD cohort 3: Active intraocular inflammation in the study 
eye, > 0.5+ anterior chamber cell and/or vitreous haze grading, or 
history of intraocular inflammation in either eye with previous IVT 
administration(s), history of retinal vein occlusion, previous 
treatment with brolucizumab or faricimab, and/or medical history of 
autoimmune disease that has caused ocular inflammation.
Test product(s):
BI 836880
dose:
SRD Part: 0.06 mg, 0.18 mg, 0.5 mg, 1.0 mg, 2.0 mg (single doses)
MRD Part: 1 mg (cohort 1) and 2 mg (cohort 2 and 3) (q4w)
mode of 
   administration:
Intravitreal injection
Comparator products:
Not applicable
dose
Not applicable
mode of 
   administration:
Not applicable
Duration of treatment:
SRD part: Single intravitreal dose
MRD part: 3 intravitreal doses in 4-weekly intervals (q4w)
Endpoints:
SRD part: 
Primary endpoint:

Number of patients with ocular dose limiting events (DLEs)
Secondary endpoints:

Number of patients with drug related adverse events (AEs)

Number of patients with any ocular adverse events in the 
study eye
MRD part:
Primary endpoint:

Number of patients with drug related AEs
Secondary endpoints:

Percent change from baseline in CSFT in the study eye at 
Week 12 (Visit 5)

Change from baseline in best corrected visual acuity (BCVA)
in the study eye at Week 12 (Visit 5)

Time to recurrence after the last treatment


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
Number of patients with any ocular adverse events in the 
study eye
Criteria for 
Pharmacokinetics
Further criteria of interest:
SRD part:

Systemic pharmacokinetics of BI 836880 after a single 
intravitreal dose

Systemic immunogenic response (pre-existing anti-drug 
antibody [ADA], treatment emergent ADA)
MRD part:

Systemic exposure of BI 836880 after multiple intravitreal 
doses

Systemic immunogenic response (pre-existing ADA, 
treatment emergent ADA) after multiple intravitreal doses
Criteria for 
Pharmacodynamics:
Further criteria of interest:
SRD part:

Systemic free Vascular Endothelial Growth Factor (VEGF)
and free/total ANG2 levels after a single intravitreal dose
MRD part:

Change from baseline in CSFT in the study eye at Week 12
(Visit 5)

Changes from baseline in selected parameters derived from 
color fundus photography (CFP)/optical coherence 
tomography (OCT)/OCT-angiography (OCT-A) in both eyes

Systemic free VEGF and free angiopoietin 2 (ANG2) after 
multiple intravitreal doses
Safety criteria:
Further criteria of interest:

Ocular inflammation in the study eye

Retinal haemorrhage in the study eye

BCVA reduction by more than 15 letters in the study eye

AEs including clinically relevant findings from the physical 
examination, safety laboratory tests, 12-lead 
electrocardiogram (ECG), vital signs
Statistical methods:
Descriptive statistics will be provided for all endpoints for SRD and 
MRD parts. No statistical testing is planned.
In addition, in SRD part, the dose escalation 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 (SINGLE RISING DOSE PART)
Trial Periods
Screening 
Period
Treat-
ment 
Visit
Follow-up Period
End of 
trial
Visit
1
2
3
4
5
6
7
8
Study Days
Study Week
Duration 3 
to 42 days
Day 1
4
8
Week 1
15
Week 2
22
Week 3
29
Week 4
43
Week 6
Time window for visits (days)
none
±1
±2
±2
±2
±2
±2
Informed consent
X
Demographics
X
Medical history
X
Physical examination (3)
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Laboratory tests
X
X
X
X
X
X
X
12 lead-ECG (2)
X
X
X
X
X
X
X
Review of in-/exclusion criteria
X
X
Dose Assignment
X
IVT drug administration
X
PK Sampling
X
X
X
X
X
X
Biomarker sampling
X
X
X
X
X
X
ADA sampling
X
X
X
Visual Acuity 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
Fundus Photo
X
X(4)
X(4)
X(4)
X(4)
X(4)
X(4)
X
Slit lamp and IOP
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
Completion of patient
participation (1)
X
(1)
Completion of patient participation also needs to be completed if the patient withdraws prematurely following 
assignment to dose level (see Section 3.3.4).
(2)
See Section 5.2.6; the ECGs are to be recorded shortly before the PK sampling at the respective time points; see
Appendix 10.1.
(3)
Physical examinations will also include measurement of weight and height (height only at Visit 1).
(4)
Only to be done if considered medically necessary by the principal investigator.


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FLOW CHART II (MULTIPLE RISING DOSE PART, COHORT 1)
Trial Periods
Screening 
Period
Treatment Period
Follow-up Period
End of 
Trial(1)
Visit
1
2
3
4
5
6
7
8
Study Day
Study Week
-14
1
29
Week 4
57
Week 8
85
Week 12
113
Week 16
141
Week 20
169
Week 24
Time window for visits (days)
±10
none
±3
±3
±3
±3
±3
±3
Informed consent
X
Demographics
X
Medical history
X
Physical examination (5)
X
X
Vital signs
X
X
X
X
X
X
X
X
Laboratory tests
X
X
X
X
X
X
X
X
12 lead-ECG (2)
X
X
X
X
X
Review of in-/exclusion crit.
X
X
Dose Assignment
X
IVT drug administration
X
X
X
PK sampling
X
X
X
X
X
X
X
Biomarker sampling
X
X
X
X
X
X
X
ADA sampling
X
X
X
X
X
Biobanking 
X(3)
Visual Acuity 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(4)
X(4)
X(4)
X(4)
X(4)
X(4)
X
Slit lamp
X
X
X
X
X
X
X
X
IOP
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
Completion of patient
participation (1)
X
(1)
Completion of patient participation also needs to be completed if the patient withdraws prematurely following 
assignment to dose level (see Section 3.3.4).
(2)
See Section 5.2.6; the ECGs are to be recorded shortly before the PK sampling at the respective time points; see 
Appendix 10.1.
(3)
Collection of biobanking samples is optional. Participating patients are required to give informed consent specifically 
for biobanking. Samples will be stored at a biobanking facility for future research. DNA biobanking requires only one 
blood sample to be taken, preferably at Visit 2. However, collection at later visits is permitted as long as the informed 
consent for biobanking remains valid.
(4)
Only to be done if considered medically necessary by the principal investigator.
(5)
Physical examinations will also include measurement of weight and height (height only at Visit 1).


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FLOW CHART III (MULTIPLE RISING DOSE PART, COHORT 2)
Trial Periods
Screening 
Period
Treatment Period
Follow-up Period
End of 
Trial(1)
Visit
1
2
2a(6)
3
3a(6)
4
4a(6)
5
6
7
8
Study Day
-14
1
2
29
30
57
58
85
113
141
169
Study Week
Week 4
Week 8
Week 
12
Week 
16
Week 
20
Week 
24
Time window for visits (days)
±10
none
+6
±3
+6
±3
+6
±3
±3
±3
±3
Informed consent
X
Demographics
X
Medical history
X
Physical examination (5)
X
X
Vital signs
X
X
X
X
X
X
X
X
Laboratory tests
X
X
X
X
X
X
X
X
12 lead-ECG (2)
X
X
X
X
X
Review of in-/exclusion crit.
X
X
Dose Assignment
X
IVT drug administration
X
X
X
PK sampling
X
X
X
X
X
X
X
Biomarker sampling
X
X
X
X
X
X
X
ADA sampling
X
X
X
X
X
Biobanking 
X(3)
Visual Acuity 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(4)
X(4)
X(4)
X(4)
X(4)
X(4)
X
Slit lamp
X
X
X
X
X
X
X
X
X
X
X
IOP
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
Completion of patient
participation (1)
X
(1)
Completion of patient participation also needs to be completed if the patient withdraws prematurely following 
assignment to dose level (see Section 3.3.4).
(2)
See Section 5.2.6; the ECGs are to be recorded shortly before the PK sampling at the respective time points; see 
Appendix 10.1.
(3)
Collection of biobanking samples is optional. Participating patients are required to give informed consent specifically 
for biobanking. Samples will be stored at a biobanking facility for future research. DNA biobanking requires only one 
blood sample to be taken, preferably at Visit 2. However, collection at later visits is permitted as long as the informed 
consent for biobanking remains valid.


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(4)
Only to be done if considered medically necessary by the principal investigator.
(5)
Physical examinations will also include measurement of weight and height (height only at Visit 1). 
(6) 
Additional safety procedures may be performed according to local safety standard practice.


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FLOW CHART IV (MULTIPLE RISING DOSE PART, COHORT 3)
Trial Periods
Screening 
Period
Treatment Period
Follow-up Period
End of 
Trial(1)
Visit
1
2
2a(6)
3
3a(6)
4
4a(6)
5
6
7
8
Study Day
-14
1
2
29
30
57
58
85
113
141
169
Study Week
Week 4
Week 8
Week 
12
Week 
16
Week 
20
Week 
24
Time window for visits
(days)
±10
none
+6
±3
+6
±3
+6
±3
±3
±3
±3
Informed consent
X
Demographics
X
Medical history
X
Physical examination (5)
X
X
Vital signs
X
X
X
X
X
X
X
X
Laboratory tests
X
X
X
X
X
X
X
X
12 lead-ECG (2)
X
X
X
X
X
Fluorescein angiography (7)
X
Review of in-/exclusion crit.
X
X
Dose Assignment
X
IVT drug administration
X
X
X
PK sampling
X
X
X
X
X
X
X
Biomarker sampling
X
X
X
X
X
X
X
ADA sampling
X
X
X
X
X
Biobanking 
X(3)
Visual Acuity 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 (multi-field) (4)
X
X
X
X
X
X
X
X
X
X
X
Fundus Photo (widefield)
X
X
X
X
X
X
X
X
X
X
X
Slit lamp
X
X
X
X
X
X
X
X
X
X
X
IOP
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
Completion of patient
participation (1)
X
(1)
Completion of patient participation also needs to be completed if the patient withdraws prematurely following 
assignment to dose level (see Section 3.3.4).
(2)
See Section 5.2.6; the ECGs are to be recorded shortly before the PK sampling at the respective time points; see 
Appendix 10.1.


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(3)
Collection of biobanking samples is optional. Participating patients are required to give informed consent specifically 
for biobanking. Samples will be stored at a biobanking facility for future research. DNA biobanking requires only one 
blood sample to be taken, preferably at Visit 2. However, collection at later visits is permitted as long as the informed 
consent for biobanking remains valid.
(4)
Vitreous haze assessment to be completed with every examination.
(5)
Physical examinations will also include measurement of weight and height (height only at Visit 1). 
(6)
Additional safety procedures may be performed according to local safety standard practice.
(7)
Fluorescein angiography imaging during Visits 2-8 should be performed at the discretion of the investigator, e.g. if 
signs of inflammation are observed.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART I (SINGLE RISING DOSE PART)............................................................5
FLOW CHART II (MULTIPLE RISING DOSE PART, COHORT 1).............................6
FLOW CHART III (MULTIPLE RISING DOSE PART, COHORT 2) ...........................7
FLOW CHART IV (MULTIPLE RISING DOSE PART, COHORT 3)............................9
TABLE OF CONTENTS ......................................................................................................11
ABBREVIATIONS................................................................................................................15
1.
INTRODUCTION...............................................................................................17
1.1
MEDICAL BACKGROUND.............................................................................17
1.2
DRUG PROFILE................................................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................19
1.4
BENEFIT - RISK ASSESSMENT.....................................................................20
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........22
2.1.1
Main objectives....................................................................................................22
2.1.2
Primary endpoint(s)............................................................................................22
2.1.3
Secondary endpoint(s) ........................................................................................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................24
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................26
3.3
SELECTION OF TRIAL POPULATION .......................................................27
3.3.1
Main diagnosis for trial entry ............................................................................27
3.3.2
Inclusion criteria .................................................................................................27
3.3.3
Exclusion criteria ................................................................................................30
3.3.4
Withdrawal of patients from therapy or assessments .....................................31
3.3.4.1
Withdrawal from trial treatment ...........................................................................31
3.3.4.2
Withdrawal of consent for trial participation........................................................32
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................32
3.3.5
Replacement of patients......................................................................................32
4.
TREATMENTS...................................................................................................33
4.1
INVESTIGATIONAL TREATMENTS ...........................................................33
4.1.1
Identity of the Investigational Medicinal Products..........................................33
4.1.2
Selection of doses in the trial..............................................................................33
4.1.3
Method of assigning patients to treatment groups...........................................34


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4.1.4
Drug assignment and administration of doses for each patient......................35
4.1.5
Intravitreal Injection Technique .......................................................................36
4.1.6
Masking and procedures for unmasking ..........................................................37
4.1.6.1
Masking.................................................................................................................37
4.1.6.2
Unmasking and breaking the code........................................................................37
4.1.7
Packaging, labelling, and re-supply...................................................................37
4.1.8
Storage conditions...............................................................................................37
4.1.9
Drug accountability.............................................................................................37
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................38
4.2.1
Restrictions ..........................................................................................................38
4.2.1.1
Restrictions regarding concomitant treatment ......................................................38
4.2.1.2
Restrictions on diet and life style..........................................................................38
4.2.1.3
Contraception requirements..................................................................................38
4.2.2
Other treatments and emergency procedures..................................................39
4.3
TREATMENT COMPLIANCE........................................................................39
5.
ASSESSMENTS..................................................................................................40
5.1
ASSESSMENT OF EFFICACY........................................................................40
5.2
ASSESSMENT OF SAFETY.............................................................................40
5.2.1
Dose limiting event..............................................................................................40
5.2.2
Time to recurrence..............................................................................................41
5.2.3
Physical examination ..........................................................................................41
5.2.4
Vital signs.............................................................................................................42
5.2.5
Safety laboratory parameters ............................................................................42
5.2.6
Electrocardiogram ..............................................................................................44
5.2.7
Other safety parameters.....................................................................................44
5.2.8
Assessment of adverse events.............................................................................44
5.2.8.1
Definitions of AEs ................................................................................................44
5.2.8.1.1
Adverse event........................................................................................................44
5.2.8.1.2
Serious adverse event............................................................................................44
5.2.8.1.3
AEs considered “Always Serious”........................................................................45
5.2.8.1.4
Adverse events of special interest (AESIs)...........................................................45
5.2.8.1.5
Intensity (severity) of AEs....................................................................................46
5.2.8.1.6
Causal relationship of AEs....................................................................................46
5.2.8.2
Adverse event collection and reporting ................................................................47
5.2.8.2.1
AE collection.........................................................................................................47
5.2.8.2.2
AE reporting to sponsor and timelines..................................................................47
5.2.8.2.3
Information required .............................................................................................48
5.2.8.2.4
Pregnancy..............................................................................................................48
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................49
5.3.1
Assessment of pharmacokinetics .......................................................................49
5.3.2
Methods of sample collection .............................................................................49
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................50
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................50
5.4.1
Plasma derived protein biomarkers..................................................................50
5.4.1.1
Methods and timing of sample collection.............................................................51


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5.5
OTHER ASSESSMENTS...................................................................................51
5.5.1
Immunogenicity assessment...............................................................................51
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................52
6.
INVESTIGATIONAL PLAN.............................................................................53
6.1
VISIT SCHEDULE.............................................................................................53
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................53
6.2.1
Single Rising Dose Part.......................................................................................53
6.2.1.1
Screening Visit......................................................................................................53
6.2.1.2
Treatment period and end of trial visit SRD part..................................................54
6.2.2
Multiple Rising Dose Part ..................................................................................54
6.2.2.1
Screening Visit......................................................................................................54
6.2.2.2
Treatment period and end of trial visit MRD part ................................................55
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................57
7.1
STATISTICAL DESIGN - MODEL.................................................................57
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................59
7.3
PLANNED ANALYSES.....................................................................................60
7.3.1
Primary endpoint analyses.................................................................................60
7.3.2
Secondary endpoint analyses .............................................................................60
7.3.4
Safety analyses.....................................................................................................61
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................61
7.4
INTERIM ANALYSES ......................................................................................62
7.5
HANDLING OF MISSING DATA ...................................................................62
7.6
RANDOMISATION ...........................................................................................62
7.7
DETERMINATION OF SAMPLE SIZE .........................................................63
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........65
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................65
8.2
DATA QUALITY ASSURANCE ......................................................................66
8.3
RECORDS...........................................................................................................66
8.3.1
Source documents ...............................................................................................66
8.3.2
Direct access to source data and documents.....................................................67
8.3.3
Storage period of records ...................................................................................68
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................68
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........68
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................68
8.6
TRIAL MILESTONES.......................................................................................69
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................69
9.
REFERENCES....................................................................................................71
9.1
PUBLISHED REFERENCES............................................................................71
9.2
UNPUBLISHED REFERENCES......................................................................72
10.
APPENDICES.....................................................................................................73


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10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.........................................................................................................73
10.2
TRIAL BIOMARKER PLAN............................................................................74
10.3
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
AND DATA SCENARIOS .................................................................................74
10.4
IMPLICATIONS OF CORONAVIRUS DISEASE 2019................................79
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................80
11.1
GLOBAL AMENDMENT 1 ..............................................................................80
11.2
GLOBAL AMENDMENT 2 ..............................................................................84
11.3
GLOBAL AMENDMENT 3 ..............................................................................85
11.4
GLOBAL AMENDMENT 4 ..............................................................................92
11.5
GLOBAL AMENDMENT 5 ..............................................................................93
11.6
GLOBAL AMENDMENT 6 ............................................................................100
11.7
GLOBAL AMENDMENT 7 ............................................................................102


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ABBREVIATIONS
ADA
Anti-Drug Antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
AMD
Age-related macular degeneration
ANG2
Angiopoietin 2
AUC
Area Under the Curve
AUEC
Area Under the Effect-time Curve
BCVA
Best Corrected Visual Acuity
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
CA
Competent Authority
CFP
Color Fundus Photography
CI
Coordinating Investigator
CMC1
C-X9-C Motif Containing 1
CMC2
C-X9-C Motif Containing 2
CNV
Choroidal Neovascularisation
COVID-19
Coronavirus Disease 2019
CRA
Clinical Research Associate
CRC
Central Reading Center
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organization
CSFT
Central Subfield Thickness
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug-Induced Liver Injury
DLE
Dose Limiting Event
eDC
Electronic Data Capture
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EMA
European Medicines Agency
EOT
End of Trial
ERS
Evaluable Responders’ Set
ETDRS
Early Treatment Diabetic Retinopathy Study
EudraCT
European Clinical Trials Database
EWOC
Escalation with overdose control
FA
Flurescence Angiography
FAS
Full Analysis Set
FDA
Food and Drug Administration
FiH
First-in-Human
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GMP
Good Manufacturing Practice
HR
Heart Rate
IB
Investigator’s Brochure


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ICF
Informed Consent Form
IEC
Independent Ethics Committee
IOI
Intra-Ocular Inflammation
IOP
Intra-Ocular Pressure
iPD
Important Protocol Deviation
IQRM
Integrated Quality and Risk Management
IRB
Institutional Review Board
IRT
Interactive Response Technology
IRF
Intra-Retinal Fluid
ISF
Investigator Site File
IVT
Intravitreal
LPDD
Last Patient Drug Discontinuation
LPO
Last Patient Out
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRD
Multiple Rising Dose
MTD
Maximum Tolerated Dose
NEI
National Eye Institute
NOAEL
No Observed Adverse Effect Level
OCT
Optical Coherence Tomography
OCT-A
Optical Coherence Tomography - Angiography
OIR
Oxygen Induced Retinopathy
OPU
Operating Unit
PD
Pharmacodynamics
PlGF
Placental Growth Factor
PED
Pigment Epithelial Detachment
PK
Pharmacokinetics
REP
Residual Effect Period
RPE
Retinal Pigment Epithelium
SAE
Serious Adverse Event
SD-OCT
Spectral Domain Optical Coherence Tomography
SHRM
Subretinal Hyper-Reflective Material
SMC
Safety Monitoring Committee
SoC
Standard of Care
SOP
Standard Operating Procedure
SRD
Single Rising Dose
SRF
Sub-Retinal Fluid
SUN
Standardization of Uveitis Nomenclature
SUSAR
Suspected Unexpected Serious Adverse Reactions
TMF
Trial Master File
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
VA
Visual Acuity
VEGF
Vascular Endothelial Growth Factor
wAMD
Wet Age-related Macular Degeneration
WG
Working Group
WHO
World Health Organization
WOCBP
Women of childbearing potential
YAG
Yttrium Aluminum Garnet


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Age-related macular degeneration (AMD) is a common cause of legal blindness in the elderly 
population of the developed world. Approximately 10% of individuals aged 65 to 74 years, 
and 30% of those aged 75 to 85 years, show signs of AMD [R13-1509]. Early stage AMD is 
associated with the accumulation of drusen and disturbances of the retinal pigment epithelium 
(RPE). Morphology, number, and location of drusen relative to macula are indicative of 
disease progression, although over 75% of patients with early AMD never progress to either 
of the two forms of advanced AMD over 10 years. 
Clinically, advanced AMD is classified into the nonexudative or atrophic form and the 
exudative “wet” or neovascular form and occurs in 15% and 10% of AMD patients 
respectively. Wet AMD is the more aggressive and debilitating form of AMD and is caused 
by the growth of abnormal choroidal neovascular membranes (CNV). New vessels sprout 
from the choriocapillaris, grow under the RPE or retina, and leak serum and blood. Fluid 
accumulation in the sub-RPE and subretinal spaces along with the neurosensory retina 
usually leads to measurable macular thickening. Involvement of the fovea by the CNV, 
edema and hemorrhage may profoundly impair visual acuity (VA) and loss of vision can be 
precipitous. 
Intravitreally administered therapies that target vascular endothelial growth factor (VEGF) 
have become the standard of care, and have led to significant improvements in lesion 
morphology, vascular leakage, and, most importantly, improvement in VA.
Despite the availability of anti-VEGF therapies, AMD causes 50% of irreversible blindness 
in the developed world today. In many patients, it is difficult to continue long term treatment 
requiring frequent visits to the retinal specialists. Intravitreal (IVT) injections also present a 
risk to patients and a burden to both patients and caregivers. First, there is the potential for 
serious side effects associated with each IVT injection procedure, including endophthalmitis, 
retinal detachments, traumatic cataract, and increased intra-ocular pressure (IOP). Second, 
monthly treatment and monthly monitoring, which may continue for a patient’s lifetime, is a 
substantial burden to patients, ophthalmologists, and the healthcare system. Extensive efforts 
have been undertaken to lower the injection frequency of anti-VEGF agents in wet Age-
related Macular Degeneration (wAMD) [R13-4487]. However, unmet medical need still 
exists for new therapies that allow for a reduced frequency of IVT injections. The second 
major aspect of unmet medical need concerns further improvement in maintenance therapy 
and incremental VA gains over current therapies, especially in patients not sufficiently 
responded to the available anti-VEGF treatments.
1.2
DRUG PROFILE
BI 836880 is an anti-angiogenesis agent composed of VEGF-A and angiopoietin 2 (ANG2) 
binding domains with a third domain that binds to human serum albumin for improved half-
life extension. BI 836880 is highly potent and showed efficacy in preclinical animal models 
for pathological retinal angiogenesis and neovascular leakage following IVT injection.
BI 836880 is selective for VEGF-A and ANG2, as the molecule does not bind to the related
growth factors VEGF-B, -C, -D, placental growth factor (PlGF) and angiopoietin1 (ANG1).
BI 836880 inhibits VEGF and Ang2- mediated intracellular signaling and functional activity.


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It was found to be cross reactive to cynomolgus VEGF, as well as mouse, rat and cynomolgus
ANG2 which indicates cynomolgus monkey as the most suitable species for pharmacological
and toxicological studies.
In rodents, BI 836880 is not binding VEGF but ANG2 only. Nevertheless, BI 836880 is
efficacious in a mouse oxygen induced retinopathy (OIR) model on pathological
neoangiogenesis comparable to Eylea™, a potent inhibitor of the VEGF pathway
[n00253677]. In cynomolgus monkeys BI 836880 is crossreactive to VEGF and ANG2. On 
laser induced CNV in cynomolgus monkeys, a disease model for neovascular wAMD, 
BI 836880 was superior to Lucentis™ on the reduction of clinically relevant severe lesions
[n00256189] The potential for superior clinical efficacy of dual VEGF and ANG2 inhibition 
over VEGF inhibition is supported by these preclinical data.
After intravenous administration in the monkey, BI 836880 displayed dose-dependent
pharmacokinetics (PK) (higher clearance and shorter half-life at lower doses; lower clearance 
and longer half-life at higher doses) [n00234399]. After IVT administration in the monkey, 
BI 836880 displayed a biphasic clearance in the vitreous humor, with a short initial half-life 
of 3 days and a long terminal half-life of 13 days. The long terminal half-life is likely due to 
the formation of BI 836880-albumin complex in the terminal phase [n00258450]. After IVT
coadministration of BI 836880 and human albumin in rabbit eyes, human albumin extended 
the half-life of BI 836880 by 3-fold [n00259128]. The albumin concentration in the human 
vitreous humor is significantly higher than monkey vitreous humor. BI 836880 is expected to 
exist mostly in the BI 836880-albumin complex form in human vitreous humor and the ocular 
half-life of BI 836880 in human is predicted to be 21 days [n00259128].
For a more detailed description of the drug profile please refer to the current Investigator’s 
Brochure (IB) [c21397543]. At the time of data cut-off for the current IB (25 March 2022), 
the SRD part of the trial described here (1336-0007) was completed: 15 patients had been 
treated with a single dose of intravitreal BI 836880 and followed up until the end of trial visit 
(EOT). In the ongoing MRD part, 14 patients had received at least one dose of BI 836880
(Table 1.2: 1). Six patients in the SRD part and 10 patients in the MRD part were reported 
with an adverse event (AE) after trial drug administration.
Table 1.2: 1
Summary of patient exposure to BI 836880*
Trial part/cohort
1 dose
2 doses
3 doses
Total patients 
exposed per cohort
SRD
15
---
---
15
MRD/cohort 1
2
8
10
MRD/cohort 2
1
2
1
4
* At the time of data cut off for the current IB (25 March 2022)
In the SRD part, all of the corresponding 6 AEs were eye disorders (conjunctival 
haemorrhage in the study eye, subretinal fluid in the study eye, dry eye in the study eye, 2 
vitreous floaters in the study eye, neovascular AMD in the fellow eye). None of the reported 
AEs was judged as related to BI 836880 by investigators or fulfilled criteria for dose-limiting 
events. The AEs of neovascular AMD and of subretinal fluid were reported as of moderate 
intensity, the other AEs were rated as mild. The AE of neovascular AMD in the fellow eye 
was considered serious. All AEs but the neovascular AMD, the subretinal fluid and the dry 


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eye were recovered by the end of follow up.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3
RATIONALE FOR PERFORMING THE TRIAL
IVT anti-VEGF injections are the current gold standard for treatment of patients with wet 
AMD. Anti-VEGF therapies are recognized to be effective and fast acting. However, the 
injection frequency (once every month or once every 2 months) is a burden and considered to 
be problematic for many patients to adhere to for a long time. Furthermore, many wet AMD 
patients do not have vision gain after anti-VEGF treatment and some continue to lose vision.
Treatment with a dual anti-VEGF/ANG2 antibody is anticipated to have better efficacy than
current anti-VEGF treatments and also has the potential to allow for a lower injection 
frequency.
This trial will consist of a single rising dose (SRD) part and a multiple rising dose (MRD)
part including MRD cohorts 1, 2, and 3. Since this is the First-in-Human (FiH) application 
with IVT route of administration, the SRD part and the MRD cohort 1 of this trial will 
include patients who have not sufficiently responded to anti-VEGF treatment and still have 
active disease with significant retinal edema after a minimum of three previous injections.
After safety has been investigated in SRD and the first 3 patients of MRD cohort 1, the MRD 
cohort 2 will start to evaluate treatment-naïve patients. This treatment-naïve population was 
initially thought to be the final target population, however, an exploratory analysis of the 
available interim data (patients from SRD, MRD cohorts 1 & 2 of the current trial) suggests
that BI 836880 may reduce CSFT, PED, SRHM, and/or PCV in an additional subset of
patients (see Figure 1.3: 1). These patients included those with wAMD that was not 
sufficiently controlled despite receiving frequent standard of care (SoC) treatment. Therefore,
it is expected that patients previously receiving frequent SoC treatment every 4-8 weeks, so 
called “frequent flyers” (frequently treated patients; MRD cohort 3) will highly benefit from 
IVT administration of BI 836880.


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In the SRD part of the trial, 5 rising doses are planned to be administered intravitreously. 
Safety and tolerability will be established unless dose-limiting safety or tolerability issues are 
noted.
In the MRD part, three multiple dose cohorts will be studied over a 24 week-period. After an 
initial active treatment period of 12 weeks (3 injections in 4 weekly intervals) patients will be 
followed up for an additional 12 weeks without further injections to study the durability of 
the treatment effect and to identify the need for additional standard treatment and the time to 
development of recurrence of any retinal fluid. This will help to guide injection frequency 
intervals in later studies.
The therapeutic benefit or specific adverse events (AE) in patients cannot always be 
anticipated during the trial setup. Later on, there may be new scientific knowledge about 
biomarkers and other factors contributing to diseases or the action of a drug. In order to be 
able to address future scientific questions, patients will be asked to voluntarily donate 
biospecimens for banking. If the patient agrees, banked samples may be used for future drug 
development projects, e.g. to identify patients that are more likely to benefit from a treatment 
or experience an AE, and thereby better match patients with therapies or to gain mechanistic 
understanding of drug effects and/or to identify genetic or other factors associated with 
response to therapy or the risk of adverse drug reactions.
1.4
BENEFIT - RISK ASSESSMENT
Based on available non-clinical data and based on clinical data from other compounds with a 
comparable mode of action BI 836880 is assessed to be generally safe for IVT use in humans 
(c21397543).
This is the first study using an IVT route of administration for this compound. However, IVT 
administration of an antibody that simultaneously binds to VEGF and ANG2 (faricimab, 
previously referred to as bispecific antibody RG7716) for treatment of wAMD has previously 
been tested in humans in a Phase 1 clinical trial [R18-0309], and a Phase 2 clinical trial [R21-
0692]. In the Phase 1 trial, the co-adminstration of RG7716 was reported to be well tolerated 
and to exhibit a favourable safety profile overall [R18-0309]. In addition, there was
preliminary evidence of improvements in BCVA and anatomic parameters for this mode of


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action. In the Phase 2 trial, faricimab maintained vision and anatomic improvements 
comparable with SoC in wAMD in treatment naïve patients, resulting in the start of Phase 3 
trials. These data support that the combination of anti-VEGF and anti-ANG2 can be used 
safely in patients with wAMD.
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 favorable 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 leave the decision to the treating investigators/sites on which material to 
use if it meets the specifications as described in the IMP handling instructions for BI 836880.
This trial will include in the SRD part and MRD cohort 1 patients with an insufficient 
response to the standard treatment for wAMD (IVT anti-VEGF therapy). Therefore, although 
this is a newly developed drug at an early stage of testing and an individual benefit cannot be 
guaranteed, trial treatment may result in an individual benefit to the individual patient. In
addition, due to the long duration of the disease the patient may directly benefit from the drug
development based on the results of this trial.
For the MRD cohort 2, treatment-naïve patients will be included based on a positive safety 
assessment as confirmed by the Safety Monitoring Committee (SMC), after three patients of 
MRD cohort 1 reach Visit 5, i.e. 4 weeks after the third injection. 
For MRD cohort 3, frequently treated patients will be included (defined as patients receiving 
anti-VEGF every 4-8 weeks on average). These frequently treated patients are the intended 
final target population for BI 836880, because of the remaining unmet medical need for these 
patients to receive a higher potency anti-VEGF therapy. BI 836880 has shown potential 
efficacy signals in pretreated patients in the SRD/MRD part of the study and could therefore 
have a role in the treatment of patients needing frequent anti-VEGF therapy.
The following safety measures have been implemented to mitigate the risk and ensure early 
detection of intraocular inflammation (IOI): fluorescein angiography (FA) imaging will be 
required at screening and wide-angle fundus photography with a vitreous haze assessment 
will be required at every visit. Reports of IOI will be treated as an AE of special interest 
(AESI), see also Section 5.2.8.1.4.
Furthermore, although rare, a potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. Therefore, this trial requires timely detection, 
evaluation, and follow-up of laboratory alterations in selected liver laboratory parameters to 
ensure patients´ safety, see also Section 5.2.8.1.4, AESIs. The implications of the current 
Coronavirus Disease 2019 (COVID-19) pandemic are summarized in Section 10.4.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective is to investigate ocular and systemic safety and tolerability as well as 
disease improvement of BI 836880 after a single IVT injection and after multiple IVT
injections of several doses.
2.1.2
Primary endpoint(s)
SRD part:

Number of patients with ocular dose limiting events (DLEs) from drug administration
until end of trial (EOT). For definition of DLEs, refer to Section 5.2.1.
MRD part:

Number of patients with drug related AEs from drug administration until EOT.
2.1.3
Secondary endpoint(s)
SRD part:

Number of patients with drug related AEs

Number of patients with any ocular AEs in the study eye
MRD part:

Percent change from baseline in Central Subfield Thickness (CSFT) in the study eye 
at Week 12 (Visit 5), for each dose

Change from baseline in BCVA in the study eye at Week 12 (Visit 5)

Time to recurrence after the last treatment

Number of patients with any ocular AEs in the study eye


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This trial will consist of an SRD part followed by an MRD part. Both parts of the trial will be 
conducted non-randomized, open-label, and uncontrolled.
SRD part:
The starting dose is 0.06 mg. Dose-escalation will be restricted to a maximum of 200% from 
the previous dose up to doses of 0.5 mg, and to a maximum of 100% from the previous dose
from dose 0.5 mg onwards. The maximum planned dose is 2 mg. For any dose-escalation 
cohort, at least 3 patients will be required. However, in the case that only 2 patients are 
evaluable and neither has experienced a DLE within the evaluation period (7 days after drug 
administration), then dose-escalation might occur based on these 2 patients if a joint decision 
of the Safety Monitoring Committee (SMC), see Section 8.7 is reached. Refer to Figure 3.1: 1
for a schematic representation of the dose escalation. For each dose group a single patient 
will be dosed on day 1 in each cohort, and only after a favorable safety and tolerability 
assessment on day 4 the remaining 2 patients will be dosed. 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]. Cohorts of patients will receive escalating doses of 
BI 836880. Each cohort will consist of newly enrolled patients. 
The BLRM provides estimates for the probability of observing an ocular DLE for each dose 
level in the study as patient information becomes available. The corresponding methodology 
is described in Section 7.1 and in Appendix 10.3. At any time in the trial, it will not be 
permitted to escalate to a dose which does not fulfil the EWOC principle. 
The maximum tolerated dose (MTD) is considered as reached if at least 6 patients have been 
evaluated at a dose level which is the model’s recommendation for the next dose cohort. Note 
the MTD will likely be the highest feasible dose, 2 mg, rather than the highest tolerable dose 
in a strict sense.


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Figure 3.1: 1 Schematic representation of the dose escalation process in the SRD part of the 
trial
The SMC recommends the size for the next dose escalation cohort. After all patients in a 
cohort have either experienced an ocular DLE or have been observed for at least the 7 days 
evaluation period without experiencing a DLE, the Bayesian model 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. As a sensitivity analysis, the BLRM might also be run again 
shortly before the SMC meeting, using all data available up to this time point. Based on the 
model results and on additional information (PK, pharmacodynamics [PD], patient profiles), 
the members of the SMC will reach a joint decision on the next dose level to be investigated.
If DLEs are observed in the first two consecutive patients of a previously untested dose level, 
subsequent enrolment to that cohort will be stopped. The BLRM will be re-run to confirm 
that the dose level still fulfils the EWOC principle. Based on this information, the SMC will 
evaluate whether the next patients will be enrolled at the same dose level, or if they will be 
enrolled at a lower dose level.
The SMC may decide on stopping the dose escalation after the above criterion for MTD is 
fulfilled. Further patients may be included to confirm that the EWOC criterion is still 
fulfilled. 
MRD part:
The MRD part will consist of a first part (1 mg) with 11 treatment-resistant patients
(cohort 1), a second part (2 mg) with 4 treatment-naïve patients (cohort 2), and approximately
12 frequently treated patients (cohort 3; inclusion criteria defined in Section 3.3.2). These are 
the two highest doses established by the SMC as safe and tolerable during the SRD part. 
Patients that had received a dose in the SRD part of the trial will not be included. In the MRD 


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groups, patients will receive three consecutive doses over a 3-month period (once a month 
dosing, Figure 3.1: 2). The SMC will decide on dose escalation after 3 patients from the first 
MRD cohort have completed visit 5 (first follow up visit). In all patients included in the 
MRD parts of the trial, safety and efficacy will be studied to 12 weeks after the treatment 
period. 
Figure 3.1: 2 Schematic representation of the dose escalation process in the MRD part of the 
trial
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This trial is designed to establish a safe and effective dose for further testing in phase II trials. 
The trial consists of separate SRD and MRD parts. This trial will not use a placebo 
comparison because inclusion of a placebo arm would withhold patients with wAMD from an 
effective treatment for several weeks. The objectives to establish a safe and effective dose 
can be met without a placebo comparison.
The SRD dose escalation part is included and designed to avoid exposure of too many 
patients to subtherapeutic doses while on the other hand the goal of safety and rapid dose 
finding is preserved. This part of the trial will already be done in patients because IVT
injections in healthy subjects would not be considered appropriate. Dose escalation and 
cohort size will be decided by the SMC, guided by a BLRM with overdose control. 
An EWOC design will increase the chance of treating patients at efficacious doses while 
~5 months
*
1
# mg (N = 3)
MRD cohort 1
Dose Dose
Dose
If positive SMC decision on Dose Escalation (after N = 3 of 1 mg dose)
* Second Highest Safe Dose from SRD
#
4 week intervals
Follow up
Highest Safe Dose from SRD
§
2
§ mg (N = approx. 16)
MRD cohorts 2 & 3
Dose Dose Dose
4 week intervals
Follow up
~5 months
1 mg dose group 
continues recruitment 
to total N = 11)


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reducing the risk of overdosing. The use of Bayesian models 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].
It is expected that, in the study population of patients not sufficiently responding to anti-
VEGF treatment, a reduction of fluid in the retina should be observed only after multiple 
treatments. Therefore, two MRD cohorts (3 injections in a monthly interval) will be included 
after the SRD part. This part of the trial will generate additional safety data after multiple 
dosing and allow for exploration of the time course and durability of treatment effects. These 
data will further support the definition of the injection frequency and intervals in later studies.
3.3
SELECTION OF TRIAL POPULATION
This trial will recruit up to 18 patients in the SRD part (the SRD part was completed with 
15 patients) and up to 27 patients in the MRD part (cohort 1, 2 and 3). Please refer to 
Section 7.7 for details and justification.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
A log of all 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 investigational drug or not.
3.3.1
Main diagnosis for trial entry
This study enrols patients with subfoveal choroidal neovascularization secondary to wAMD
that have insufficiently responded to previous anti-VEGF therapies who meet all inclusion 
criteria and do not meet any exclusion criterion. 
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
SRD part and MRD cohort 1 (treatment-resistant patients with wAMD):
1. Men and women over the age of 55 with active CNV secondary to AMD despite anti-
VEGF therapies (at least 3 prior injections with the last injection within 16 to 4 weeks 
before treatment). Active CNV secondary to AMD is to be defined either by recent 
fluorescein or OCT angiogram within 4 weeks prior to screening or fluorescein or OCT
angiogram obtained prior to first anti VEGF-treatment to confirm the diagnosis and still 
active according to investigator judgement.
2. Deleted.
3. For MRD part only: Central subfield retinal thickness >300 microns in the study eye on 
Heidelberg Spectralis Spectral Domain Optical Coherence Tomography (SD-OCT).
4. Presence of sub- and/or intraretinal fluid on SD-OCT in the study eye.
5. Any active CNV with subfoveal leakage in the study eye as determined by OCT 
6. No subretinal hemorrhage involving the fovea in the study eye.


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7. No significant subfoveal fibrosis or atrophy on SD-OCT in the study eye that, in the 
opinion of the investigator, is able to prevent improvement in BCVA and/or CSFT.
8. Best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) VA in the study 
eye between 75 and 24 letters inclusive (approximately 20/32 and 20/320 or 6/9.5 and 
6/95) at screening. 
9. Best-corrected VA in the non-study eye better than best-corrected VA in the study-eye. If 
both eyes are eligible and have identical VA the investigator may select the study eye.
10. Male or female patients. Women of childbearing potential (WOCBP)1 cannot be included. 
Men able to father a child must be ready and able to use highly effective methods of birth 
control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when 
used consistently and correctly. A list of contraception methods meeting these criteria is 
provided in the patient information and in Section 4.2.1.3.
11. Signed informed consent consistent with ICH GCP guidelines and local legislation prior 
to participation in the trial, which includes medication washout and restrictions.
12. Not under any administrative or legal supervision or under institutionalization due to 
regulatory or juridical order.
MRD cohort 2 (treatment-naive patients with wAMD):
1. Not applicable: Adapted to inclusion criterion #13, see below.
2. Not applicable: Deleted.
3. Not applicable: No limitation on central subfield retinal thickness.
4. Not applicable: Adapted to inclusion criterion #14, see below.
5. Not applicable: Adapted to inclusion criterion #14, see below. 
6. No subretinal hemorrhage involving the fovea in the study eye.
7. No significant subfoveal fibrosis or atrophy on SD-OCT in the study eye that, in the 
opinion of the investigator, is able to prevent improvement in BCVA and/or CSFT.
8. Not applicable: Adapted to inclusion criterion #15, see below. 
9. Not applicable: Adapted to inclusion criteria #16 and #17, see below.
10. Male or female patients. Women of childbearing potential (WOCBP)1 cannot be included. 
Men able to father a child must be ready and able to use highly effective methods of birth 
control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when 
used consistently and correctly. A list of contraception methods meeting these criteria is 
provided in the patient information and in Section 4.2.1.3.
11. Signed informed consent consistent with ICH GCP guidelines and local legislation prior 
to participation in the trial, which includes medication washout and restrictions.
12. Not under any administrative or legal supervision or under institutionalization due to 
regulatory or juridical order.
13. Men and women over the age of 55 with treatment-naïve CNV secondary to AMD.
14. Any CNV with subfoveal activity in the study eye defined as evidence of sub- and/or 
intraretinal fluid, or subretinal hyper-reflective material, or angiographic leakage.
15. Best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) VA in the study 
eye between 80 and 24 letters inclusive (approximately 20/25 and 20/320 or 6/7.5 and 
6/95) at screening.
16. Best-corrected ETDRS VA in the non-study eye 50 letters inclusive (approximately 
20/100 or 6/30) or better at screening.
17. If both eyes are eligible at screening, the study eye is the eye with the worse best-
corrected VA.


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MRD cohort 3 (frequently treated patients):
1-5. Not applicable to cohort 3.
6. No subretinal hemorrhage involving the fovea in the study eye.
7. No significant subfoveal fibrosis or atrophy on SD-OCT in the study eye that, in the 
opinion of the investigator and with the endorsement of the Sponsor, is able to prevent 
improvement in BCVA.
8-9. Not applicable to cohort 3.
10. Male or female patients. Women of childbearing potential (WOCBP)1 cannot be included. 
Men able to father a child must be ready and able to use highly effective methods of birth 
control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when 
used consistently and correctly. A list of contraception methods meeting these criteria is 
provided in the patient information and in Section 4.2.1.3.
11. Signed informed consent consistent with ICH GCP guidelines and local legislation prior 
to participation in the trial, which includes medication washout and restrictions.
12. Not under any administrative or legal supervision or under institutionalization due to 
regulatory or juridical order.
13. Not applicable to cohort 3.
14. Any CNV with subfoveal activity in the study eye defined as evidence of sub- and/or 
intraretinal fluid, or subretinal hyper-reflective material, or angiographic leakage.
15. Best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) VA in the study 
eye between 80 and 24 letters inclusive (approximately 20/25 and 20/320 or 6/7.5 and 
6/95) at screening.
16. Not applicable to cohort 3.
17. If both eyes are eligible at screening, the study eye is the eye with the worse best-
corrected VA.
18. Men and women over the age of 55 with diagnosed wAMD that:

require frequent wAMD SoC (28-56 days between the last 3 treatments)

have had ≥3 previous treatments with IVT SoC (ranibizumab, aflibercept, or
bevacizumab) in the study eye

had the last SoC injection ≥4 weeks, but no more than 8 weeks, before the first 
administration of the study drug

have been on SoC treatment ≥6 months and are within 3 years from initial wAMD 
diagnosis in the study eye
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
1. Additional eye disease in the study eye that could compromise best corrected VA
(BCVA) with visual field loss, uncontrolled glaucoma (IOP> 24 mmHg on more than 
2 consecutive measurements prior to screening), clinically significant diabetic 
maculopathy, history of ischemic optic neuropathy or retinalvascular 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.
2. Any prior intraocular surgery in the study eye other then uneventful lens replacement for 
cataract within 3 months prior to screening.
3. Aphakia or total absence of the posterior capsule. Yttrium aluminum garnet (YAG) laser 
capsulotomy permitted, more than 1 month prior to enrollment in the study eye.
4. Current or planned use of medications known to be toxic to the retina, lens or optic nerve 
(e.g. desferoximine, chloroquine/hydrochloroquine, chlorpromazine, phenothiazines, 
tamoxifen, nicotinic acid, and ethambutol).
5. Medical history or condition: Uncontrolled diabetes mellitus, with hemoglobin A1c 
(HbA1c) > 10%, myocardial infarction or stroke within 12 months of screening, active 
bleeding disorder, concomitant use of warfarin or anticoagulation therapy (use of anti-
platelet therapy such as aspirin is allowed), major surgery within 1 month of screening or 
when planned within the study period, hepatic impairment, uncontrolled hypertension.
6. Patients with a clinically relevant abnormal screening haematology, blood chemistry, or 
urinalysis, if the abnormality defines a significant disease as defined in other exclusion 
criteria. AST or ALT greater than 2.0-fold the upper limit of normal at screening. Patients 
with total bilirubin 2.5x upper limit of normal at screening. 
7. Patient with impaired renal function defined as calculated GFR< 30 mL/min.
8. Significant alcohol or drug abuse within past 2 years per investigator judgement.
9. Participation in trials: 

Previous participation in this trial. 

Previous participation in other trials for treatment of wAMD with systemic 
administration if washout period from last administration is shorter than 3 months.

MRD cohorts 1 & 3: Previous participation in other trials for treatment of wAMD
with IVT injections in the study eye if washout period from last 
administration/injection is shorter than 3 months2.

MRD cohort 2: No previous IVT injections for wAMD in the study eye2.
10. Significant disease or other medical conditions3 (as determined by medical history, 
examination and clinical investigations at screening) that may, in the opinion of the 
investigator result in the any of the following:

Put the patient at risk because of participation in the study,

Influence the results of the study,

Cause concern regarding the patient’s ability to participate in the study.
11. Known hypersensitivity to fluorescein or any of the ingredients used in the Investigational 
Medicinal Product (IMP) formulation, or any of the medications used.
12. Active intraocular inflammation in the study eye, > 0.5+ anterior chamber cell and/or 
vitreous haze grading, or history of intraocular inflammation in either eye with previous 
IVT administration(s) (anterior chamber/haze grading and intraocular imflammation
history only applicable to MRD cohort 3).
13. Active infectious conjunctivitis in either eye.


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14. Symptoms of active SARS-CoV-2 infection4.
15. Any history of retinal vein occlusion in the study eye (only applicable to MRD cohort 3).
16. Any previous treatment with brolucizumab or faricimab in either eye (only applicable to 
MRD cohort 3).
17. Medical history of autoimmune disease that has caused ocular inflammation (only 
applicable to MRD cohort 3).
2 Previous participation in other trials with IVT injections allowed if fellow eye was treated.
3 e.g. cardiac (including tachycardia), gastro-intestinal, hepatic, renal, metabolic, dermatologic, neurological, haematological, 
oncological and psychiatric. Patients with malignancy for which the patient has undergone resection, radiation or 
chemotherapy within past 5 years. Patients with treated basal cell carcinoma or fully cured squamous cell carcinoma are 
allowed.
4 Testing and management of SARS-CoV-2 infection at the discretion of investigators in accordance with local guidelines 
and policies.
3.3.4
Withdrawal of patients from therapy or assessments
Subjects may potentially be withdrawn from trial treatment or from the trial as a whole
(“withdrawal of consent”) with very different implications, please see Section 3.3.4.1 and 
Section 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 patient selection, appropriate 
explanation of the trial requirements and procedures prior to first administration of trial 
medication, as well as the explanation of the consequences of withdrawal. 
The decision to withdraw from trial treatment or from the whole trial as well as the reason
must be documented in the patient files and Case Report Form (CRF).
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision.

The patient needs to take concomitant drugs that interfere with the investigational 
product or other trial medication.

The patient can no longer be treated with trial medication for other medical reasons 
(such as surgery, AEs, other diseases, or pregnancy).

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing 
or able to stick to the trial requirements in the future.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart I, Flow Chart II, Flow Chart III, 
Flow Chart IV, and Section 6.2.
For all patients the reason for withdrawal from trial treatment (e.g. AEs) must be recorded in 
the CRF. These data will be included in the trial database and reported.


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3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.
This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore,
it may mean that further patient follow up on safety cannot occur.
If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment, please see Section 3.3.4.1
above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim (BI) 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. Emergence of any efficacy/safety information invalidating the earlier positive 
benefit-risk-assessment that could significantly affect the continuation of the trial.
3. Violation of Good Clinical Practice (GCP), the trial protocol, or the contract 
impairing the appropriate conduct of the trial.
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 patients
SRD part:
Patients withdrawn before visit 4 for a reason other than a DLE or patients who miss any visit 
out of Visits 2 to 4 are not evaluable for the occurrence of a DLE within 7 days after drug 
administration. These patients will be replaced if not decided otherwise by the SMC (in the 
scenario that there are already 2 DLE evaluable patients in the current dose group; see 
Section 3.1). Patients who come off study due to a DLE will not be replaced.
MRD part:
In case some subjects do not complete the trial according to the protocol, the trial clinical 
monitor together with the trial pharmacokineticist and the trial statistician are to decide if and 
how many subjects will be replaced. 
A replacement subject will be assigned a unique study subject number and will be assigned to 
the same treatment as the subject he or she replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
In this trial, the IMP BI 836880 will be switched from an initial trial formulation (CMC1) to 
an intended final formulation (CMC2). The new formulation will be made available for the 
treatment of MRD cohort 3.
Table 4.1.1: 1
BI 836880
Substance:
BI 836880
Pharmaceutical formulation:
Solution for IVT injection
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
50 µl BI Solution for injection with a concentration 
from 5 mg/ml (0.25 mg per dose) to 40 mg/ml (2 mg 
per dose)
Posology:
SRD part: 1 injection
MRD part: 3 injections, each separated by 4 weeks
Route of administration:
IVT injection
Table 4.1.1: 2
Diluent
Substance:
Diluent for BI 836880 concentrate for solution for 
injection 80 mg/mL, 10 mL/vial
Pharmaceutical formulation:
Diluent
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
n/a
Posology:
SRD part: 1 injection
MRD part: 3 injections, each separated by 4 weeks
Route of administration:
IVT injection
4.1.2
Selection of doses in the trial
Dose selection was driven by the invasive mode of administration and the resulting need to 
cover the potential dose range with a limited number of doses (in order to limit the number of 
subjects at risk for adverse reactions related to the mode of administration). In addition, the 
lowest dose in the trial should provide a reasonable safety margin to the no observed adverse 
effect level (NOAEL) and, on the other hand, have the potential to already result in beneficial 
effects to the patient to outweigh the risk of an AE caused by the IVT administration. 


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The Laser CNV model represents a reliable animal surrogate to estimate treatment effects of 
therapeutics for wAMD [R18-1168]. In an in-house study using such a model (n00256189)
30µg BI 836880 administered IVT into the monkey eye were interpreted to result in clinically 
meaningful improvement of the respective retinal lesions. The corresponding human dose of 
60 µg (0.06 mg) was therefore selected as starting dose as it is likely to already provide a 
therapeutic benefit over a period of 4 weeks. At the same time this dose is adequately below 
the observed corresponding NOAEL observed in the cynomolgous monkey of 500 µg 
(human corresponding dose 1000 µg or 1.0 mg) (n00255516, n00258450, n00254368) 
leading to a safety margin of more than 15 fold. 
For the lower doses a higher relative increase to the next dose (200% and 178%, respectively) 
was chosen, resulting in dose levels of 0.18 mg and 0.5 mg in order to avoid many small dose 
steps resulting in an increasing number of trial related IVT injections. For the next dose 
(1.0 mg) a smaller relative (100%) increase was chosen. If all previous doses are clinically 
well tolerated one additional dose of 2.0 mg will be tested as one of the development 
objectives is to find a dose that provides an exposure that has the potential for a decreased 
injection frequency. 
The provisional dose levels to be assigned to separate cohorts of patients are listed in 
Table 4.1.2: 1.
Table 4.1.2: 1
Provisional dose levels for escalation
Dose level
Proposed dose
Relative increment from previous 
dose
1
0.06 mg
Starting dose
2
0.18 mg
200%
3
0.5 mg
178%
4
1.0 mg
100%
5
2.0 mg
100%
4.1.3
Method of assigning patients to treatment groups
Recruitment in the trial will be started with the lowest dose group of the SRD part. The MRD 
part will recruit patients only after the SRD part has been completed and safety of the doses 
has been established. 
In the SRD part, the dose is planned to be escalated in cohorts at the pre-defined provisional 
dose levels; see Table 4.1.2: 1. Intermediate or lower dose levels, depending on the number 
of DLEs observed in the study, as long as they fulfil the EWOC criterion, may be 
investigated if agreed upon between Investigator and Sponsor. At the end of each treatment 
cohort, BI will convene a meeting with the SMC members. At the dose escalation meeting,
the clinical course for each patient in the current dose cohort will be described in detail. 
Based on that and on the results of the updated BLRM, a decision on the next dose level to be 
tested is made.
In general, recruitment will be done successively for the dose groups, i.e. if the required
number of patients for one dose group will be completed and this dose is considered safe 
based on (the BLRM model and) the clinical course, the recruitment of the next higher dose 


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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 patients, but only by 
temporal availability.
4.1.4
Drug assignment and administration of doses for each patient
BI 836880 will be administered intravitreously. “BI 836880 concentrate for solution for 
injection 80 mg/mL” and “Diluent for BI 836880 concentrate for solution for injection 80 
mg/mL” and “BI 836880 solution for injection 40 mg/mL” will be provided by BI. The 
diluent can be used for both drug preparations, “BI 836880 concentrate for solution for 
injection 80 mg/mL” and for “BI 836880 solution for injection 40 mg/mL”, if required. A site 
pharmacist or qualified personnel will prepare the ready to use drug product according to the 
“Instructions to pharmacist/qualified personnel”. The instructions will be provided by BI and 
will be filed in the ISF. 
Table 4.1.4: 1
Planned doses and treatment schedule for the SRD part
Dose group 
(mg)
Visit 2 
Day 1
Visit 3 
Day 8
Visit 4
Day 15
Visit 5
Day 22
Visit 6
Day 29
0.06
X
0.18
X
0.5
X
1.0
X
2.0
X
To determine the dose regimen for the next cohort, the available toxicity information 
(including DLEs and AEs that are not DLEs), PK, PD, as well as the recommendations from 
the BLRM will be evaluated by the SMC members at the dose decision meeting. The parties 
must reach a consensus whether further dose escalation is appropriate, or whether to 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 doses and treatment schedule for the MRD part (the two 
highest doses established by the SMC as safe and tolerable during the 
SRD part will be selected)
Dose group 
(mg)
Visit 2 
Day 1
Visit 3 
Day 29
Visit 4
Day 57
Visit 5
Day 85
Visit 6
Day 113
Visit 7
Day 141
MRD dose 1
X
X
X
MRD dose 2
X
X
X
4.1.5
Intravitreal Injection Technique
IVT injections must be carried out according to medical standards and applicable guidelines 
by a qualified physician experienced in administering IVT injections. In general, adequate 
anaesthesia and asepsis, including topical broad spectrum microbicide (e.g. povidone iodine 
applied to the periocular skin, eyelid and ocular surface) have to be ensured. Surgical hand 
disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) are 
recommended.


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4.1.6
Masking and procedures for unmasking
4.1.6.1
Masking
In this open-label trial, treatment allocation will not be concealed throughout the trial. The 
CRF will contain information on treatment.
4.1.6.2
Unmasking and breaking the code
Not applicable.
4.1.7
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated Contract Research 
Organizsation (CRO). They will be packaged and labelled in accordance with the principles 
of Good Manufacturing Practice (GMP). Re-supply to the sites will be managed via an 
Interactive Response Technology (IRT) system, which will also monitor expiry dates of 
supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
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 Trial 
Manager (CTM) (as provided in the list of contacts) must be contacted immediately.
4.1.9
Drug accountability
The investigator and/or pharmacist and/or qualified personnel and/or investigational drug 
storage manager will receive the investigational drugs delivered by the sponsor when the 
following requirements are fulfilled:

Approval of the clinical trial protocol (CTP) by the Institutional Review Board 
(IRB) / ethics committee,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority (CA),

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated CTP,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator and/or pharmacist and/or qualified personnel and/or investigational drug 
storage manager must maintain records of the product’s delivery to the trial site, the 
inventory at the site, the use for each patient, and the return to the sponsor or warehouse / 


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drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
investigator / pharmacist / qualified personnel / investigational drug storage manager will 
maintain records that document adequately that the patients were provided the doses specified 
by the CTP and reconcile all investigational products received from the sponsor. At the time 
of return to the sponsor and/or appointed CRO, the investigator / pharmacist / qualified 
personnel / investigational drug storage manager must verify that all unused or partially used 
drug supplies have been returned by the clinical trial patient and that no remaining supplies 
are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Restrictions
4.2.1.1
Restrictions regarding concomitant treatment
SRD and MRD cohorts 1 & 2: As per judgement of the investigator, administration of local 
SoC treatment such as IVT or peribulbar injections, laser, or other surgical treatment is 
allowed in clinically significant worsening of the disease. After the end of treatment with trial 
medication (during Follow-up Period, starting at Visit 5), SoC therapy is at the discretion of
the investigator. SoC therapy is, for the purpose of the present trial, considered a non-
investigational medical treatment.
MRD cohort 3: For the study eye, no other treatment (IVT or otherwise) is allowed during the 
treatment and follow up periods of the trial unless rescue criteria are met (refer to Section 
5.2.2 for rescue treatment criteria), or as deemed medically appropriate during/after Visit 6. 
Medications listed under the exclusion criteria (Section 3.3.3) are restricted during the trial.
SoC therapy is, for the purpose of the present trial, considered a non-investigational medical 
treatment.
4.2.1.2
Restrictions on diet and life style
None.
4.2.1.3
Contraception requirements
WOCBP are excluded from trial participation.
‘WOCBP (partner of a trial participant) must use a highly effective method of birth control 
per ICH M3 (R2) 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).


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
Bilateral tubal occlusion
Or
Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, 
symptothermal, post-ovulation methods; declaration of abstinence for the duration of 
exposure to study drug; and withdrawal are not acceptable.
4.2.2
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured sample concentrations 
will provide additional confirmation of compliance. Subjects who are non-compliant (for 
instance, who do not appear for scheduled visits or violate trial restrictions) may be removed 
from the trial and the CRF will be completed accordingly (for further procedures, please see 
Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
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 (CFP, OCT/OCT-A) will be transferred from the 
Central Reading Center (CRC) to the sponsor’s database. The local measurement data 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 5.2.8).
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. OCT-A 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 images will be sent to an independent CRC for evaluation. A detailed manual for OCT
image acquisition and data transmission will be provided.
Visual Acuity measured by ETDRS letter charts
BCVA will be determined by using the ETDRS VA chart starting at a test distance of 
4 meters. The BCVA score is the number of letters read correctly by the patient. The 
assessment will be performed by a trained person under specified conditions regarding 
examination room and equipment.
5.2
ASSESSMENT OF SAFETY
5.2.1
Dose limiting event
For the SRD part and MRD cohort 1:
A DLE is defined as the occurrence of any of the following events in the study eye:

Development of sterile endophthalmitis and/or sterile inflammation of the vitreous 
grade 4+ according to standardization of Uveitis Nomenclature (SUN) working group 
(WG) grading scheme for anterior chamber cells (see Table 5.2.1: 1) and a duration of 
5 or more days between day 1 and day 8

Visual decrease of more than 15 letters at any given timepoint

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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Table 5.2.1: 1
The SUN Working Group Grading Scheme for Anterior Chamber 
Cells [R18-1136]
Grade
Cells in Field1
0
<1
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.
DLE criteria are not applicable to MRD cohorts 2 and 3. Should an event involving 
intraocular inflammation/signs of vascular occlusion, decreases in visual acuity, and/or
intraocular pressure occur, the event should only be reported as an AESI as described in 
Section 5.2.8.1, and not as a DLE.
5.2.2
Time to recurrence
Time to recurrence will be assessed in the MRD part from last trial drug administration to 
occurrence of any of the following in the study eye, leading to the use of wAMD rescue 
medication as decided by the investigator:

Increase in CFST ≥75 μm with a decrease in BCVA of ≥ 5 letters compared to Visit 
5, 

OR

Decrease in BCVA of > 5 letters compared to baseline (Visit 2), due to worsening 
wAMD activity, 

OR

Decrease in BCVA of ≥ 10 letters compared to the best prior BCVA, due to 
worsening wAMD activity
The decision to treat with wAMD rescue medication should be documented in the eCRF.
5.2.3
Physical examination
A complete physical examination will be performed at the time points specified in the 
Flow Chart I, Flow Chart II, Flow Chart III, and Flow Chart IV. It includes at a minimum
general appearance, neck, lungs, cardiovascular system, abdomen, extremities, and skin.
Measurement of height and body weight will be performed at the time points specified in the 
Flow Charts.
The results must be included in the source documents available at the site. 
Color Fundus Photography
Multi-field digital fundus photographs will be obtained from both eyes by a qualified person 
according to the imaging manual. For MRD cohort 3, additional color fundus photographs 
from both eyes will be acquired from the retinal periphery to assess inflammation and from 


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the central retina to assess vitreous haze. These examinations will be performed at the 
timepoints defined in the Flow Charts I, II, III, and IV.
5.2.4
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Charts I, II, III, and IV,
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. 
5.2.5
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Tables 5.2.5: 1 and 5.2.5: 2. For the 
sampling time points please see the Flow Chart I, Flow Chart II, Flow Chart III, and Flow 
Chart IV. Patients do not have to be fasted for the blood sampling for the safety laboratory. 
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. Instructions regarding sample collection, sample handling/ processing 
and sample shipping are provided in the Laboratory Manual in the ISF. The central laboratory 
will send reports to the investigator. It is the responsibility of the investigator to evaluate the 
laboratory reports. Clinically relevant abnormal findings as judged by the investigator will be 
reported as AEs (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.8.1 and the DILI Checklist provided in the electronic data 
capture (eDC) system. The amount of blood taken from the patient concerned will be 
increased due to this additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor.


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Table 5.2.5: 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
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 

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
Table 5.2.5: 2
Safety laboratory parameters – urine
Urinalysis 
Semi quantitative

Nitrite

Protein

Glucose

Hemoglobin

Ketone

Urine pH

Leukocyte esterase (for 
WBC)
Human urine chorionic 
gonadotropin (HCG)*
*Pregnancy testing (HCG, urine) will only be performed if required by local regulations. It may also be done more 
frequently or in plasma instead of urine if required (please note: this trial will include no patients of child-bearing 
potential)


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5.2.6
Electrocardiogram
Single standard 12 lead ECGs (I, II, III, aVR, aVL, aVF, V1 – V6) will be recorded at the 
time points described in the Flow Charts. Electrode placement will be performed according to 
the method of Einthoven/Goldberger (ankles and wrists) and Wilson (chest leads). The 
recordings will be made using equipment approved or provided by the central ECG vendor. 
They will be assessed after the subjects have rested for at least 5 minutes in a supine position. 
ECG recordings at planned time points may be repeated for quality reasons like alternating 
current artefacts, muscle movements and electrode dislocation. In this case the repeated ECG 
recordings will be used if quality was better.
All ECGs will be evaluated by the cardiologist of the central ECG vendor, and in addition by 
a qualified healthcare provider at the site, if available. Clinically relevant abnormal findings 
will be reported either as baseline condition (if identified at the screening visit) or otherwise 
as AEs and will be followed up and/or treated as medically appropriate. Additional 
(unscheduled) ECGs can be recorded for safety reasons at any time based on the judgment of 
the investigator. For the screening ECG the evaluation needs to be available prior to the final 
assessment of the in/exclusion criteria. 
All ECGs will be transmitted (either electronically (preferred) or via a scanned hard-copy) to 
the central ECG vendor in order to enable a centralized and independent re-evaluation of all 
12-lead ECGs. This re-evaluation will only be done for the screening ECG if needed or if 
requested by the sponsor. Abnormalities detected during this centralised ECG evaluation will 
not necessarily qualify as AE.
5.2.7
Other safety parameters
MRD cohort 3 only: Fluorescein angiography (FA) imaging will be obtained from both eyes 
during Screening by a qualified person according to the imaging manual. Additional FA 
during Visits 2-8 should be performed at the discretion of the investigator, e.g. if signs of 
inflammation are observed.
5.2.8
Assessment of adverse events
5.2.8.1
Definitions of AEs 
5.2.8.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
5.2.8.1.2
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,


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
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.

requires inpatient hospitalisation or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect, or

is deemed serious for any other reason if it is an important medical event when based 
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 room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse.
5.2.8.1.3
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.8.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”.
In accordance with the EMA initiative on Important Medical Events, BI has set up a list of 
further AEs, which by their nature, can always be considered to be “serious” even though 
they may not have met the criteria of an SAE as defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. These events should 
always be reported as SAEs as described above.
5.2.8.1.4
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
The following are considered as AESIs:
Ocular related events (applicable to MRD cohorts 2 & 3)

Intraocular inflammation events
o
Anterior chamber cells of grade 1+ according to the Standardization of Uveitis 
Nomenclature (SUN) working group (WG) grading scheme (see 
Table 5.2.1: 1)
o
Sterile inflammation of the vitreous of 1+ according to the NEI Grading of 
vitreous haze (see Table 5.2.8.1.4: 1 below)

Signs of vascular occlusion and inflammation (vasculitis) in the retina, including 
peripheral retinal hemorrhages in the area supplied by the occluded vessel 
(hemorrhage of the macula would not be included as this is a sign of wAMD disease)

Visual acuity decrease of more than 15 letters from the previous visit


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
Persistent IOP over 30 mmHg for 3 days after study treatment is administered, despite 
rescue treatment
Table 5.2.8.1.4: 1
The NEI Grading Scale of Vitreous Haze [R22-2854]
Scale
Description
Clinical findings
0
Nil
None
0.5+
Trace
1+
Minimal
Posterior pole clearly visible
2+
Mild
Posterior pole details slightly hazy
3+
Moderate
Posterior pole details very hazy
4+
Marked
Posterior pole details barely visible
5+
Severe
Fundal details not visible
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

an elevation of AST and/or ALT > 3 fold ULN combined with an elevation of total 
bilirubin > 2 fold ULN measured in the same blood draw sample, and/or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the eDC 
system.
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.
All AEs meeting the criteria for a dose limiting event as defined in Section 5.2.1 are defined 
as AESIs for this trial.
5.2.8.1.5
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
5.2.8.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 


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Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation 
(e.g. situations where other drugs or underlying diseases appear to provide a more 
likely explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.8.2
Adverse event collection and reporting
5.2.8.2.1
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 EOT: 
- all AEs (serious and non-serious) and all AESIs.

After the individual patient’s EOT: 
the investigator does not need to actively monitor the patient for AEs but should only 
report related SAEs and related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should however, not 
be reported in the CRF.
5.2.8.2.2
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 


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unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
5.2.8.2.3
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. The investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only. All (S)AEs, including those 
persisting after individual patient’s EOT must be followed up until they have resolved, have 
been assessed as “chronic” or “stable”, or no further information can be obtained.
5.2.8.2.4
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male
trial participant becomes pregnant. This requires written consent of the pregnant partner.
Reporting and consenting must be in line with local regulations. The ISF will contain the trial
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). The ISF will contain the Pregnancy Monitoring Form for 
Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in
the CRFs. Planned time points for systemic pharmacokinetic samples are listed in 
Appendix 10.1.
Pharmacokinetic data may additionally be analysed using population pharmacokinetic
approach. For this purpose data may also be combined with data from other trials. Modelling
activities will be planned and documented separately according to internal and external
guidelines and Standard Operating Procedure (SOP).
 
 
 
5.3.2
Methods of sample collection
For the quantification of BI 836880 sample concentrations, at least 3 mL blood will be taken 
from a forearm vein in a blood drawing tube at time points specified in the Flow Chart I, 
Flow Chart II, Flow Chart III, Flow Chart IV, and in Appendix 10.1. Samples will be divided 
into duplicate aliquots and stored frozen at about -70°C at the participating sites or logistics 
CRO until shipment on dry ice to the bioanalytical laboratory of BI or a BI selected and 
authorized CRO. 
Details about sample collection, preparation, required tubes, labelling of tubes, storage and 
shipment (frequency and addresses) will be provided in a separate laboratory manual. The 
samples may be used for further methodological investigations (e.g., for stability testing),
however, only data related to the analyte will be generated by these additional investigations, 
and such data will be reported separately. The study samples will be discarded no later than
5 years after the final study report has been generated.


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5.3.4
Pharmacokinetic – pharmacodynamic relationship
No formal analysis of a pharmacokinetic/pharmacodynamic relationship is planned. 
Correlation between drug concentration and response may be made if adequate data are 
available. In addition, exploratory correlation may also be made between drug concentration
and AEs. 
Data may also be used to develop pharmacokinetic/pharmacodynamic models using nonlinear 
mixed effect modelling techniques, if feasible. For this purpose data may also be combined 
with data from other trials. Modelling activities will be planned and documented separately 
according to internal and external guidelines and SOP.
5.4
ASSESSMENT OF BIOMARKER(S)
This section refers to exploratory biomarkers. Established biomarkers of efficacy and safety 
are described and discussed in Sections 5.1 and 5.2.
5.4.1
Plasma derived protein biomarkers
The analysis of the biomarkers free VEGF as well as free/total ANG2 in plasma are 
exploratory in nature and shall determine the effect of systemic exposure of BI 836880 on the 
circulating ANG2 and VEGF receptor levels. Participation in the biomarker test is 
mandatory. Plasma biomarker studies will focus on exploring pharmacodynamic effects. 
Methods of sample collection
For quantification of free VEGF and free/total ANG2 5 ml blood will be taken from the 
forearm vein at those time points specified in the Flow Chart I, Flow Chart II, Flow Chart III, 
Flow Chart IV, and in Appendix 10.1. Plasma samples for protein biomarkers need to be 
stored at ≤-70 °C or below. Detailed instructions for sampling, handling, storage, and 
shipment of the biomarker samples will be provided in the ISF/lab manual. Date and time of 
sampling will be recorded in the eCRF.
Pharmacodynamic Analysis
The following pharmacodynamic parameters will be determined as further endpoints if 
feasible:


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Biobanking
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will only occur after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements (see Section 1.3).
5.4.1.1
Methods and timing of sample collection
For sampling timepoints see Flow Chart II, Flow Chart III, and Flow Chart IV.
DNA banking:
Approx. 8.5 mL blood will be drawn into a PAXgene Blood DNA Tube, preferably at Visit 2.
Plasma banking:
Approx.10 mL blood will be drawn into an Ethylenediaminetetraacetic acid (EDTA blood 
collection tube.
Serum banking:
Approx. 8.5 mL blood will be drawn into a serum separation tube.
For all biological samples collected, detailed instructions on sampling, preparation, 
processing, shipment and storage are provided in the laboratory manual. Plasma and serum 
samples will be stored at an external biobanking facility contracted by the Sponsor; DNA, 
extracted from the original whole blood sample, will be stored at the Sponsor.
5.5
OTHER ASSESSMENTS
5.5.1
Immunogenicity assessment
Methods of ADA sample collection
For the determination of anti-drug antibodies (ADA), approximately 3 mL of blood will be
taken from a forearm vein in a blood drawing tube at those time points specified in the 
Flow Chart I, Flow Chart II, Flow Chart III, Flow Chart IV, and in Appendix 10.1.
Details about sample collection, preparation, storage and shipment are described in the
laboratory manual.


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5.6
APPROPRIATENESS OF MEASUREMENTS
All other measurements performed during this trial are standard measurements and will be 
performed in order to monitor patients’ safety and to determine pharmacokinetic and 
pharmacodynamic parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that 
might occur as a result of administration of trial medication. The safety assessments are 
standard, are accepted for evaluation of safety and tolerability of an orally administered drug 
and are widely used in clinical trials. The pharmacokinetic parameters and measurements 
outlined in Section 5.3 are generally used assessments of drug exposure. The biomarkers and 
pharmacodynamic parameters and measurements outlined in Section 5.4 and 5.5 are of 
exploratory nature only.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All ophthalmic exams will be performed in both eyes and should be performed in specific
order described below.
Before pupil dilation: BCVA assessment and ocular tonometry
After dilation: slit lamp examination, SD-OCT, Fundus photography, OCT- angiography, and 
FA (FA required at screening or at the discretion of the investigator during subsequent visits,
for cohort 3 only).
Additional ocular tonometry may also be performed after treatment at the discretion of the 
investigator. 
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, Flow Chart III, Flow Chart IV, and in the Appendix 10.3. Additional details 
regarding visit procedures are provided below.
6.2.1
Single Rising Dose Part
6.2.1.1
Screening Visit
Screening Period
The screening visit does not need to be done with the patient in a fasted state.
All patients must sign an Informed Consent consistent with ICH GCP guidelines prior to any 
study specific procedures, this includes the option that the patient signs the Informed Consent 
during an extra contact to the study site prior to the actual screening visit. The patient should 
be recorded on the enrolment log as a screened patient when Visit 1 is performed.
Visit 1 is the beginning of the screening period. As soon as eligibility of enrolled patients is 
confirmed, the treatment visit (Visit 2) may be performed.
Baseline Conditions
Any pre-existing medical conditions considered as relevant by the investigator, excluding the 
indication of the trial, are recorded into the eCRF in the appropriate page.
Any abnormal clinical significant findings observed during ophthalmological examination 
with slit lamp at Visit 1 need to be documented as Baseline Conditions.
Medical History:
All relevant medical history according to the investigator judgment will be captured in the 
eCRF.
IRT:
All patients that are screened must be registered with IRT. If the patient results in a screen 
failure, IRT should be notified as soon as possible and within the screening period. Details of 
IRT procedures can be found in the IRT manual located in the ISF.
Re-screening:
Patients who do not fulfil all eligibility criteria for a reason that later resolves and allows
eligibility criteria to be met within a 12-week period after initial screening visit, can be 


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rescreened up to one time. For re-screening, patient must be registered in IRT, which will 
then provide new patient number, and patient must sign new Informed Consent Form (ICF). 
Imaging of retina (SD-OCT, OCT-A, fundus photography) does not need to be repeated at the 
re-screening visit if the corresponding criteria for inclusion of the study eye were met at the 
initial screening visit and the images are not older than 28 days at the re-screening visit; 
otherwise new images have to be performed.
6.2.1.2
Treatment period and end of trial visit SRD part
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 Visit 2 procedures after the other ophthalmologic assessments in the Flow Chart I have 
been performed (please see Section 4.1.5 for details). An additional tonometry may be 
performed after IVT injection to monitor intraocular pressure.
Patients must continue to be followed according to the visit schedule (unless they withdraw 
consent for further follow-up) in order to collect data at the end of the planned observation 
period. Unscheduled visits will be possible at the discretion of the investigator at any time for 
safety reason. The unscheduled visit may include any assessments considered necessary by 
the investigator. All unscheduled visits should be described and documented in the medical 
/source record. The investigator may decide to administer standard treatment for wAMD 
during the follow-up period as deemed medically appropriate.
Visit 8/End of Trial:
The Visit 8/EOT will be performed 14 days after the Visit 7 (see Flow Chart I). 
The Visit 8/EOT is the final visit and the Trial completion page in the eCRF has to be 
entered.
Withdrawal of consent
If a patient is not willing to continue in the trial and wants to withdraw consent prior to the 
end of the trial, Visit 7 should be scheduled as soon as possible, and also Visit 8/EOT should 
be performed to assess for safety.
If patient refuses to participate at a Visit 7 or Visit 8, the trial completion page of the eCRF 
has to be filled in.
6.2.2
Multiple Rising Dose Part
6.2.2.1
Screening Visit
Screening Period
The screening visit does not need to be done with the patient in a fasted state.
All patients must sign an Informed Consent consistent with ICH GCP guidelines prior to any 
study specific procedures, this includes the option that the patient signs the Informed Consent 
during an extra contact to the study site prior to the actual screening visit. The patient should 
be recorded on the enrolment log as a screened patient when Visit 1 is performed.
Visit 1 is the beginning of the screening period. As soon as eligibility of enrolled patients is 
confirmed, the first treatment visit (Visit 2) may be performed.
If the patient does not meet inclusion/exclusion criteria, the patient must be recorded in eCRF 
as a screen failure.


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Baseline Conditions
Any pre-existing medical conditions considered as relevant by the investigator, excluding the 
indication of the trial, are recorded into the eCRF in the appropriate page.
Any abnormal clinically significant findings observed during ophthalmological examination 
with slit lamp at Visit 1 need to be documented on Baseline Conditions.
IRT:
All patients that are screened must be registered with IRT. If the patient results in a screen 
failure, IRT should be notified as soon as possible and within the screening period. Details of 
IRT procedures can be found in the IRT manual located in the ISF.
Re-screening:
Patients who do not fulfil all eligibility criteria 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 without new IRT registration. For re-screening beyond this time 
period (up to one time), patient must be registered in IRT, which will then provide new 
patient number, and patient must sign new ICF. Imaging of retina (SD-OCT, OCT-A, fundus 
photography, and/or fluorescein angiography) does not need to be repeated at the re-
screening visit if the corresponding criteria for inclusion of the study eye were met at the 
initial screening visit and the images are not older than 28 days at the re-screening visit; 
otherwise, new images have to be performed.
6.2.2.2
Treatment period and end of trial visit MRD part
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 Visit 2, Visit 3, and Visit 4 procedures after the other ophthalmologic assessments in the 
Flow Charts II, III, and IV have been performed (please see Section 4.1.5 for details). An 
additional tonometry may be performed after IVT injection to monitor intraocular pressure.
In the MRD part cohorts 2 and 3, additional safety assessments/visits will be carried out 
within a week after V2, V3, V4, respectively. 
Patients must continue to be followed according to the visit schedule (unless they withdraw 
consent for further follow-up) in order to collect data at the end of the planned observation 
period. Unscheduled visits will be possible at the discretion of the investigator at any time for 
safety reason. The unscheduled visit may include any assessments considered necessary by 
the investigator. All unscheduled visits should be described and documented in the medical 
/source record. The investigator may decide to administer standard treatment for wAMD 
during the follow-up period (for MRD cohort 3 during/after Visit 6) as deemed medically 
appropriate.
Visit 8/End of Trial:
The Visit 8/EOT will be performed 28 days after the Visit 7 (see Flow Charts II, III, and IV). 
The Visit 8/EOT is the final visit and the Trial completion page in the eCRF has to be 
entered.


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Withdrawal of consent
If a patient is not willing to continue in the trial and want to withdraw consent prior to the end 
of the trial, Visit 7 should be scheduled as soon as possible, and also Visit 8/EOT should be 
performed to assess for safety.
If patient refuses to participate at a Visit 7 or Visit 8, the trial completion page of the eCRF 
has to be filled in.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This trial will consist of an SRD part followed by an MRD part. Both parts of the trial will be 
conducted non-randomized, open-label, and uncontrolled. The main objective is to 
investigate ocular and systemic safety and tolerability as well as disease improvement of 
BI 836880 after a single IVT injection and after multiple IVT injections of several doses.
SRD part:
The dose escalation will be guided by a Bayesian 2-parameter logistic regression model with 
overdose control [R13-4803, R13-4806]. For a given dose, the EWOC criterion is that there 
should be less than 25% risk that the true ocular DLE rate is above 0.25.
The model is given as follows:
logit(πd) = log(α) + β*log(d/d*),
where logit(π) = log(π/(1-π)), πd represents the probability of having a DLE in the evaluation 
period at dose d, d* = 2 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 dose level with the highest posterior 
probability of the DLE rate falling in the target interval [0.00, 0.25) among the doses 
fulfilling EWOC. Thus, it should be unlikely (< 25% posterior probability) that the DLE rate 
at that dose will exceed 0.25. However, the maximum allowable dose increment for the 
subsequent cohort will be no more than 200% from the previous dose up to doses of 0.5 mg, 
and to a maximum of 100% from the previous dose from dose 0.5 mg onwards. Dose 
escalation will continue up to the 2 mg dose as long as the EWOC criterion for the next dose 
level is fulfilled. At the final dose, at least 6 treated patients are required. However, the SMC 
may decide to include additional number of patients at this dose level.
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.


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For the current study, no relevant information in the form of human data was 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 0.06 mg would equal 0.01, and the median DLE rate at 
the maximum feasible dose of 2 mg would equal 0.10. This yields μ1 = (-2.197, -0.380). 
The standard deviations were set such that large uncertainty about the parameter means is 
reflected, and the correlation was set to 0, thus yielding σ1,11 = 2, σ1,22 = 1 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 0.06 mg would equal 0.10, and 
the median DLE rate at 2 mg would equal 0.40. These assumptions yield 
μ2 = (-0.405, -0.671). The standard deviations and correlations were set identical to the 
weakly informative prior, i.e. 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 0.06 mg would equal 0.001, and 
the median DLE at 2 mg would equal 0.01. These assumptions yield 
μ3 = (-4.595, -0.417). The standard deviations and correlations were set to σ3,11 = 5, 
σ3,22 = 0.01, therefore almost fixing the slope parameter to its mean. 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 large, showing the low 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 1.7 patients. A detailed evaluation of the model using hypothetical 
data scenarios and operating characteristics is provided in Appendix 10.3.
Table 7.1: 1
Summary of prior distribution
Prior Component
Mixture Weight
Mean Vector
SD Vector
1: Weakly inf.
0.900
-2.197  -0.380
2.00  1.00
2: High Tox.
0.050
-0.405  -0.671
2.00  1.00
3: Low Tox.
0.050
-4.595  -0.417
5.00  0.01


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Table 7.1: 2
Prior probabilities of DLEs at selected doses
Dose
Probability of true DLE rate in
Quantiles
[0, 0.25)
[0.25, 1]
Mean
SD
2.5%
50%
97.5%
0.06
0.917
0.083
0.067
0.151
0.000
0.007
0.599
0.18
0.887
0.113
0.088
0.172
0.000
0.014
0.682
0.5
0.839
0.161
0.119
0.197
0.000
0.030
0.764
1
0.790
0.210
0.154
0.218
0.000
0.053
0.817
2
0.696
0.304
0.212
0.249
0.001
0.101
0.882
Figure 7.1: 1 Prior medians and 95% credible intervals 
The prior may be updated once the trial has started in case new data that can be used will be 
available. Only patients 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.
MRD part
There will be 2 dose groups of the second highest safe (cohort 1) and the highest safe dose 
level (cohorts 2 and 3) fulfilling the EWOC criterion after completion of the SRD part. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
There are no hypotheses tested in this exploratory trial.


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7.3
PLANNED ANALYSES
The main analysis populations are defined below. Analyses will be performed by dose/cohort 
and overall in each trial part. Patients will be analysed according to the assigned treatment, 
unless otherwise specified. In the SRD part, patients who are replaced during the DLE
evaluation period will be excluded from the determination of the MTD (see Section 3.1).
Important protocol deviations (iPDs) will be defined in the Integrated Quality and Risk 
Management (IQRM) plan. The handling of patients with iPDs will be described in the 
TSAP.
Treated Set (TS)
The TS will consist of all patients who were treated with at least one dose of BI 836880.
Full Analysis Set (FAS; only MRD part)
The FAS will consist of all patients who were treated with at least one dose of BI 836880 and 
have baseline and on-treatment CSFT measurements for the study eye.
Evaluable Responders’ Set (ERS, MRD cohort 3 only)
The ERS will consist of all patients who completed three doses of BI 836880 and have SD-
OCT measurements at Week 16 (Visit 6).
In the TSAP, the FAS and ERS definitions may be updated, and further analysis data sets 
may be defined.
7.3.1
Primary endpoint analyses
No primary efficacy endpoint has been defined for this study.
SRD part:
The primary safety endpoint “Number of patients with ocular DLEs from drug administration 
until EOT” will be analysed descriptively, based on the TS.
For the definition of ocular DLEs, please refer to Section 5.2.1.
MRD part:
The primary safety endpoint “Number of patients with drug related AEs from drug 
administration until EOT” will be analysed descriptively, based on the TS.
7.3.2
Secondary endpoint analyses
In principle, all secondary endpoints will be analysed descriptively, based on the TS. The 
analysis of percent change from baseline in CSFT in the study eye at Week 12 (Visit 5) will 
be done by dose, based on the FAS. 


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7.3.4
Safety analyses
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
Standard BI summary tables and listings will be produced. For BI 836880, the residual effect 
period (REP) after IVT administration is not known. Therefore, all AEs with an onset 
between start of treatment and the respective EOT visit will be assigned to the on-treatment 
period for evaluation. The safety analysis will be performed by ‘treatment at onset’.
All treated patients 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 AEs will concentrate on treatment-emergent AEs, i.e. all 
AEs occurring between start of treatment and the EOT visit. AEs that start before first drug 
intake and deteriorate under treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of the MedDRA at the 
database lock.
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 patients 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.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
The derivation of pharmacokinetic parameters is described in detail in the BI SOP 
001-MCS-36-472. The determination of pharmacodynamic parameters AUEC, Emax, Emin will 
follow the principles described for the respective PK parameters.
All evaluable patients who received at least one dose of BI 836880 will be included in the 
pharmacokinetic/ PD analysis. Patients who are considered as not evaluable will be listed 
with their individual sample concentrations and individual pharmacokinetic/ PD parameters, 
however, will not be included in descriptive statistics for sample concentrations, 
pharmacokinetic/ PD parameters or other statistical assessment.
Every effort will be made to include all concentration and response data in an analysis. If not 
possible, a case by case decision is required whether the value should only be excluded from 
half-life estimation or the complete analysis.

If a concentration is only excluded from half-life determination, it will be used for all
other calculations (e.g. descriptive statistics) and for graphical presentation.

If a concentration value is excluded from all calculations, it will not be presented
graphically or used for the calculation of descriptive statistics and parameter
determination. However, the excluded concentration itself will be listed in the Clinical 
Trial Report (CTR) associated with an appropriate flag.


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Concentrations will be used for graphs and calculations in the format that is reported in the
bioanalytical report. Noncompartmental pharmacokinetic analyses of the sample
concentration-time data will be performed using a validated software program, e.g. Phoenix
WinNonlin. Only concentrations within the validated concentration range will be used for the
calculation of pharmacokinetic parameters. For pre-dose samples, the actual sampling time
will be set to zero.
Sample concentrations will be plotted graphically versus time for all evaluable subjects as
listed in the drug concentration-time tables. For the presentation of the mean profiles, the 
geometric and arithmetic mean and the planned blood sampling times will be used. If the
actual sampling time deviates significantly from the planned time, the corresponding sample
concentration will be excluded from the calculation of descriptive statistics.
If the number of patients included allows, the following descriptive statistics will be 
calculated for analyte concentrations as well as for all pharmacokinetic parameters: N, 
arithmetic mean, standard deviation, minimum, median, maximum, P10, Q1, Q3, P90, 
arithmetic coefficient of variation, geometric mean, and geometric coefficient of variation. 
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. The descriptive statistics of pharmacokinetic 
parameters will be calculated using the individual values with the number of decimal places 
as provided by the evaluation program. Then the individual values as well as the descriptive 
statistics will be reported with three significant digits in the CTR.
7.4
INTERIM ANALYSES
The sponsor will continuously monitor the safety. In the SRD part, the dose escalation design 
foresees that the sponsor and the SMC perform regular safety evaluations. Likewise, in the 
MRD part, the SMC will decide on the dose escalation. These evaluations will be unmasked 
to dose.
No formal interim analysis of efficacy data is foreseen, although efficacy data when available 
may be considered as part of the safety evaluations. A preliminary analysis of efficacy data 
will be performed after the completion of Visit 5 of the first dose group of the MRD part. The 
preliminary efficacy results will be distributed to the Sponsor’s trial team, but they will not be 
part of the CTR. A preliminary analysis of PK data will be performed after completion of the 
SRD part.
7.5
HANDLING OF MISSING DATA
No imputation will be performed on missing efficacy data. 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.
7.6
RANDOMISATION
No randomisation will be performed. Patients will be assigned to escalating dose groups by 
order of admission into the trial.


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7.7
DETERMINATION OF SAMPLE SIZE
No formal statistical power calculations to determine sample size were performed for this 
explorative study.
For the SRD part, a maximum of 18 patients will be expected for this trial based on the 
number of dose levels/cohorts that are tested. Fewer patients might be needed based on the 
recommendation of the SMC and the criteria specified (see Section 7.1). However, the actual 
number of patients will depend on the number of dose cohorts tested. Based on the simulation 
study to evaluate operating characteristics of the BLRM (see Appendix 10.3), about
18 evaluable patients are expected to be treated in the dose escalation part for the model to 
have reasonable operating characteristics relating to its MTD recommendation.
For the MRD part cohort 1 and cohort 2, a size of 10 subjects per dose group is in general 
considered as sufficient for the exploratory evaluation of multiple dose safety and PK. The 
drop out rate is expected to be higher for the treatment-naïve patients in cohort 2 as compared 
to the treatment-resistant patients in cohort 1. To allow for dropouts, 10 to 12 patients will be 
included in MRD cohort 1 and approximately 16 patients will be included in MRD cohort 2
and 3 combined (in total approximately 42 patients in the trial). In case some subjects do not 
complete the trial according to the protocol, the trial clinical monitor together with the trial 
pharmacokineticist and the trial statistician are to decide if and how many subjects will be 
replaced.
Further, based on results from [R18-0309] for a comparable patient group and drug product, 
and based on the inclusion criteria for the current trial, it is assumed that the actual percent 
decrease in CSFT at Week 12 is above 25%. In Table 7.7: 1, the probability to observe a 
median percent decrease in CSFT at Week 12 in different pre-defined regions is displayed for 
a set of scenarios, and for sample sizes 10 and 15, assuming a normal distribution for the 
percent decrease with standard deviation 16 (also based on the above publication). These 
results are based on simulations using R Version 3.5.1. Details on the simulation program can 
be found in the TMF.
Table 7.7: 1
Probability to observe a median percent decrease in CSFT at Week 12 
within pre-defined regions based on sample sizes N=10, 15, for 
different true median percent decreases 
N
True Value of Median 
Percent Decrease [%]
Obs < 18%
Obs in [18,20) %
Obs 20%
10
13
80.0
8.0
11.9
19
43.3
13.4
43.3
25
11.8
8.1
80.1
15
13
83.7
7.8
8.6
19
42.2
15.6
42.2
25
8.5
7.9
83.7
Obs: Observed value of median percent decrease in CSFT [%]


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For example, if the true median percent decrease in CSFT at Week 12 was 25%, the 
probability to observe a median percent decrease in CSFT at Week 12 of at least 20% would 
be around 80%. In contrast, if the true median percent decrease in CSFT at Week 12 was only 
13%, then the probability to observe a median percent decrease of at least 20% would be 
around 12%.
For the MRD cohort 3, no formal sample size calculation has been applied. It is expected that 
using approximately 12 patients will be sufficient for this cohort.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC)
and the harmonised standards for Medical Devices (ISO 14155, current version).
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 Tripartite Guideline 
for GCP, relevant BI SOPs, the EU regulation 536/2014 the Japanese GCP regulations 
(Ministry of Health and Welfare Ordinance No. 28, March 27, 1997) and other relevant 
regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The BI 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 per the 
project publication strategy, interim cohort data will be published as available, while full 
results will be published after CTR finalization.
The certificate of insurance cover is made available to the investigator and the patients and is
stored in the ISF.
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 IRB / Independent Ethics Committee (IEC) and CA according to 
national and international regulations. The same applies for the implementation of changes 
introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient according to ICH GCP and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional patient-information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional patient
information must be given to each patient.
The investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. 
The patient must be given sufficient time to consider participation in the trial. The 
investigator obtains written consent of the patient’s own free will with the ICF after 
confirming that the patient understands the contents. The investigator must sign (or place a 
seal on) and date the ICF. 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 


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should be conducted according to the sponsor’s instructions. The consent and re-consenting 
process should be properly documented in the source documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
During the site visit the sponsor’s Clinical Research Associate (CRA) or auditor must be 
granted access to the original patient file (please see Section 8.3.2). The investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted from any copy of the patients’
source documents before sending them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient
was informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date (mandatory), and end date (if available))

SAEs (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)


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
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 patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and/or 
remote monitoring calls and in-house data quality review. The frequency of site monitoring 
will be determined by assessing all characteristics of the trial, including its nature, objective, 
methodology and the degree of any deviations of the intervention from normal clinical 
practice.
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.
An adaptive approach to clinical trial monitoring will be utilised. The sponsor will perform a 
risk assessment of the trial to determine the extent and nature of monitoring required in order
to ensure the reliability and robustness of the results. Regular review of risk reports will 
provide sponsor oversight during trial conduct and direct monitoring activities to the areas of 
greatest risk which have the most potential impact to patient safety and data quality.
The investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access should be granted to all source documents 
(paper and e-records) including progress notes, copies of laboratory and medical test results. 
The CRA and auditor 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 ICH GCP.
An adaptive approach to clinical trial monitoring will be utilised. This is initiated by an 
assessment of the risk associated with the trial combined with identification of critical data 
and processes. An Integrated Quality and Risk Management Plan documents the strategies 
involved with the implementation of onsite, offsite and central monitoring activities in order 
to direct focus to the areas of greatest risk which have the most potential impact to patient
safety and data quality. Trial oversight is achieved by regular review of a report of risk which 
then influences any monitoring adaptations. 
The investigator /institution will allow on-site trial-related monitoring, audits, IRB/IEC 
review and regulatory inspections. Direct access should be granted to all source documents 
(paper and e-records) including progress notes, copies of laboratory and medical test results


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The CRA and auditor 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 ICH GCP.
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. 
Exemptions from expedited reporting are described in Section 5.2.8.2, if applicable.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the World Health 
Organization (WHO) GCP handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent.

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place.

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage.

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data.


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
Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking ICF.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Out” (LPO)). The “Last Patient Drug Discontinuation” (LPDD) date is 
defined as the date on which the last patient at an individual trial site ends trial medication (as 
scheduled per protocol or prematurely). Individual investigators will be notified of Suspected 
Unexpected Serious Adverse Reactions (SUSARs) occurring with the trial medication until 
30 days after LPDD 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 patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by BI.
A CI is responsible to coordinate investigators at the different sites participating in this trial.
Tasks and responsibilities are defined in a contract. 
A Study Monitoring Committee (SMC) composed of the co-ordinating investigator, 
participating investigators with treated patients in the cohort that will be evaluated in the 
meeting and members of the BI trial team and the head of early clinical operations as trial 
independent member will be established to review individual and aggregated safety data at 
regular intervals to determine the safety profile and risk/benefit ratio and decide on the next 
dose level and the next cohort size, or the appropriacy of further enrolment. 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 clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a Clinical Trial Leader (CTL), responsible for coordinating all required 
activities, in order to 

manage the trial in accordance with applicable regulations and internal SOPs,


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
direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate training and information of CTM, 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 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 service and an IRT vendor will be used in this trial. Details will be 
provided in the IRT Manual and Central Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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).
R13-1509
Eye Diseases Prevalence Research Group. Prevalence of age-related 
macular degeneration in the United States. Arch Ophthalmol (Chicago) 
2004. 122:564-572.
R13-4487
Holz FG, Amoaku W, Donate J, Guymer RH, Kellner U, Schlingemann 
RO, Weichselberger A, Staurenghi G, SUSTAIN Study Group. Safety and 
efficacy of a flexible dosing regimen of ranibizumab in neovascular age-
related macular degeneration: the SUSTAIN study. Ophthalmology 
(Rochester) 2011. 118(4):663-671.
R13-4803
Neuenschwander B, Branson M, Gsponer T, Critical aspects of the 
Bayesian approach to phase I cancer trials. Stat Med 2008; 27: 2420 – 2439.
R13-4806
Babb J, Rogatko A, Zacks S, Cancer phase I clinical trials: efficient dose 
escalation with overdose control. Stat Med 1998; 17: 1103 – 1120.
R13-4881
FDA's critical path initiative (page last updated: 12/28/2012).
http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/u
cm07668 9.htm (access date: 8 November 2013); Silver Spring: U.S. Food 
and Drug Administration (2012).
R18-0309
Chakravarthy U, Bailey C, Brown D, Campochiaro P, Chittum M, Csaky K, 
et al. Phase 1 trial of anti-vascular endothelial growth factor/anti-
angiopoietin 2 bispecific antibody RG7716 for neovascular age-related 
macular degeneration. Ophthalmol Retina 2017. 1(6):474-485.  
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.  
R18-1168
Krzystolik MG, Afshari MA, Adamis AP, Gaudreault J, Gragoudas ES, 
Michaud NA, et al. Prevention of experimental choroidal 
neovascularization with intravitreal anti-vascular endothelial growth factor 
antibody fragment. Arch Ophthalmol (Chicago) 2002. 120(3):338-346.  
R21-0692
Khanani AM, Patel SS, Ferrone PJ, Osborne A, Sahni J, Grzeschik S, et al. 
Efficacy of Every Four Monthly and Quarterly Dosing of Faricimab vs 
Ranibizumab in Neovascular Age-Related Macular Degeneration - The 
STAIRWAY Phase 2 Randomized Clinical Trial. JAMA Ophthalmology
2020. 138/9: 964-972.


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R22-2854
Nussenblatt RB, Palestine AG, Chan CC, et al. Standardization of vitreal
inflammatory activity in intermediate and posterior uveitis. Ophthalmology 
(Rochester) 1985. 92: 467-471.
9.2
UNPUBLISHED REFERENCES
c21397543
BI 836880 Investigator´s Brochure (wet Age-related Macular Degeneration 
[wAMD]). Current Version.
n00234399
Pharmacokinetics immunogenicity of BI 836880 in male cynomolgus 
monkeys after intravenous dosing of BI 836880 (PK-12-1020). 
19 May 2014.
n00253677
Efficacy of anti-Ang2/anti-VEGF nanobody BI 836880 in a mouse model
of oxygen-induced retinopathy (OIR). MD2016/06/Lab6. 17 Nov 2017.
n00254368
13-Week Toxicity Study of BI 836880 Following Intravitreous 
Administration in Cynomolgus Monkeys with an 8-Week Recovery, Part: 
Toxicokinetics. 21 Feb 2018.
n00255516
13-Week Toxicity Study of BI 836880 Following Intravitreous 
Administration in Cynomolgus Monkeys with an 8-Week Recovery,
16R102. 22 May 2018.
n00256189
Efficacy of BI 836880 in a Monkey Laser-Induced Choroidal Neovascular 
(CNV) Model Following Intravitreal Injection, 5700737. 17 Nov 2017
n00258450
Pharmacokinetics of BI 836880 after intravitreal administration to 
Cynomolgus monkeys, A206/16FU(B6007). 29 Sep 2017.
n00259128
Prediction of BI 836880 vitreal pharmacokinetics in Humans. Nov 2017.
001-MCS-36-472 Corporate SOP: Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics. Version 3.0


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10.
APPENDICES
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING
Table 10.1: 1
Time schedule for PK/PD blood sampling during SRD part
Cours
e
Visit
Day
Planned Time 
[h]
Planned 
Time [h]
PK 
BI 836880
ADA
VEGF/
ANG2
1
V2
1
Before IVT 
administration 
of BI 836880
-0:05 -
-1:00
x
x
x
Drug 
administration
0:00
V3
4
(+/- 1 
day)
3 days after 
treatment
72:00
x
x
V4
8
(+/- 2 
days)
1 week after 
treatment
168:00
x
x
V5
15
(+/- 2 
days)
2 weeks after 
treatment
336:00
x
x
x
V7
29
(+/- 2 
days)
4 weeks after 
treatment
672:00
x
x
EOT
V8
43
(+/- 2 
days)
6 weeks after 
treatment
1008:00
x
x
x


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Table 10.1: 2
Time schedule for PK/PD blood sampling during MRD part
Course
Visit
Day
Planned Time 
[h]
Planned 
Time [h]
PK 
BI 836880
ADA
VEGF/
ANG2
1
V2
1
Before 1st 
IVT 
administration 
of BI 836880
-0:05
(-4 h)
x
x
x
1st drug 
administration
0:00
2
V3
29
(+/- 3 
days)
Before 2nd  
ivt 
administration 
of BI 836880
671:55
(-2 h)
x
x
x
2nd drug 
adminstration
672:00
3
V4
57
(+/- 3 
days)
Before 3rd  
ivt 
administration 
of BI 836880
1343:55
(-2 h)
x
x
x
3rd drug 
administration
1344:00
FUP
V5
85
(+/- 3 
days)
Follow up 
period
2016:00
(+/- 2 h)
x
x
x
FUP
V6
113
(+/- 3 
days)
Follow up 
period
2688:00
(+/- 2 h)
x
x
FUP
V7
141
(+/- 3 
days)
Follow up 
period
3360:00
(+/- 2 h)
x
x
EOT
V8
169
(+/- 3 
days)
End of Trial
4032:00
(+/- 2 h)
x
x
x
10.2
TRIAL BIOMARKER PLAN
Not applicable.
10.3
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE AND 
DATA SCENARIOS
A BLRM with overdose control will be used to guide dose escalation in this study. The 
BLRM is introduced in Section 7.1, which also specifies the prior for the model. After 
patients in each cohort have completed the evaluation period of 7 days, the prior distribution 
will be updated through Gibbs sampling procedures with the accumulated DLE data from the 
evaluation period. Posterior probabilities for the rate of DLEs will be summarised from the 


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BLRM. Selection of the next dose will be based on these probabilities as well as on other 
safety and laboratory data.
The purpose of this statistical appendix is to present performance metrics (operating 
characteristics) that illustrate the precision of the design in estimating the MTD (see 
Section 3.1) under various dose-toxicity relationships through computer simulation. These 
results are summarized in Table 10.3: 3. In addition, recommendations of the next dose level
by the BLRM with overdose control principle are provided under various hypothetical 
outcome scenarios in early cohorts, to show how it facilitates on-study dose-escalation 
decisions (see Table 10.3: 1). For simplicity reasons, a cohort size of 3 patients who are all 
evaluable is assumed. 
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.3: 1. These scenarios reflect potential on-
study data constellations and related escalation as allowed by the model and the planned dose 
groups. It is assumed that each cohort has exactly three patients who are all evaluable. For 
each scenario, the probability of overdose for the current dose, as well as the next potential 
dose and related probabilities of target dosing and over-dosing are shown.
For example, scenario 1 represents the case that no DLE is observed in 3 patients at the 
starting dose of 0.06 mg. In this case, the next planned dose permitted by the model and the 
200% escalation rule is 0.18 mg. In contrast, scenario 2 assumes that there is one DLE 
observed in the first dose group. This would mean overtoxicity from the beginning, and the 
recommendation would be to stop the trial.  
In scenario 3, there is no DLE after the first 2 dose groups, which would allow the trial to 
continue to the next dose level. In scenario 4, the first DLE occurs in dose group 0.18 mg. 
Then the recommendation would be to repeat that dose. Scenario 5 shows that the trial would 
continue to the next dose level 0.5 mg if no additional DLE was observed in the 0.18 mg dose 
group. 
However, if there was another DLE (as in scenario 6), then the recommendation would be to 
go back to dose 0.06 mg. If there was no further DLE then (scenario 7), one could go up 
again to dose 0.18 mg. Escalation to the next dose group would only be allowed in case there 
was no further DLE in this dose group in additional 6 patients (see scenarios 8 and 9). 
Scenario 10 shows the case where the trial runs through up to the highest possible dose group 
2 mg without any DLE and having observed a total of 18 patients (6 were required for the 
MTD). Scenarios 11 and 12 show that it is even possible to have one DLE in the 2 mg dose 
group and still to complete the trial with a total of 18 patients. However, if there were 2 DLEs 
in the highest dose group, then the model would recommend to return to dose 1 mg (scenario 
13).


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Table 10.3: 1 
Hypothetical data scenarios
Scenario
Dose 
(mg)
# Pat.
# DLE
Current Dose: 
P(OD)
Next recomm. 
dose
Next dose:
P(TD)
P(OD)
1
0.06
3
0
0.016
0.18
0.968
0.032
2
0.06
3
1
0.308
N/A
N/A
N/A
3
0.06
0.18
3
3
0
0
0.011
0.5
0.964
0.036
4
0.06
0.18
3
3
0
1
0.182
0.18
0.818
0.182
5
0.06
0.18
3
6
0
1
0.074
0.5
0.789
0.211
6
0.06
0.18
3
6
0
2
0.290
0.06
0.874
0.126
7
0.06
0.18
6
6
0
2
0.062
0.18
0.808
0.192
8
0.06
0.18
6
9
0
2
0.105
0.18
0.895
0.105
9
0.06
0.18
6
12
0
2
0.049
0.5
0.773
0.227
10
0.06
0.18
0.5
1
2
3
3
3
3
6
0
0
0
0
0
0.010
2
0.990
0.010
11
0.06
0.18
0.5
1
2
3
3
3
3
3
0
0
0
0
1
0.220
2
0.780
0.220
12
0.06
0.18
0.5
1
2
3
3
3
3
6
0
0
0
0
1
0.098
2
0.902
0.098
13
0.06
0.18
0.5
1
2
3
3
3
3
6
0
0
0
0
2
0.327
1
0.961
0.039


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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 MTD. 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 6 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 medians

Scenario 2: aligned with prior means

Scenario 3: high-toxicity scenario

Scenario 4: low-toxicity scenario

Scenario 5: non-logistic dose-toxicity scenario

Scenario 6: low-toxicity followed by high-toxicity
Table 10.3: 2 
Assumed true dose-toxicity scenarios
Scenario
Dose (mg)
0.06
0.18
0.5
1
2
1: Prior Med
P(DLE)
0.007
0.014
0.030
0.053
0.101
2: Prior Mean
0.067
0.088
0.119
0.154
0.212
3: High Tox
0.100
0.150
0.200
0.280
0.400
4: Low Tox
0.001
0.005
0.012
0.086
0.127
5: Non-Logistic
0.040
0.010
0.180
0.280
0.360
6: Low-High
0.001
0.011
0.047
0.181
0.500
For each of these scenarios, 1000 trials were simulated. Each cohort consisted of 3 patients 
and dose escalation complied with the following rule:
Escalate to the maximum dose which satisfies the overdose criterion and is ≤ 200% 
increase from the current dose. 
The MTD was considered reached if at least 6 patients have been evaluated at a dose level 
which is the model’s recommendation for the next dose cohort. A minimum number of 
15 patients in the trial was required, and the maximum allowed patient number was 21.
It was then assessed how often a dose was declared as MTD with true DLE rate in the 
targeted or in the overdosing range. Furthermore, the average, minimum and maximum 
number of patients per trial and the average number of DLEs per trial are reported. Results 
are shown in Table 10.3: 3.


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Table 10.3: 3 
Simulated operating characteristics
Scenario
% of trials declaring a MTD with true 
DLE rate in
% of early 
stopped trials
# Patients
# DLEs
[0, 0.25)
target dosing
[0.25,1]
overdosing
Mean
(Min-Max)
Mean
(Min-Max)
1
94.4
0
5.6
17.97
(3-21)
0.87
(0-4)
2
70.2
0
29.8
15.33
(3-21)
1.80
(0-6)
3
38.8
17.1
44.1
13.55
(3-21)
2.38
(0-6)
4
98.3
0
1.7
17.75
(3-21)
0.99
(0-4)
5
37.8
36.8
16.4
16.42
(3-21)
2.36
(0-6)
6
77.8
7
15.2
18.67
(3-21)
2.41
(0-6)
In scenario 1, which reflects the case that the true dose-toxicity is aligned with prior medians,
94.4% of the simulated trials declared a dose as MTD with true DLT rate in the targeted 
toxicity range. Note that 5.6% of the simulated trials stopped either because there was no 
MTD determined after 21 patients had been observed (3.5%) or because of high toxicity 
(2.1%). This latter is mostly due to the cases that 1 DLT is observed out of 3 patients at the 
starting dose of 0.06 mg. In reality, this situation would rarely happen as the safety profile of 
starting dose is expected to be good. 
In scenario 2, the assumed dose toxicities are higher than in scenario 1. This results in a 
higher percentage of early stopped trials (about 30%). In this case, about 70% of the trials 
would end with an estimated MTD within the targeted toxicity range, but none in the 
overdosing range.
In Scenario 3 (high-toxicity scenario), only 38.8 % of the trials trials declared a dose as MTD 
with true DLT rate in the targeted toxicity range. In 17.1% of the trials, the estimated MTD 
was in the overdosing range. Scenario 4 (low-toxicity scenario) shows the best results, as 
would be expected. 
Scenarios 5 and 6 showed worse operating characeristics; however, they are reasonable given 
the quite large deviations from the underlying BLRM. 
The mean patient numbers range from 13.6 patients (Scenario 3) to 18.7 patients (Scenario 
6), and the maximum number of patients was 21. Therefore, the patient numbers are as 
expected and increase when moving away from the high-toxicity scenario.
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 non-logistic 
case (scenario 5), the probabilities of recommending a dose with true P(DLT) ≥ 25 as MTD 


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are much smaller than the probabilities of recommending a dose with true P(DLT) < 25% as 
MTD.
On-study recommendations based on the model are consistent with the clinical decision 
making process, and should be considered in conjunction with other available clinical 
information by the BI clinical trial team and study investigators in deciding the dose levels to 
be tested in order to determine the MTD estimate.
R version 3.3.2 was used for data scenarios and simulations.
10.4
IMPLICATIONS OF CORONAVIRUS DISEASE 2019
At the time of evaluating the fourth dose group of the SRD part in this trial, the COVID-19 
pandemic emerged with worldwide impact on daily life. To allow for thorough evaluation of 
potential additional risks to trial participants in the course of this pandemic, the trial was 
temporarily put on hold in March 2020. At that timepoint, a total of ten patients had been 
treated with one single intravitreal injection of BI 836880. Available data did not show dose-
limiting events, drug-related adverse events, nor systemic adverse events.
The trial has been re-initiated in July 2020 after potential additional risks for study 
participants with regard to COVID-19 have been evaluated. 
Currently, there is no evidence that based on the pharmacological mechanism and existing 
non-clinical data the compound may increase the risk of progression of COVID-19 infection. 
No effects related to this MoA on the immune system are currently known. In conclusion, 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. As such, risk mitigation measures, such as measures to 
reduce patients’ exposure will be implemented, if required. Enrolment will only happen when 
the local situation allows for patients to travel to the trial site, and all precautionary measures 
(e.g. use of protective personal/patients equipment) will be implemented, in line with local 
instructions and recommendations.
The investigators will take the totality of information related to each single patient and the 
local COVID-19 situation into consideration when performing the individual benefit-risk 
assessment on a case-by-case basis. Considering all aspects, the investigator will decide upon 
each patient’s (continued) participation in the trial. BI as the sponsor, where required, will 
support the investigators in their decision finding. It is acknowledged that the investigator 
may decide to implement protocol deviations where this protects the safety, wellbeing and/or 
is in the best interest of the patient.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
26 Sep 2019
EudraCT number
EU number
2017-001221-40
BI Trial number
1336-0007
BI Investigational Product(s)
BI 836880
Title of protocol
Safety, tolerability and pharmacodynamics of 
single rising intravitreal and multiple rising 
intravitreal doses of BI 836880 in patients with 
wAMD (open label, non-randomized, 
uncontrolled).
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
x
Section to be changed
Flow Chart I
Description of change
ADA sampling at Visit 5 added
Rationale for change
Alignment with Table 10.1: 1
Section to be changed
Flow Chart II
Description of change
ADA sampling added; Footnote (2) corrected
Rationale for change
Alignment with Table 10.1: 2
Section to be changed
2.1.3
Description of change

Number [N (%)] of patients with any ocular 
AEs (eye disorders)
[…]

Percent change from baseline in Central 
Subfield Thickness (CSFT) at week 12, for 
each dose 

Change from baseline in BCVA at week 12
was changed to

Number [N (%)] of patients with any ocular 
AEs (eye disorders) in the study eye
[…]

Percent change from baseline in Central 
Subfield Thickness (CSFT) in the study eye at 
week 12, for each dose 

Change from baseline in BCVA in the study 
eye at week 12
Rationale for change
Clarification of the endpoints
Section to be changed


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Description of change
Rationale for change
Section to be changed
3.1, 4.1.2, 7.1, 10.3
Description of change
300% 
was changed to
200%;
278% 
was changed to
178%;
Rationale for change
Correction of the calculated relative dose 
increases
Section to be changed
4.1.6.1 Blinding 
Description of change
“Within the central ECG lab, the staff involved 
with interval measurements will be blinded with 
respect to the treatment and also with regard to 
the recording date and time as well as planned
time points of the ECGs. The interval 
measurements for a given patient will be 
performed in a random and blinded sequence by a 
single technician.
If an interim safety analysis of ECG data is 
required, a part of the staff of the central ECG lab 
may be unblinded. This part of the staff will be 
strictly separated from the blinded staff members 
who are involved with ECG interval 
measurements and assessments of ECGs.”
deleted
Rationale for change
No ECG interval measurements are collected in 
the data base; open label trial
Section to be changed
5.2.1 Dose Limiting Events
Description of change
Signs of vascular occlusion in the retina, 
including peripheral retinal hemorrhage 
(hemorrhage of the macula would not be included 


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as this is a symptom of the disease; peripheral 
retinal hemorrhage may be a sign of vascular 
occlusion).
was changed to
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
Clarification of the criterion
Section to be changed
5.2.8.1 Definitions of AEs 
Description of change
The investigator must report SAEs, AESIs, and 
non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via 
fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific 
contact details will be provided in the ISF). The 
same timeline applies if follow-up information 
becomes available. In specific occasions the 
investigator could inform the sponsor upfront via 
telephone. This does not replace the requirement 
to complete and fax the BI SAE form.
was changed to
The investigator must report SAEs, AESIs, and 
non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form 
immediately (within 24 hours ) to the sponsor’s 
unique entry point (country specific reporting 
process will be provided in the ISF). The same 
timeline applies if follow-up information becomes 
available. In specific occasions the investigator
could inform the sponsor upfront via telephone. 
This does not replace the requirement to complete 
and send the BI SAE form.
Rationale for change
From 01 Oct 2019 SAEs may be submitted to BI 
by means other than Fax.
Section to be changed
7.2
Description of change
“There are no hypotheses tested in this 
exploratory trial.”  added
Rationale for change
Clarification
Section to be changed
7.3.4
Description of change
“A centralised evaluation of all 12-lead ECGs 
recordings (see Section 5.2.6) will be the basis for 
the ECG variables QT, HR, QTcF, QTcB, PR, 
QRS, RR, and further derived ECG endpoints. 
The baseline value of an ECG variable is defined 


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as the mean of the triplicate ECG measurements 
prior to drug administration. The derivation of the 
quantitative and qualitative ECG endpoints and 
their analyses will be described in the TSAP.”  
deleted
Rationale for change
No ECG interval measurements are collected in 
the data base; ECGs are only checked for baseline 
conditions or adverse events.
Section to be changed
10.3
Description of change
The value 0.100 in the specification for the non-
logistic scenario in Table 10.3: 2
was changed to
0.010
Rationale for change
Correction


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11.2
GLOBAL AMENDMENT 2
Date of amendment
11 Nov 2019
EudraCT number
EU number
2017-001221-40
BI Trial number
1336-0007
BI Investigational Product(s)
BI 836880
Title of protocol
Safety, tolerability and pharmacodynamics of 
single rising intravitreal and multiple rising 
intravitreal doses of BI 836880 in patients with 
wAMD (open label, non-randomized, 
uncontrolled).
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
X
Section to be changed
3.3.2 Inclusion criteria
Description of change
Inclusion #1 – State of the art methods for 
diagnosis of wAMD were included
Inclusion #2 – It was clarified that this criterion is 
only applicable for the MRD part
Inclusion #7 – the degree of fibrosis was clarified
Rationale for change
Clarification of Inclusion criteria


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11.3
GLOBAL AMENDMENT 3
Date of amendment
06 Oct 2020
EudraCT number
EU number
2017-001221-40
BI Trial number
1336-0007
BI Investigational Product(s)
BI 836880
Title of protocol
Safety, tolerability and pharmacodynamics of 
single rising intravitreal and multiple rising 
intravitreal doses of BI 836880 in patients with 
wAMD (open label, non-randomized, 
uncontrolled).
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
X
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Clinical Trial Protocol Synopsis: Endpoints, 
Criteria for PK, Criteria for PD, Safety Criteria
Description of change
‘Number [N (%)]’ was changed to ‘Number’ 
throughout the Clinical Trial Protocol; ‘eye 
disorders’ was deleted from ‘ocular adverse 
events’ description; ‘in the study eye’ was added 
to Endpoints, as applicable; ‘Change from 
baseline in CSFT at week 12’ was moved to 
Criteria for Pharmacodynamics; ‘color fundus 
photography (CFP)’ was added as further Criteria 
for Pharmacodynamics; ‘in both eyes’ was added 
to ‘Changes from baseline in selected parameters 
derived from color fundus photography 
(CFP)/optical coherence tomography 
(OCT)/OCT-A’; ‘in the study eye’ was added to 
Safety Criteria, as applicable.
Rationale for change
Clarification: Adaptations were introduced to 
more accurately describe respective endpoints 
and criteria.
Section to be changed
FLOW CHART I (SRD)
Description of change
a) ‘Biobanking’ and according footnote 3 were 
deleted.
b) New footnote 3 was added: ‘Physical 
examinations will also include measurement of 
weight and height (height only at Visit 1).’
Rationale for change
a) Clarification: no biobanking will be performed 
in SRD.


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b) Clarification of physical examinations, 
according to 5.2.3.
Section to be changed
FLOW CHART II (MRD)
Description of change
a) Additional assessments were added: PK and 
Biomarker sampling at Visits 6, 7, 8 and 
additional ADA sampling at Visit 8. 
b) New footnote 5 was added: ‘Physical 
examinations will also include measurement of 
weight and height (height only at Visit 1)’.
Rationale for change
a) Extended PK/biomarker sampling to improve 
characterization of the terminal half-life and 
target binding duration in plasma of BI°836880 
and hence improve modelling of vitreous 
concentration and target binding. Extended ADA 
analysis will improve the assessment of the 
immunogenicity potential of BI°836880 after 
intral-vitreal administration.
b) Footnote 5: Clarification of physical 
examinations, according to 5.2.3.
Section to be changed
Last Paragraph of 1.2 Drug Profile
Description of change
Addition of: ‘Within the trial described here 
(1336-0007), ten patients had been treated with 
intravitreal BI 836880 at a time of an initial data 
cut-off on 24 Mar 2020. Three patients were 
reported with an AE; all 3 AEs were eye 
disorders (conjunctival haemorrhage in the study 
eye, subretinal fluid in the study eye, neovascular 
AMD in the fellow eye). None of the reported 
AEs was judged as related to BI°836880 by 
investigators or fulfilled criteria for dose-limiting 
events. The AE of neovascular AMD was 
considered serious.’
Rationale for change
Extract from the current IB to inform that none of 
the reported AEs was judged as related to IMP in 
the first 10 patients treated. 
Section to be changed
Last Paragraph of 1.4 Benefit-Risk Assessment; 
Appendix 10.4
Description of change
At the end of 1.4 it was added:
‘The implications of the current Coronavirus 
Disease 2019 (COVID-19) pandemic are 
summarized in Section 10.4.’
To Appendix ‘10.4 IMPLICATIONS OF 
CORONAVIRUS DISEASE 2019’ was added: 
‘At the time of evaluating the fourth dose group 
of the SRD part in this trial, the COVID-19 
pandemic emerged with worldwide impact on 
daily life. To allow for thorough evaluation of 
potential additional risks to trial participants in 


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the course of this pandemic, the trial was 
temporarily put on hold in March 2020. At that 
timepoint, a total of ten patients had been treated 
with one single intravitreal injection of 
BI 836880. Available data did not show dose-
limiting events, drug-related adverse events, nor
systemic adverse events.
The trial has been re-initiated in July 2020 after 
potential additional risks for study participants 
with regard to COVID-19 have been evaluated. 
Currently, there is no evidence that based on the 
pharmacological mechanism and existing non-
clinical data the compound may increase the risk 
of progression of COVID-19 infection. No effects 
related to this MoA on the immune system are 
currently known. In conclusion, 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. As such, 
risk mitigation measures, such as measures to 
reduce patients’ exposure will be implemented, if 
required. Enrolment will only happen when the 
local situation allows for patients to travel to the 
trial site, and all precautionary measures (e.g. use 
of protective personal/patients equipment) will be 
implemented, in line with local instructions and 
recommendations.
The investigators will take the totality of 
information related to each single patient and the 
local COVID-19 situation into consideration 
when performing the individual benefit-risk 
assessment on a case-by-case basis. Considering 
all aspects, the investigator will decide upon each 
patient’s (continued) participation in the trial. BI 
as the sponsor, where required, will support the 
investigators in their decision finding. It is 
acknowledged that the investigator may decide to 
implement protocol deviations where this protects 
the safety, wellbeing and/or is in the best interest 
of the patient‘.
Rationale for change
Clarification that the impact of the current 
COVID-19 pandemic was carefully evaluated, 
that the overall benefit – risk assessment is 
considered to remain positive, and that the trial 
conduct will follow local instructions and 
recommendations to mitigate potential risks. 


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Section to be changed
Section 2.1.2 Primary endpoint(s), 2.1.3 
Secondary endpoint(s), 2.2.2 Further endpoints
Description of change
See also changes introduced to the Clinical Trial 
Protocol Synopsis.
‘Number [N (%)]’ was changed to ‘Number’ 
throughout the Clinical Trial Protocol; ‘eye 
disorders’ was deleted from ‘ocular AEs’ 
description. To Further endpoints in SRD part
was added: ‘color fundus photography (CFP)’ 
and the specification ‘for each time point and in 
both eyes.’
Changes in Further endpoints in MRD part:  

‘in the study eye’ was added to ‘Change from 
baseline in CSFT at week 12’

‘Change from baseline in BCVA in the study 
eye over time’ was added 

Further timepoints were added to ‘Systemic 
BI 836880 exposure’, i.e., C112d (56 days after 
last treatment), C140d (84 days after last 
treatment), and C168d (112 days after last 
treatment)

Further timepoints were added to ‘Systemic 
free VEGF and ANG2 levels’, i.e., E112d (56 
days after last treatment), E140d (84 days after 
last treatment), and E168d (112 days after last 
treatment)

‘CFP’ was added to ‘selected parameters’, 
and it was specified ‘for each time point and 
in both eyes’
Rationale for change
Clarification: several adaptations were introduced 
to more accurately describe respective endpoints.
Section to be changed
Section 3.1 Overall trial design and plan
Description of change
‘by the SMC’ was added to the sentence ‘The two 
highest doses established as safe and tolerable 
during the SRD part will be selected to be used in 
the MRD…’
Rationale for change
Clarification
Section to be changed
Section 3.3.2 Inclusion criteria #1
Description of change
‘Screening’ was replaced with ‘Treatment’, as 
such, respective inclusion criteria #1 reads as 
follows: ‘…active CNV secondary to AMD 
despite anti-VEGF therapies (at least 3 prior 
injections with the last injection within 12 to 4
weeks before treatment)’
Rationale for change
Clarification; no VEGF therapies at least 4 weeks 
before treatment (not before screening) is 
considered adequate
Section to be changed
Section 3.3.2 Inclusion criteria #10


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Description of change
‘Female subjects must be of non-childbearing 
potential.’ was changed to: ‘Male or female 
patients. Women of childbearing potential 
(WOCBP)1 cannot be included. Men able to 
father a child must be ready and able to use 
highly effective methods of birth control per ICH 
M3 (R2) that result in a low failure rate of less 
than 1% per year when used consistently and 
correctly. A list of contraception methods 
meeting these criteria is provided in the patient 
information and in section 4.2.1.3.
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.’
Rationale for change
Clarification of the definition of childbearing 
potential and appropriate contraceptive advice for 
male subjects able to father a child.
Section to be changed
a) Section 4.1.4 and 4.1.9 and b) Table 4.1.4: 2
Description of change
a) ‘qualified personnel’ was added as an 
alternative to a site pharmacist to prepare the 
ready to use drug product and to ensure drug 
accountability
b) ‘the two highest doses established by the SMC 
as safe and tolerable during the SRD part will be 
selected’ was added to the title of the table
Rationale for change
Clarification
Section to be changed
Section 4.2.1.1 Restrictions
Description of change
‘EOT’ visit was substituted by ‘during Follow-up 
Period, starting at Visit 5’. 
Rationale for change
Correction: Standard of care is allowed starting at 
Visit 5.
Section to be changed
Section 4.2.1.3 Restrictions
Description of change
Header ‘Restrictions regarding women of 
childbearing potential (WOCBP)’ was changed to 
‘Contraception requirements’.
Further, it was added:
‘WOCBP (partner of a trial participant) must use 
a highly effective method of birth control per ICH 
M3 (R2) that results in a low failure rate of less 
than 1% per year when used consistently and 


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correctly if their sexual partner is a man able to 
father a child.

Combined (estrogen and progestogen 
containing) hormonal birth control that 
prevents ovulation (oral, intravaginal, 
transdermal).

Progestogen-only hormonal birth control that 
prevents ovulation (oral, injectable, 
implantable).

Intrauterine device (IUD) or intrauterine 
hormone-releasing system (IUS).

Bilateral tubal occlusion
Or
Patients must abstain from male-female sex. This 
is defined as being in line with the preferred and 
usual lifestyle of the patient. Periodic abstinence 
e.g. calendar, ovulation, symptothermal, post-
ovulation methods; declaration of abstinence for 
the duration of exposure to study drug; and 
withdrawal are not acceptable.’
Rationale for change
Clarification of contraceptive requirements for 
male subjects with pregnant or non-pregnant 
WOCBP.
Section to be changed
Section 5.2.1 Dose limiting event 
Description of change
Deletion of ‘within the evaluation period (7 days 
after drug administration)’, addition of ‘in the 
study eye’
Rationale for change
Correction: timeframe of DLE is not limited to 7 
days after drug administration
Section to be changed
Section 5.2.2 Time to recurrence 
Description of change
Deletion of ‘a) For patients with dry retina after 
treatment: detection of any new intra- or 
subretinal fluid.
b) For patients with wet retina after treatment: 
any increase in retinal fluid (excluding Pigment 
Epithelial Detachments) compared to baseline’ 
and addition of 
‘…in the study eye, leading to the use of wAMD 
rescue medication as decided by the investigator:
-
Increase in CFST ≥75 μm with a decrease in 
BCVA of ≥ 5 letters compared to Visit 5, 
OR
-
Decrease in BCVA of > 5 letters compared to 
baseline (Visit 2), due to worsening wAMD 
activity, 
OR


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-
Decrease in BCVA of ≥ 10 letters compared 
to the best prior BCVA, due to worsening 
wAMD activity’
Rationale for change
Clarification of criteria to accurately determine 
recurrence leading to the use of rescue medication
Section to be changed
Section 5.3.1 Assessments of pharmacokinetics, 
MRD part
Rationale for change
Addition of:
‘• C112d (concentration of the analyte in serum 
56 days after the third treatment)
• C140d (concentration of the analyte in serum 84 
days after the third treatment)
• C168d (concentration of the analyte in serum 
112 days after the third treatment)’.
Rationale for change
Information about additional PK assessments 
Section to be changed
Section 5.4.1 Plasma derived protein biomarkers, 
MRD part
Rationale for change
Addition of:
‘• E112d (systemic level of free ANG2 and free 
VEGF 56 days after the third treatment)
• E140d (systemic level of free ANG2 and free 
VEGF 84 days after the third treatment)
• E168d (systemic level of free ANG2 and free 
VEGF 112 days after the third treatment)’.
Rationale for change
Information about additional biomarker 
assessments 
Section to be changed
Section 6.1 Visit schedule
Description of change
‘and ocular tonometry’ was added as assessment 
before pupil dilation. ‘Fluorescein angiography’
was changed to ‘OCT-angiography’. ‘Additional 
ocular tonometry may also happen after treatment 
on discretion of the investigator’ was added.
Rationale for change
Clarification of timepoints for ocular tonometry 
and correction (fluorescein angiography is not a 
trial procedure but OCT-A).
Section to be changed
Sections 6.2.1.2 and 6.2.2.2
Description of change
The sentence ‘An additional tonometry will be 
performed after IVT injection to monitor 
intraocular pressure’ was changed to ‘An 
additional tonometry may be performed after IVT
injection to monitor intraocular pressure’.
Rationale for change
Correction as tonometry after IVT may happen on 
discretion of the investigator.
Section to be changed
Section 6.2.2.2 Visit 8/End of Trial
Description of change
‘The Visit 8/EOT will be performed 14 days after 
the Visit 7’ was changed to ‘The Visit 8/EOT will 
be performed 28 days after the Visit 7’.


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Rationale for change
Correction of the Trial Timelines. A 28 day 
period is defined as follow-up timeline after Visit 
7. 
Section to be changed
Section 7.4 Interim analysis 
Description of change
Addition of the sentence: ‘Likewise, in the MRD 
part, the SMC will decide on the dose escalation.’
Addition of the sentences: ‘A preliminary 
analysis of efficacy data will be performed after 
the completion of Visit 5 of the first dose group 
of the MRD part. The preliminary efficacy results 
will be distributed to the trial team, but they will 
not be part of the CTR. A preliminary analysis of 
PK data will be performed after completion of the 
SRD part.’
Rationale for change
Clarification of preliminary analysis.
Section to be changed
Table 10.1: 2 Time schedule for PK/PD blood 
sampling
Description of change
Addition of three rows (FUP V6, FUP V7, EOT 
V8) according to time of sampling.
Rationale for change
To be consistent with the PK, Biomarker, and 
ADA sampling points introduced in this 
amendment. 
11.4
GLOBAL AMENDMENT 4
Date of amendment
26 Mar 2021
EudraCT number
EU number
2017-001221-40
BI Trial number
1336-0007
BI Investigational Product(s)
BI 836880
Title of protocol
Safety, tolerability and pharmacodynamics of 
single rising intravitreal and multiple rising 
intravitreal doses of BI 836880 in patients with 
wAMD (open label, non-randomized, 
uncontrolled).
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
X
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Section 3.3.2 Inclusion criteria 
Description of change
#1.: Changing ’12 weeks’ to ’16 weeks’
#2.: Deleting this criterion
#3.: Changing ‘350 microns’ to ‘330 microns’ 


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Rationale for change
Adaptation of these selected inclusion criteria 
aims to increase recruitment as initial eligibility 
criteria were too restrictive. 
The changes are not considered to have 
meaningful impact on safety for the patients.
Section to be changed
Section 3.3.3 Exclusion criteria
Description of change
#1.: Specifying ‘IOP>24’ as ‘IOP>24 mmHg on 
more than 2 consecutive measurements prior to 
treatment’
#3.: Changing ‘3 months’ to ‘1 month‘
#9.: Changing to: ‘Previous participation in this 
trial. Previous participation in other trials for 
treatment of wAMD with systemic administration 
and/or with IVT injections in the study eye if 
washout period from last administration/injection 
is lower than 3 months. Previous participation in 
other trials with IVT injections allowed if fellow 
eye was treated.’ 
Rationale for change
Adaptation of these selected exclusion criteria 
aims to increase recruitment as initial eligibility 
criteria were too restrictive. Clarification of the 
topic ‘IOP’ and ‘previous participation in other 
trials’ in more detail.
The changes are not considered to have 
meaningful impact on safety for the patients.
11.5
GLOBAL AMENDMENT 5
Date of amendment
28 July 2021
EudraCT number
EU number
2017-001221-40
BI Trial number
1336-0007
BI Investigational Product(s)
BI 836880
Title of protocol
Safety, tolerability and pharmacodynamics of 
single rising intravitreal and multiple rising 
intravitreal doses of BI 836880 in patients with 
wAMD (open label, non-randomized, 
uncontrolled).
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
X
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only


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Section to be changed
Cover Page: Clinical phase; Clinical Trial 
Protocol Synopsis
Description of change
Clinical Phase ‘I’ was changed to ‘I/IIa’.
Rationale for change
MRD cohort 2 will start to evaluate treatment-
naïve patients: this population will be the final 
target population.
Section to be changed
Clinical Trial Protocol Synopsis and section 1.3; 
section 3.1; section 3.3
Description of change
Number of patients entered/treated: 15 in the 
SRD part (instead of 18) and 27 in the MRD part 
(instead of 24; MRD cohort 1 = 12 patients, MRD 
cohort 2 = 15 patients); total number of patients
was not changed. First MRD cohort = 1 mg; 
second MRD cohort = 2 mg. 
Rationale for change
Clarification: The two highest safe and tolerable 
doses (1 mg and 2 mg) were established with 
15 patients in the SRD part; the drop out rate is 
expected to be higher in the MRD cohort 2 
compared to the MRD cohort 1.
Section to be changed
Clinical Trial Protocol Synopsis: Diagnosis
Description of change
Addition of ‘…treatment-naïve wAMD for MRD 
cohort 2’.
Rationale for change
Switch to target population in MRD cohort 2.
Section to be changed
Clinical Trial Protocol Synopsis: Main in- and 
exclusion criteria
Description of change
Addition of: ‘For MRD cohort 2: Men and 
women over the age of 55 with treatment-naïve 
CNV secondary to AMD.’
Rationale for change
Clarification of main eligibility criteria.
Section to be changed
Clinical Trial Protocol Synopsis: Test product, 
dose
Description of change
Addition to the MRD part: ‘1 mg and 2 mg 
(q4w)’.
Rationale for change
1 mg and 2 mg were selected for the MRD part as 
the two highest doses established as safe and 
tolerable during the SRD part.
Section to be changed
Flow Charts
Description of change
Addition of ‘Flow Chart III (Multiple Rising 
Dose Part, Cohort 2’. Examinations/visits as in 
Flow Chart II with additional safety visits V2a, 
V3a, and V4a (with slit lamp examination, AE 
check, and concomitant therapy questionning, 
respectively) within a week after injection. At 
these visits, addition of footnote ‘(6): Additional 
safety procedures may be performed according to 
local safety standard practice.’


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Rationale for change
As treatment-naïve patients are treated, addition 
of safety visits/procedures to ensure patient 
safety. 
Section to be changed
1.2 Drug Profile
Description of change
Adaptation of the AE and PK section as follows: 
‘In the SRD part of the trial described here (1336-
0007), 15 patients had been treated with 
intravitreal BI 836880 and followed up until the 
end of trial visit. Six patients were reported with 
an AE after trial drug administration; all of the 
corresponding 6 AEs were eye disorders 
(conjunctival haemorrhage in the study eye, 
subretinal fluid in the study eye, dry eye in the 
study eye, 2 vitreous floaters in the study eye, 
neovascular AMD in the fellow eye). None of the 
reported AEs was judged as related to BI°836880 
by investigators or fulfilled criteria for dose-
limiting events. The AEs of neovascular AMD 
and of subretinal fluid were reported as of 
moderate intensity, the other AEs were rated as 
mild. The AE of neovascular AMD in the fellow 
eye was considered serious. All AEs but the 
neovascular AMD, the subretinal fluid and the 
dry eye were recovered by the end of follow up. 
A preliminary pharmacokinetic analysis of the 
available data from the SRD part of 1336-0007 
was conducted. The plasma exposure (Cmax and 
AUC) increased in a dose proportional manner 
and reached gMean Cmax of 88.0 ng/mL and 
gMean AUC0-∞of 20 900 ng·h/mL for the 2 mg 
dose. Compared with the exposure after 
intravenous administration of 720 mg BI 836880, 
the exposure after intravitreal administration was 
very low (<1/1000).
In the MRD part of the trial, two patients of the 
MRD cohort 1 received three intravitreal doses 
and one patient of the MRD cohort 1 received 
two intravitreal doses of BI 836880 at the time of 
a data cut-off on 28 July 2021. Two patients were 
reported with an AE after trial drug 
administration; one of the corresponding 2 AEs 
was an eye disorder (vitreous floaters in the study 
eye). None of the reported AEs was judged as 
related to BI°836880 by investigators or fulfilled 
criteria for dose-limiting events. Both AEs were 
reported as of mild intensity.’


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Rationale for change
Available data for PK and AEs were incorporated 
to extend the current information of the drug 
profile. 
Section to be changed
1.3 Rationale for performing the trial
Description of change
Adaption of the paragraph referring to which 
patients will be included, as follows: ‘This trial 
will consist of a single rising dose (SRD) part and 
a multiple rising dose (MRD) part including 
MRD cohorts 1 and 2. Because this is the Fist-in-
Human (FiH) application with IVT route of 
administration, the SRD part and the MRD cohort 
1 of this trial will include patients who have not 
sufficiently responded to anti-VEGF treatment 
and still have active disease with significant 
retinal edema after a minimum of three previous 
injections. After safety has been investigated in 
SRD and first 3 patients of MRD cohort 1, the 
MRD cohort 2 will start to evaluate treatment-
naïve patients: this population will be the final 
target population, as it is expected to include the 
patients that can receive the biggest benefit with 
IVT administration of BI 836880.’
Rationale for change
Rationale for the inclusion of treatment-naïve 
patients in the MRD cohort 2.
Section to be changed
1.4 Benefit-Risk Assessment; 9. References
Description of change
Adaptation of the information on RG7716 and 
addition of reference R21-0692:  ‘However, IVT 
administration of an antibody that simultaneously 
binds to VEGF and ANG2 (faricimab, previously 
referred to as bispecific antibody RG7716) for 
treatment of wAMD has previously been tested in 
humans in a Phase 1 clinical trial [R18-0309], and 
a Phase 2 clinical trial [R21-0692]. In the Phase 1 
trial, the co-adminstration of RG7716 was 
reported to be well tolerated and to exhibit a 
favourable safety profile overall [R18-0309]. In 
addition, there was preliminary evidence of 
improvements in BCVA and anatomic parameters 
for this mode of action. In the Phase 2 trial, 
faricimab maintained vision and anatomic 
improvements comparable with SoC in wAMD in 
treatment naïve patients, resulting in the start of 
Phase 3 trials.
These data support that the combination of anti-
VEGF and anti-ANG2 can be used safely in 
patients with wAMD refractory to anti-VEGF 
monotherapy and in treatment-naïve patients.’


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Rationale for change
Both, Phase I and Phase II data have been 
published for faricimab that were considered for 
the benefit-risk evaluation of BI 836880.
Section to be changed
1.4 Benefit-Risk Assessment
Description of change
Addition of: ‘BI recommends the use of material 
for intraocular drug delivery, which is according 
to   standard medical practice. This material is not 
officially approved for intraocular drug delivery, 
with associated potential risks. Long-term 
experience as standard of medical care suggest a 
favorable 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 leave the decision to the 
treating investigators/sites on which material to 
use if it meets the specifications as described in 
the IMP handling instructions for BI 836880.’
Rationale for change
Following release of a caution statement by 
Becton Dickinson (BD), who supply materials for 
use in this trial, a risk-benefit evaluation and 
associated mitigation steps was performed and 
incorporated into the trial protocol.
Section to be changed
1.4 Benefit-Risk Assessment
Description of change
Addition of ‘For the MRD cohort 2, treatment-
naïve patients will be included based on a 
positive safety assessment as confirmed by the 
Safety Monitoring Committee (SMC), after three 
patients of MRD cohort 1 reaching Visit 5, i.e., 
one month after the third injection. Treatment-


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naïve patients are the intended final target 
population for BI 836880, because it is expected 
that these patients can get the biggest benefit 
from this treatment.’
Rationale for change
Clarification on MRD cohort 2 as the target 
population.
Section to be changed
Figure 3.1: 2 Schematic representation of the 
dose escalation process in the MRD part 
Description of change
It was specified: second highest safe dose from 
SRD = 1 mg (N=12); highest safe dose from the 
SRD = 2 mg (N=15). 
Rationale for change
Two doses have been established, and second 
MRD cohort changed from N=12 to N=15.
Section to be changed
3.3.2 Inclusion criteria
Description of change
Addition of:
‘SRD part and MRD cohort 1:’
Addition of:
‘MRD cohort 2:
1. Not applicable: Adapted to inclusion criterion 
#13, see below.
2. Not applicable: Deleted.
3. Not applicable: No limitation on central 
subfield retinal thickness.
4. Not applicable: Adapted to inclusion criterion 
#14, see below.
5. Not applicable: Adapted to inclusion criterion 
#14, see below. 
6. No subretinal hemorrhage involving the fovea 
in the study eye.
7. No significant subfoveal fibrosis or atrophy on 
SD-OCT in the study eye that, in the opinion of 
the investigator, is able to prevent improvement 
in BCVA and/or CSFT.
8. Not applicable: Adapted to inclusion criterion 
#15, see below. 
9. Not applicable: Adapted to inclusion criteria 
#16 and #17, see below.
10. Male or female patients. Women of 
childbearing potential (WOCBP)1 cannot be 
included. Men able to father a child must be 
ready and able to use highly effective methods of 
birth control per ICH M3 (R2) that result in a low 
failure rate of less than 1% per year when used 
consistently and correctly. A list of contraception 
methods meeting these criteria is provided in the 
patient information and in Section 4.2.1.3
11. Signed informed consent consistent with ICH 
GCP guidelines and local legislation prior to 


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participation in the trial, which includes 
medication washout and restrictions.
12. Not under any administrative or legal 
supervision or under institutionalization due to 
regulatory or juridical order.
13. Men and women over the age of 55 with 
treatment-naïve CNV secondary to AMD.
14. Any CNV with subfoveal activity in the study 
eye defined as evidence of sub- and/or intraretinal 
fluid, or subretinal hyper-reflective material, or 
angiographic leakage.
15. Best-corrected Early Treatment Diabetic 
Retinopathy Study (ETDRS) VA in the study eye 
between 80 and 24 letters inclusive 
(approximately 20/25 and 20/320 or 6/7.5 and 
6/95) at screening.
16. Best-corrected ETDRS VA in the non-study 
eye 50 letters inclusive (approximately 20/100 or 
6/30) or better at screening.
17. If both eyes are eligible at screening, the 
study eye is the eye with the worse best-corrected 
VA.’
Rationale for change
Adaptation and addition of inclusion criteria 
specifically for MRD cohort 2.
Section to be changed
3.3.3 Exclusion criteria 
Description of change
Adaptation of Exclusion criterion #9 as follows:
‘9. Participation in trials:  
•
Previous participation in this trial. 
•
Previous participation in other trials for 
treatment of wAMD with systemic 
administration if washout period from last 
administration/injection is shorter than 
3 months.
•
MRD cohort 1: Previous participation in 
other trials for treatment of wAMD with IVT 
injections in the study eye if washout period 
from last administration/injection is shorter 
than 3 months2. 
•
MRD cohort 2: No previous IVT 
injections for wAMD in the study eye2.
2Previous participation in other trials with 
IVT injections allowed if fellow eye was 
treated.’
Rationale for change
Adaptation of this exclusion criterion to clarify 
differentiate exclusion criteria between MRD 
cohorts 1 and 2. 
Section to be changed
3.3.4.1; 5.; 6.; throughout the protocol


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Description of change
Addition of ‘and Flow Chart III’.
Rationale for change
Reference to the newly introduced Flow Chart III 
for MRD cohort 2. 
Section to be changed
4.1.4. Drug assignment 
Description of change
Addition of ‘and “BI 836880 solution for 
injection 40 mg/mL” ’.
Rationale for change
Reference to a new formulation that will become 
available for use.
Section to be changed
6.2.2.2 Treatment period and end of trial visit 
MRD part
Description of change
Addition of: ‘In the MRD part cohort 2, 
additional safety assessments/visits will be 
carried out within a week after V2, V3, V4, 
respectively.’
Rationale for change
To ensure adequate safety visits/assessments for 
treatment-naïve patients.
Section to be changed
7.7 Determination of Sample Size 
Description of change
Addition of: ‘The drop out rate is expected to be 
higher for the treatment-naïve patients in cohort 2 
as compared to the treatment-resistant patients in 
cohort 1. To allow for dropouts, 12 patients will 
be included in MRD cohort 1 and 15 patients will 
be included in MRD cohort 2.’
Rationale for change
Explanation for sample size for cohort 2. 
Section to be changed
8.3.2 Direct access to source data and documents
Description of change
Addition of: ‘and/or remote monitoring calls’.
Rationale for change
Clarification: Takes into account remote 
monitoring.
Section to be changed
Table 10.1: 2 Time schedule for PK/PD blood 
sampling during MRD part; column ‘Planned 
Time [h]’
Description of change
Extension of pre-dose sampling time window to   
-2 h and of follow-up sampling time window to 
+/- 2 h.
Rationale for change
To allow higher operational flexibility for PK/PD 
blood sampling in the MRD part.
11.6
GLOBAL AMENDMENT 6
Date of amendment
25 Oct 2021
EudraCT number
EU number
2017-001221-40
BI Trial number
1336-0007
BI Investigational Product(s)
BI 836880
Title of protocol
Safety, tolerability and pharmacodynamics of 
single rising intravitreal and multiple rising 
intravitreal doses of BI 836880 in patients with 


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wAMD (open label, non-randomized, 
uncontrolled).
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
X
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Clinical Trial Protocol Synopsis and throughout 
the CTP (Sections 1.3; 3.1; 7.7 and Figure 3.1: 2)
Description of change
Specification of cohort sizes in MRD part, 
i.e., ’10 to 12’ (instead of ‘12’) for MRD cohort 1 
and ’10 to 17’ (instead of ‘15’) for MRD cohort 
2; illustration that cohort 1 and cohort 2 will run 
overlapping after the SMC.
Rationale for change
No change of total number of patients, 
adaptations taking into account a potential higher 
drop-out rate in treatment-naïve patients where 
follow-up until EoT is particularly important. 
Clarification of Figure 3.1: 2.
Section to be changed
Clinical Trial Protocol Synopsis and 3.3.2 
Description of change
Incl#3.: Change ‘CSFT > 330 µm’ to ‘CSFT > 
300 µm’ for MRD cohort 1.
Rationale for change
Adaptation of this selected inclusion criteria aims 
to increase recruitment as former eligibility 
criteria were too restrictive. 
Section to be changed
3.1 Overall Trial Design and Plan; MRD part
Description of change
Deletion of ‘Although anti-VEGF gives a fast 
response in treatment-naïve patients, in this group 
of patients with wAMD who had not sufficiently 
responded to anti-VEGF treatment, it is expected 
that a reduction of fluid in the retina should be 
observed only after multiple treatments’.
Rationale for change
Misleading sentence as MRD part no longer 
exlusively consists of patients who had not 
sufficienly responded to anti-VEGF treatment. 
Section to be changed
3.3.2 Inclusion criteria
Description of change
Incl#8: Change ‘ETDRS VA in the study eye 
between 70 and 24 letters inclusive’ to ‘between 
75 and 24 letters inclusive (approximately 20/32 
or 6/9.5)’.
Rationale for change
Positive safety data support to broaden this 
criterion to allow treatment-resistant patients with 
ETDRS VA up to 75 to be enrolled as well. 
Section to be changed
4.1.1. Identity of Investigational Medicinal 
Product 


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Description of change
Addition of ’Table 4.1.1: 2’ in order to describe 
the diluent. 
Rationale for change
For completeness/clarification: Investigational 
Medicinal Product includes BI 836880 and 
diluent. 
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each patient
Description of change
Addition of: ‘The diluent can be used for both 
drug preparations, “BI 836880 concentrate for 
solution for injection 80 mg/mL” and for 
“BI 836880 solution for injection 40 mg/mL”, if 
required.’
Rationale for change
Continuation of 1336-0007 1 mg MRD cohort 
with “BI 836880 solution for injection 40 
mg/mL” drug product and diluent if treatment 
goes beyond February 2022 as the “BI 836880 
concentrate for solution for injection 80 mg/mL” 
drug product expires end of February 2022.
Section to be changed
6.2. Re-Screening
Description of change
Addition of ‘without new IRT registration’ if re-
screen within 12 weeks, ‘beyond this time period 
(up to one time)’ with IRT registration.
Rationale for change
Clarification.
Section to be changed
8. Publication Policy
Description of change
Deletion of ‘As a rule, no trial results should be 
published prior to finalization of the CTR.’ and 
addition of ‘As per the project publication 
strategy, interim cohort data will be published as 
available, while full results will be published after
CTR finalization.’
Rationale for change
Clarification.
11.7
GLOBAL AMENDMENT 7
Date of amendment
28 Sep 2022
EudraCT number
EU number
2017-001221-40
BI Trial number
1336-0007
BI Investigational Product(s)
BI 836880
Title of protocol
Safety, tolerability and pharmacodynamics of 
single rising intravitreal and multiple rising 
intravitreal doses of BI 836880 in patients with 
wAMD (open label, non-randomized, 
uncontrolled).
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
X


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To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Clinical Trial Protocol Synopsis and throughout 
the CTP (Sections 3.1 Overall trial design and 
plan; 7.7 Determination of sample size;
Figure 3.1: 2)
Description of change
Revision and clarification of patients entered, 
cohort sizes, and dose groups in MRD part.
For number of patients entered (synopsis):
‘Approximately Up to 42; 15 in the SRD part 
and approximately up to 27 in the MRD part’
For number of patients on each treatment
(synopsis):
‘SRD part: 15, in different dose groups
MRD part: 11 10 to 12 patients in dose group 1 
(= MRD cohort 1); approximately 16 10 to 17
patients in dose group 2, (4 patients from MRD
cohort 2, 12 patients from cohort 3).’
For Section 3.1: ‘The MRD part will consist of a 
first partcohort (1 mg) with 1110 to 12
treatment-resistant patients and(cohort 1), a 
second partcohort (2 mg) with 410 to 17
treatment-naïve patients (cohort 2), and 
approximately 12 frequently treated patients 
(cohort 3; inclusion criteria defined in 
Section 3.3.2).’, amendment of n numbers and 
layout of Figure 3.1: 2
For Section 7.7: ‘To allow for dropouts, 10 to 12 
patients will be included in MRD cohort 1 and 
approximately 16 10 to 17 patients will be 
included in MRD cohort 2 and 3 combined (in 
total approximately not more than 42 patients in 
the trial). In case some subjects do not complete 
the trial according to the protocol, the trial 
clinical monitor together with the trial 
pharmacokineticist and the trial statistician 
are to decide if and how many subjects will be 
replaced.’ and ‘For the MRD cohort 3, no 
formal sample size calculation has been 
applied. It is expected that using 


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approximately 12 patients will be sufficient for 
this cohort.’
Rationale for change
No change of total number of patients. Added the 
word “approximately” to account for potential 
variability in number of patients entered and 
number of patients that are randomized.
Reiterated replacement strategy.
Patients on each treatment adapted with results 
from completed SRD and MRD cohorts 1 and 2, 
12 patients allocated to cohort 3.
Clarification and addition of MRD cohort 3
patients to text in Section 3.1 and Figure 3.1: 2.
Section to be changed
Clinical Trial Protocol Synopsis: Diagnosis
Description of change
Addition of: ‘patients within 3 years of initial 
wAMD diagnosis for MRD cohort 3.’
Rationale for change
Additional requirement of patient population for 
MRD cohort 3
Section to be changed
Clinical Trial Protocol Synopsis: Main in- and 
exclusion criteria
Description of change
Addition to main inclusion: ‘For MRD cohort 3: 
Men and women over the age of 55 with active 
CNV secondary to wAMD that require frequent 
intravitreal (IVT) treatment (28 to 56 days
between treatments) with ranibizumab, 
aflibercept, or bevacizumab for standard of care 
for at least 6 months, with the last IVT 
administration between 4-8 weeks before the first 
study drug administration.’
Addition to main exclusion: ‘For MRD cohort 3: 
Active intraocular inflammation in the study eye, 
> 0.5+ anterior chamber cell and/or vitreous haze 
grading, or history of intraocular inflammation in 
either eye with previous IVT administration(s), 
history of retinal vein occlusion, previous 
treatment with brolucizumab or faricimab, and/or 
medical history of autoimmune disease that has 
caused ocular inflammation.’
Rationale for change
Update of main eligibility criteria for MRD 
cohort 3
Section to be changed
Clinical Trial Protocol Synopsis: Test product, 
dose
Description of change
Addition to the MRD part: ‘1 mg (cohort 1) and 
2 mg (cohort 2 and 3) (q4w)’
Rationale for change
Clarification of dose groups and cohort allocation
Section to be changed
Clinical Trial Protocol Synopsis: Endpoints & 
Criteria for Pharmacodynamics; 2.1.3 Secondary 


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endpoints; 7.3.2/7.3.3 Secondary/Further 
endpoint analyses
Description of change
Added week and visit numbers
Rationale for change
Clarification
Section to be changed
Clinical Trial Protocol Synopsis: Statistical 
Methods; 7.7 Determination of sample size
Description of change
Reworded to make clear that no statistical testing 
is planned for descriptive statistics
Added to 7.7: ‘For the MRD cohort 3, no formal 
sample size calculation has been applied. It is 
expected that using approximately 12 patients 
will be sufficient for this cohort.’
Rationale for change
Clarification
Section to be changed
Flow Charts
Description of change
Addition of ‘Flow Chart IV (Multiple Rising 
Dose Part, Cohort 3)’. Examinations/visits as in 
Flow Chart III with Fundus photos (multi-field 
and widefield) added to treatment period safety 
visits. 
Added fluorescein angiography to Screening with 
footnote ‘(7): Fluorescein angiography imaging 
during Visits 2-8 should be performed at the 
discretion of the investigator, e.g. if signs of 
inflammation are observed’
Added row to differentiate between multi-field 
and widefield fundus photos that are required at 
every visit, rather than at the discretion of the 
investigator. Changed footnote 4 to ‘Vitreous 
haze assessment to be completed with every 
examination’
Added row with Study Week to all flow charts.
Rationale for change
Adapted to include additional safety 
measurements required for MRD cohort 3, and 
for clarity (Study week)
Section to be changed
3.3.4.1; 5.; 6.; throughout protocol
Description of change
Addition of ‘and Flow Chart IV’ and ‘cohort 3’
Rationale for change
Reference to the newly introduced Flow Chart IV 
and MRD cohort 3
Section to be changed
1.2 Drug profile 
Description of change
Updated current summary of clinical safety data 
including descriptions of 2 SAEs reported in 
MRD cohort 1. Added references
Rationale for change
Update
Section to be changed
1.3 Rationale for performing the trial 
Description of change
Described evidence of efficacy detected during 
exploratory analysis of interim data in patients 


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requiring frequent standard of care which are the 
target patient population for MRD cohort 3
Rationale for change
Description of exploratory interim data and the 
unmet medical need for cohort 3 patient 
population to receive less frequent, higher 
potency therapy. 
Section to be changed
1.4 Benefit-Risk assessment 
Description of change
Removed paragraph referring to systemic 
administration of BI 836880 currently in 
development for use in oncology
Described unmet medical need of frequently
treated patient population
Described added safety measures: FA imaging 
during screening, wide angle CFP with vitreous 
haze assessment at every visit and requirement to 
report any intraocular inflammation events as
AESIs.
Rationale for change
PK data from SRD part showed <1/1000 systemic
plasma levels after IVT compared to intraveneous
exposure, therefore clinical data is unlikely to be 
similar/comparable
Updates to benefit-risk assessment (favorable)
Section to be changed
Description of change
Rationale for change
Section to be changed
3.3.1 Main diagnosis for trial entry; 3.3.2 
Inclusion criteria
Description of change
Added to 3.3.1: ‘who meet all inclusion criteria 
and do not meet any exclusion criterion.’
Added to 3.3.2:
MRD cohort 3 (frequently treated patients):
1-5. Not applicable to cohort 3.
6. No subretinal hemorrhage involving the fovea 
in the study eye.
7. No significant subfoveal fibrosis or atrophy 
on SD-OCT in the study eye that, in the 
opinion of the investigator and with the 


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endorsement of the Sponsor, is able to prevent 
improvement in BCVA.
8-9. Not applicable to cohort 3.
10. Male or female patients. Women of 
childbearing potential (WOCBP)1 cannot be 
included. Men able to father a child must be 
ready and able to use highly effective 
methods of birth control per ICH M3 (R2) 
that result in a low failure rate of less than 1% 
per year when used consistently and correctly. 
A list of contraception methods meeting these 
criteria is provided in the patient information 
and in Section 4.2.1.3.
11. Signed informed consent consistent with ICH 
GCP guidelines and local legislation prior to 
participation in the trial, which includes 
medication washout and restrictions.
12. Not under any administrative or legal 
supervision or under institutionalization due 
to regulatory or juridical order.
13. Not applicable to cohort 3.
14. Any CNV with subfoveal activity in the study 
eye defined as evidence of sub- and/or 
intraretinal fluid, or subretinal hyper-
reflective material, or angiographic leakage.
15. Best-corrected Early Treatment Diabetic 
Retinopathy Study (ETDRS) VA in the study 
eye between 80 and 24 letters inclusive 
(approximately 20/25 and 20/320 or 6/7.5 and 
6/95) at screening.
16. Not applicable to cohort 3.
17. If both eyes are eligible at screening, the 
study eye is the eye with the worse best-
corrected VA.
18. Men and women over the age of 55 with 
diagnosed wAMD that:
•
require frequent wAMD SoC (28-56 days 
between the last 3 treatments)
•
have had ≥ 3 previous treatments with 
IVT SoC (ranibizumab, aflibercept, or 
bevacizumab) in the study eye
•
had the last SoC injection ≥ 4 weeks, but 
no more than 8 weeks, before the first 
administration of the study drug
•
have been on SoC treatment ≥ 6 months 
and are within 3 years from initial wAMD 
diagnosis in the study eye


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Added cohort patient population description to 
heading for each set of inclusion criteria
Rationale for change
Adaptation and addition of inclusion criteria 
specifically for MRD cohort 3. Clarification
Section to be changed
3.3.3 Exclusion criteria
Description of change
Added:
9. Participation in trials: 

Previous participation in this trial. 

Previous participation in other trials 
for treatment of wAMD with systemic 
administration if washout period from 
last administration is shorter than 3 
months.

MRD cohorts 1 & 3: Previous 
participation in other trials for 
treatment of wAMD with IVT 
injections in the study eye if washout 
period from last 
administration/injection is shorter than 
3 months2.

MRD cohort 2: No previous IVT 
injections for wAMD in the study 
eye2.
12. Active intraocular inflammation in the study 
eye, > 0.5+ anterior chamber cell and/or 
vitreous haze grading, or history of 
intraocular inflammation in either eye with 
previous IVT administration(s) (anterior 
chamber/haze grading and intraocular 
imflammation history only applicable to 
MRD cohort 3).
13. Active infectious conjunctivitis in either eye.
14. Symptoms of active SARS-CoV-2 
infection4. 
15. Any history of retinal vein occlusion in the 
study eye (only applicable to MRD cohort 
3).
16. Any previous treatment with brolucizumab
or faricimab in either eye (only applicable 
to MRD cohort 3).
17. Medical history of autoimmune disease 
that has caused ocular inflammation (only 
applicable to MRD cohort 3).
2 Previous participation in other trials with IVT injections allowed 
if fellow eye was treated.
3 e.g. cardiac (including tachycardia), gastro-intestinal, hepatic, 
renal, metabolic, dermatologic, neurological, haematological, 
oncological and psychiatric. Patients with malignancy for which 
the patient has undergone resection, radiation or chemotherapy 


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within past 5 years. Patients with treated basal cell carcinoma or 
fully cured squamous cell carcinoma are allowed.
4 Testing and management of SARS-CoV-2 infection at the 
discretion of investigators in accordance with local guidelines 
and policies.
Rationale for change
Adaptation of exclusion criterion 9 to clarify 
differentiate between MRD cohorts 1, 2, and 3. 
Added/amended exclusion criteria 12, 14-17 to 
exclude patients with a high potential of 
developing ocular inflammation from MRD 
cohort 3.
Section to be changed
3.3.5 Replacement of patients
Description of change
Amended 3.3.5: ‘Patients withdrawn before visit 
4 for another reason other than a DLE or patients 
who miss any visit out of Visits 2 to 4 are not 
evaluable for the occurrence of a DLE within 7 
days after drug administration. These patients will 
be replaced if not decided otherwise by the SMC 
(becausein the scenario that there are already 2 
DLE evaluable patients in the current dose group; 
see Section 3.1). Patients who come off study due 
to a DLE will not be replaced.’
Rationale for change
Reworded for clarification, no change to 
replacement criteria
Section to be changed
4.1.1 Identity of the Investigational Medicinal 
Products
Description of change
Added: ‘In this trial, the IMP BI  836880 will be 
switched from an initial trial formulation (CMC1) 
to an intended final formulation (CMC2). The 
new formulation will be made available for the 
treatment of MRD cohort 3.’
Rationale for change
Reference to a new formulation that will become 
available for use.
Section to be changed
4.1.6.1, 4.1.6.2 Blinding and procedures for 
unblinding; 7.4 Interim Analysis
Description of change
Rephrased all instances of “blinded” to “masked”
Rationale for change
In accordance with current nomenclature for 
retinopathy studies
Section to be changed
4.2.1.1 Restrictions regarding concomitant 
treatment; 5.2.2 Time to recurrence; 6.2.2.2 
Treatment period and end of trial visit MRD part
Description of change
4.2.1.1 Reworded to: 
‘SRD and MRD cohorts 1 & 2: As per 
judgement of the investigator, administration of 
local SoC treatment such as IVT or peribulbar 
injections, laser, or other surgical treatment is 
allowed in clinically significant worsening of the 
disease. After the end of treatment with trial 
medication (during Follow-up Period, starting at 


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Visit 5), SoC therapy is at the discretion of the 
investigator. SoC therapy is, for the purpose of 
the present trial, considered a non-investigational 
medical treatment.
MRD cohort 3: For the study eye, no other 
treatment (IVT or otherwise) is allowed during 
the treatment and follow up periods of the trial 
unless rescue criteria are met (refer to Section 
5.2.2 for rescue treatment criteria), or as 
deemed medically appropriate during/after 
Visit 6. Medications listed under the exclusion 
criteria (Section 3.3.3) are restricted during 
the trial. SoC therapy is, for the purpose of the 
present trial, considered a non-investigational 
medical treatment.’
Added to 5.2.2: ‘The decision to treat with 
wAMD rescue medication should be documented 
in the eCRF.’
6.2.2.2 Amended: ‘The investigator may decide 
to administer standard treatment for wAMD 
during the follow-up period (for MRD cohort 3 
during/after Visit 6) as deemed medically 
appropriate.’
Rationale for change
Clarification that SoC therapy should be 
administered and documented if there is a 
worsening in disease before Visit 6, and as 
deemed medically appropriate during/after 
Visit 6.
Section to be changed
5.2.1 Dose limiting event; 5.2.8.1.4 Adverse 
events of special interest
Description of change
Added to 5.2.1: Heading to SRD and MRD 
cohort 1 criteria and ‘DLE criteria are not 
applicable to MRD cohorts 2 and 3. Should an 
event involving intraocular inflammation/signs of 
vascular occlusion, decreases in visual acuity, 
and/or intraocular pressure occur, the event 
should only be reported as an AESI as described 
in Section 5.2.8.1, and not as a DLE.’
Added to 5.2.8.1.4: detailed AESI criteria for 
ocular related events (intraocular inflammation, 
signs of retinal vascular occlusion, decreases in 
visual acuity, and intraocular pressure). Added 
NEI grading scale of vitreous haze 
(Table 5.2.8.1.4: 1)
Rationale for change
Clarification, additional AESI criteria described 
for cohorts receiving maximum dose (MRD 
cohorts 2 & 3)


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Section to be changed
5.2.3 Physical examination
Description of change
Amended and added to description of color 
fundus photography: ‘Seven-field or modified 4-
Multi-field digital fundus photographs will be 
obtained from both eyes by a qualified person 
according to the imaging manual. For MRD 
cohort 3, additional color fundus photographs 
from both eyes will be acquired from the 
retinal periphery to assess inflammation and 
from the central retina to assess vitreous haze.’
Rationale for change
Clarification and description of added 
requirement of multi-field and widefield color
fundus photography for cohort 3 (safety 
requirement)
Section to be changed
5.2.6 Electrocardiogram
Description of change
Amended: ‘All ECGs will be evaluated by the 
cardiologist of the central ECG vendor, or and in 
addition by a qualified cardiologist healthcare 
provider at the site, if available.’
Rationale for change
Clarification and to allow operational flexibility. 
This change is not considered to have an impact 
to the safety of patients.
Section to be changed
5.2.7 Other safety parameters; 6.1 Visit schedule; 
6.2.2.1 Screening Visit
Description of change
Added to other safety parameters: ‘MRD cohort 3 
only: Fluorescein angiography (FA) imaging will 
be obtained from both eyes during Screening by a 
qualified person according to the imaging 
manual. Additional FA during Visits 2-8 should 
be performed at the discretion of the investigator, 
e.g. if signs of inflammation are observed.’
Added to visit schedule: ‘After dilation: slit lamp 
examination, SD-OCT, Fundus photography, and
OCT- angiography, and FA (FA required at 
screening or at the discretion of the 
investigator during subsequent visits, for 
cohort 3 only).’
Added to Re-screening: ‘Imaging of retina (SD-
OCT, OCT-A, fundus photography, and/or 
fluorescein angiography) does not need to be 
repeated at the re-screening visit’
Rationale for change
Description of added requirement of fluorescein 
angiography for cohort 3 (safety requirement)
Section to be changed
5.2.8.2.4 Pregnancy
Description of change
Added: ‘Similarly, potential drug exposure during 
pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires 


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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.’
Rationale for change
In line with local US amendment 2 requiring 
written consent of the pregnant partner of a study 
participant for drug exposure reporting and 
pregnancy outcome.
Section to be changed
7 Statistical methods and determination of sample 
size
Description of change
Amended 7.1: ‘There will be 2 consecutive 
cohorts dose groups of the highest and the
second highest safe (cohort 1) and the highest
safe dose level (cohorts 2 and 3) fulfilling the 
EWOC criterion after completion of the SRD 
part.’
Amended 7.3: ‘Analyses will be performed by 
dose/cohort and overall in each trial part.’
Added/amended 7.3: 
‘Evaluable Responders’ Set (ERS, MRD 
cohort 3 only)
The ERS will consist of all patients who 
completed three doses of BI 836880 and have 
SD-OCT measurements at Week 16 (Visit 6).
In the TSAP, the FAS and ERS definitions may 
be updated, and further analysis data sets may
be defined.’
Added 7.3.3: ‘The analysis of responders in MRD 
cohort 3 will be based on TS and/or ERS. More 
details will be described in the TSAP.’
Amended 7.7: ‘For example, if the true median 
percent decrease in CSFT at Week 12 was 
25%, the probability to observe a median percent 
decrease in CSFT at Week 12 of at least 20% 
would be around 80%’
Rationale for change
Update/clarification of analytical details 
regarding newly added MRD cohort 3
Section to be changed
8.1 Trial approval, patient information, informed 
consent
Description of change
Removed ‘or the patient’s legally accepted 
representative’
Rationale for change
In line with local German amendments 1& 2
Section to be changed
Section 1 Introduction; Section 9 References
Description of change
Added: R22-2854, n00253677, n00259128
Updated: draft references with final dates
Removed: R07-4722, R09-4830, R16-0366, 
c02353883, unpublished reference author names


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Rationale for change
Update, added references to introduction
Section to be changed
Table 10.1: 2 Time schedule for PK/PD blood 
sampling during MRD part; column ‘Planned 
Time [h]’
Description of change
Extension of before 1st IVT dose sampling time 
window to -4 h.
Rationale for change
To allow higher operational flexibility for PK/PD 
blood sampling


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17360540
8.0
clinical-trial-protocol-version-08
Safety, tolerability and pharmacodynamics of single rising intravitreal and multiple
rising intravitreal doses of BI 836880 in patients with wAMD (open label,
non-randomized, uncontrolled).
Approval-Clinical Program
29 Sep 2022 09:28 CEST
Approval-
 Medicine
29 Sep 2022 09:49 CEST
Approval-Clinical Trial Leader
29 Sep 2022 09:58 CEST
Author-Trial Clinical
Pharmacokineticist
29 Sep 2022 10:22 CEST
Author-Statistician
29 Sep 2022 15:44 CEST
Verification-Paper Signature
Completion
30 Sep 2022 07:47 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17360540
8.0

SAP_001.pdf: 
ABCD
BI-VQD-12681-S-G_50-415_AD-01 (5.0)
TRIAL STATISTICAL ANALYSIS PLAN
TITLE PAGE
Document No.:
c31147466-02
BI Trial No.:
1336-0007
Title:
Safety, tolerability and pharmacodynamics of single rising 
intravitreal and multiple rising intravitreal doses of BI 836880 in 
patients with wAMD (open label, non-randomized, uncontrolled).
(Including Protocol Amendments No.1-7 [c17360540-08])
Investigational
Product:
BI 836880
Responsible trial 
statisticians:
Email:
 
Date of statistical 
analysis plan:
02 FEB 2024
Version:
2.0
Page 1 of 36
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
INTERCURRENT EVENTS .............................................................................15
6.4
SUBJECT SETS ANALYSED...........................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................17
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................18
7.
PLANNED ANALYSIS......................................................................................19
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........21
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................21
7.3
TREATMENT COMPLIANCE........................................................................21
7.4
PRIMARY OBJECTIVE ANALYSIS..............................................................21
7.4.1
Main analysis.......................................................................................................21
7.4.4
Supplementary analysis......................................................................................22
7.5
SECONDARY OBJECTIVE ANALYSIS........................................................23
7.5.1
Key secondary objective analysis.......................................................................23
7.5.2
Secondary objective analysis..............................................................................23
7.6
FURTHER OBJECTIVE ANALYSIS..............................................................24
7.6.1 
Ophthalmic endpoints.........................................................................................24
7.6.2
Pharmacokinetic/Pharmacodynamic endpoints...............................................27
7.7
EXTENT OF EXPOSURE.................................................................................28
7.8
SAFETY ANALYSIS..........................................................................................28
7.8.1
Adverse Events ....................................................................................................28
7.8.2
Laboratory data ..................................................................................................30
7.8.3
Vital signs.............................................................................................................30


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7.8.4
ECG......................................................................................................................31
7.9
OTHER ANALYSIS...........................................................................................31
7.9.1
Biomarker analyses.............................................................................................32
7.9.2
PK / PD analyses .................................................................................................32
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............33
9.
REFERENCES....................................................................................................34
11.
HISTORY TABLE..............................................................................................36


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LIST OF TABLES
Table 6.1: 1 Treatments and labels used in the analysis – SRD part .......................................12
Table 6.1: 2 Treatments and labels used in the analysis – MRD part......................................12
Table 6.2: 1 Important Protocol Deviations.............................................................................14
Table 6.4: 1 Subject sets analyzed ...........................................................................................16
Table 6.7: 1 Visit intervals for efficacy endpoints (CSFT, BCVA, responder analysis) and 
IOP....................................................................................................................18
Table 7.5.2: 1 Censoring Rules for time to recurrence ............................................................24
Table 7.6.1: 1 Numeric ophthalmic endpoints from OCT.......................................................25
Table 7.6.1: 2 Numeric ophthalmic endpoints from OCT-A...................................................26
Table 7.6.1: 3 Categorical ophthalmic endpoints from CFP ...................................................27
Table 11: 1 History table..........................................................................................................36


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
ALT
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI
Body mass index 
CSFT
Central Subfield Thickness 
CV
Arithmetic Coefficient of Variation 
DBLM
Database Lock Meeting
DLE
Dose Limiting Event
ES
Enrolled Set
EOT
End of Trial
FAS
Full Analysis Set
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
IOP
Intraocular Pressure
iPD
Important Protocol Deviation
IQRMP
Integrated Quality and Risk Management Plan
IRF
Intra-retinal Fluid
IVT
Intravitreal
LLT
Lower Level Term
Max
Maximum
Min
Minimum
MRD
Multiple Rising Dose
N
Number of non-missing observations
OCT
Optical Coherence Tomography
P10
10th percentile
P90
90th percentile
PED
Pigment Epithelial Detachment
Q1
1st quartile


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Term
Definition / description
Q3
3rd quartile
q4w
Once in 4-weekly interval
RAGe
Report Appendix Generator system
SD
Standard Deviation
SD-OCT
Spectral Domain Optical Coherence Tomography
SHRM
Subretinal Hyper-Reflective Material
SMC
Safety Monitoring Committee
SoC
Standard of Care
SOC
System Organ Class
SRD
Single Rising Dose
SRF
Sub-Retinal Fluid
SUN
Standardization of Uveitis Nomenclature
TS
Treated Set
WHO-DD
World Health Organization Drug Dictionary


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3. INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data. 
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomization. 
Study data (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR). 
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 8.1.1 or higher, 
) or SAS Version 9.4 (or later 
version). 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
 and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 


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4. CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in CTP will be performed and are described in more detail in this 
TSAP. 
The baseline definition of CTP was clarified in TSAP: 
In CTP Section 5.1 it is ‘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’. If an actual time is given in the data, 
it will be checked whether the measurement at visit 2 was done before or after trial drug 
administration. If it is done after administration, the measurement will not be used as a 
baseline measurement. The baseline definition was updated to ‘The baseline value is defined 
as the last measurement before first administration of BI 836880 (= value at V2, in case no 
actual time is given in data)’.  
The definition of responder in further endpoints was clarified in TSAP. In CTP section 2.2.2, 
one of the further endpoints in MRD part is “Responder (yes/no) defined as absence of intra-
retinal or sub-retinal fluid (IRF/SRF) or resolution of SHRM/PED in the study eye at Week 
16 (Visit 6, cohort 3 only)”. This definition is modified as: “Responder (yes/no) defined as 
resolution of IRF and SRF or resolution of SHRM/PED in the study eye at Week 16 (Visit 6, 
cohort 3 only)”. To avoid redundancy, endpoint “Absence (yes/no) of intra-retinal or sub-
retinal fluid (IRF, SRF) in the study eye at Week 16 (Visit 6, cohort 3 only)” and “Resolution 
(yes/no) of subretinal hyper-reflective material/retinal pigment epithelial detachment 
(SHRM/PED) in the study eye at Week 16 (Visit 6, cohort 3 only)” could be removed. 


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5.
ENDPOINTS
The pharmacokinetic and pharmacodynamic parameters listed in Section 2.2 of the CTP for 
drug BI 836880 will be calculated according to the BI Standard Operating Procedure (SOP) 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ [001-MCS-36-472] (4).
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP: 
SRD part: 

Number of patients with ocular dose limiting events (DLEs) from drug administration 
until end of trial (EOT).  
For definition of DLEs, refer to Section 7.4. 
MRD part: 

Number of patients with drug related AEs from drug administration until EOT. 
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: 
SRD part: 

Number of patients with drug related AEs 

Number of patients with any ocular AEs in the study eye 
MRD part: 

Percent change from baseline in Central Subfield Thickness (CSFT) in the study eye at 
Week 12 (Visit 5), for each dose 

Change from baseline in BCVA in the study eye at week 12 (Visit 5) 

Time to recurrence after the last treatment 

Number of patients with any ocular AEs in the study eye


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of dose groups, 
selection of doses, refer to CTP Sections 3 and 4.  
The trial will consist of an SRD part followed by an MRD part. Both parts will be conducted 
open-label, non-randomized, and uncontrolled. 
It was planned to assign up to 42 patients in total, up to 15 in the SRD part (5 sequential dose 
groups comprising 3 patients each) and 27 in the MRD part (11 patients in dose group 1 (first 
cohort) and 16 patients in dose group 2 (4 patients from cohort 2 and 12 patients from cohort 
3)).  
For details of dosage and formulation see Tables 6.1:1 and 6.1:2 below. 
Table 6.1: 1 Treatments and labels used in the analysis – SRD part 
Dose group
Treatment
Short Label
1
A
BI 836880, 80 mg/mL solution, 0.06 mg, ivt
BI 0.06mg
2
B
BI 836880, 80 mg/mL solution, 0.18 mg, ivt
BI 0.18mg
3
C
BI 836880, 80 mg/mL solution, 0.5 mg, ivt
BI 0.5mg
4
D
BI 836880, 80 mg/mL solution, 1.0 mg, ivt
BI 1mg
5
E
BI 836880, 80 mg/mL solution, 2.0 mg, ivt
BI 2mg
Table 6.1: 2 Treatments and labels used in the analysis – MRD part 
Dose group
Treatment
Short Label*
1
F
BI 836880 Concentrate for Solution for Injection 
80 mg/mL, diluted with Diluent to 20 mg/mL 
solution, 1.0 mg, ivt
BI 1mg q4w 
– cohort 1  
2
G
BI 836880 Concentrate for Solution for Injection 
80 mg/mL, diluted with Diluent to 40 mg/mL 
solution, 2.0 mg, ivt
BI 1mg q4w 
– cohort 2
3
H
BI 836880 solution for injection 40 mg/mL, 2.0 
mg, ivt
BI 1mg q4w 
– cohort 3
* cohort 1: resistant patients, cohort 2: naïve patients, cohort 3; frequently treated patients 
Cohorts 2 and 3 are displayed separately although belonging to the same dose group. 


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Section 7.3.4 of the CTP:  
For BI 836880, the residual effect period (REP) after IVT administration is not known. 
Therefore, all AEs with an onset between start of treatment and the respective EOT visit will 
be assigned to the on-treatment period for evaluation.  
Thus, no follow-up period is considered in this trial. The following separate study phases will 
be defined for the analyses of AEs: 

Screening (ranging from 0:00h (midnight) on the day of informed consent until the 
first administration time of BI 836880) 

On treatment
o
BI treatment (separately for each treatment, ranging from the time of first 
administration of BI 836880 until 0:00h (midnight) on the day after trial 
completion date) – labelled with the short labels defined in tables above 
The following AE displays will be provided in the report: 
Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT) of the CTR 
displays: 
In these displays, the on-treatment phase will be analysed (labelled with the short label of the 
study treatment - the actual treatment is equal to the study treatment). Screening will not be 
included in this analysis. In Section 15.3, a total overall, on treatment phases included in this 
analysis ("Total") will be provided in addition.  
In Section 15.4 and Appendix 16.2 (Listings) of the CTR displays, the screening period will 
be included, and no totals will be provided. 
Tables of vital signs and laboratory values will present results for the above mentioned on 
treatment phase. 
For detailed information on the handling of the treatments refer to the Technical TSAP ADS 
(analysis data set) plan and the Analysis Data Reviewers guide.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Important PDs will be reviewed at Medical Quality Review Meetings (MQRM) and/or TOM
conducted periodically during the trial. 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)" (10).
Section 7.3 of the CTP: Important protocol deviations (iPDs) will be defined in the 
Integrated Quality and Risk Management (IQRM) plan.
Categories which are considered to be iPDs in this trial were defined in the integrated quality 
and risk management plan (IQRMP) prior to trial initiation. The iPD list was transferred into 
the iPD specification file (due to changes in the SOP). Within this transfer some minor 
adaptations were made to comply with new naming conventions and categorizations. 


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IPDs will be identified no later than in the Report Planning Meeting, and the iPD categories 
will be updated as needed.
If any iPDs are identified, they are to be summarized into categories and will be captured in 
the decision log (16) and/or via iPD specification file (sdtm-dv-domain-specification) (12). 
Both documents will be stored within the TMF in EDMS.
The iPDs will be summarised and listed. 
Table 6.2: 1 Important Protocol Deviations 
Category 
/ Code
Description
Comment
Excluded 
from
A
Eligibility Criteria
A1
Eligibility Criteria
Critical inclusion/exclusion criteria 
violated
No analysis 
sets
A2
Eligibility Criteria
Withdrawal criteria as defined in 
the protocol met, but subject was 
not withdrawn
No analysis 
sets
B
Informed Consent
B1
Informed Consent
Required Informed Consent not 
available/not done
All 
analysis 
sets
B2
Informed Consent
Informed consent given late
No analysis 
sets
C
Trial Medication and 
Randomization
C1
Trial Medication and 
Randomization
Incorrect dose injected
ERS
C2
Trial Medication and 
Randomization
Treatment out of protocol defined 
window
ERS
D
Concomitant Medication
D1
Concomitant Medication
Improper medication washout
ERS
D2
Concomitant Medication
Prohibited medication use
ERS
E
Critical Study 
Procedure/Assessment
E2
Critical Study 
Procedure/Assessment
OCT assessment out of window  
ERS
F
Safety Procedures/SAE Reporting


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Category 
/ Code
Description
Comment
Excluded 
from
F1
Safety Procedures/SAE Reporting
Critical safety procedure not 
followed
No analysis 
sets
G
Privacy/Data Protection
G1
Privacy/Data Protection
Privacy and/or data protection 
violated
No analysis 
sets
Q
Non-important COVID-19 Related
Q1
Non-important COVID-19 Related
Missed examination
No analysis 
sets
Q2
Non-important COVID-19 Related
Missed visit
No analysis 
sets
Q3
Non-important COVID-19 Related
Drug shipment
No analysis 
sets
6.3
INTERCURRENT EVENTS
This section is not applicable.
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)
The TS will consist of all patients who were treated with at least one dose of BI 836880.
Full Analysis Set (FAS; only MRD part)
The FAS will consist of all patients who were treated with at least one dose of BI 836880 and 
have baseline and on-treatment CSFT measurements for the study eye in the time interval 
from drug administration to week 12. It will be used for the analysis of CSFT (change and 
percent change) only.
Evaluable Responders’ Set (ERS, MRD cohort 3 only):
The ERS will consist of all patients who completed three doses of BI 836880 and have SD-
OCT measurements at Week 16 (Visit 6) and haven’t received SoC or any prohibited 
medication through week 16.
Patients with iPDs related to efficacy assessments that are expected to majorly affect the 
validity of assessment of efficacy at week 16 will be excluded from ERS. These include for 


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e.g., lack of compliance (including missed treatments, treatment misallocation and
treatment/OCT assessment outside window), missing data, SoC or any prohibited medication, 
improper assessment at reading center and deviation from inclusion/exclusion criteria.
Any dropouts or withdrawals prior to completion of three doses of BI 836880 will be 
considered as a criterion of exclusion from ERS. In addition, any dropouts or withdrawals 
after completion of three doses of BI 836880 will also be excluded from ERS, unless SD-
OCT measurements are available for that patient at Week 16.
Pharmacokinetic parameter analysis set (PKS):
This set includes all subjects in the treated set (TS)
-
who received at least one dose of the test product BI 836880 and
-
who provide at least one PK endpoint that was not excluded due to a protocol 
deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, 
a subject will be included in the PKS, even if he contributes only one PK 
parameter value for one period to the statistical assessment.
Descriptive and model-based analyses of PK parameters will be based on the PKS.
Table 6.4: 1 Subject sets analyzed
Class of endpoint
ES
TS
FAS
ERS
PKS
Primary endpoints 
X
Analysis of CSFT (percent) 
change from baseline – MRD part 
only
X
Other secondary and further 
endpoints 
X
Responder analysis
X
Safety parameter
X
Demographic/baseline parameter
X
Important protocol deviations
X
Disposition/Disclosure 
(enrolment)
X
PK, ADA and PD analysis
X


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in CTP, Section 7.5.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
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.
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
Section 7.5 of the CTP: Missing baseline laboratory values will be imputed by the respective 
values from the screening visit.


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6.7 BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before first administration of BI 836880
(= value at V2, in case no actual time is given in data). 
Section 5.1 of the CTP: For the endpoints, baseline is defined as the value at Visit 2; if not 
measured at Visit 2 then baseline is the value at Visit 1.
The acceptable time windows for visits are given in the CTP Flow Chart.
Adherence to time windows will be checked via the consistency check listings at the 
MQRM/RPM/DBLM.
To utilize all available data, including values collected between protocol-specified visit 
windows and unscheduled visits, time intervals will be defined for analysis of efficacy data. If 
multiple values are recorded within a visit interval, the value collected closest to the planned 
visit date will be included in analyses of efficacy endpoints (CSFT, BCVA, and responder 
analysis) and IOP. 
Unscheduled measurements of laboratory data and vital signs data will be assumed to be 
repeat measurements of the most recent scheduled measurement (e.g. for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement.  
Table 6.7: 1 Visit intervals for efficacy endpoints (CSFT, BCVA, responder analysis) and IOP 
Interval Definition 
Visit
Planned 
day
From (day)
To (day)
Visit description
1
-28 to -3
NA
-1
Screening
2
1
1
1
Baseline
3
29
2
43
Week 4
4
57
44
71
Week 8
5
85
72
99
Week 12
6
113
100
127
Week 16
7
141
128
155
Week 20
8
169
156
Last assessment date
Week 24


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7.
PLANNED ANALYSIS
If not stated otherwise, the SRD part and the MRD part will be analyzed separately. The 
MRD part consists of three cohorts which will be shown in one table, except for the tables 
based on ERS which is defined for Cohort 3 only.
Safety analysis (refer to Section 7.8) will be performed by
and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
The prior specified in the CTP, Section 7.1 will be used in all BLRM evaluations.
Descriptive data analysis of PK parameters and concentrations will be performed by the 
and will be 
presented in Section 15.6 of the CTR and Appendix 16.1.13.5.
Descriptive data analysis of biomarker/PD parameters and concentrations will be performed 
by the 
and will 
be presented in Section 15.7 of the CTR and Appendix 16.1.13.6.
Descriptive data analysis of ADA results will be performed by the 
 and will be presented in Section 15.8 of 
the CTR and Appendix 16.1.13.7.
The format of the listings and tables will follow the BI standards (see BI-KMED-BDS-HTG-
0045) (6) except for those generated for PK-calculations following BI standards for PK/PD 
analysis (5).
The individual values of all patients will be listed, sorted by dose group, cohort (MRD part 
only), patient number, and visit. 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations as well as for all PK parameter, the following descriptive statistics 
will additionally be calculated:
Nobs 
number of observations
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation


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P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
Section 7.3.5 of the CTP:
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. The descriptive statistics of pharmacokinetic 
parameters will be calculated using the individual values with the number of decimal places 
as provided by the evaluation program. Then the individual values as well as the descriptive 
statistics will be reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories available in 
the CRF and will display the number of observations in a category, as well as the percentage 
(%) for each dose group. Percentages will be rounded to one decimal place and will be based 
on all patients in the respective subject set whether they have non-missing values or not. The 
category 'missing' will be displayed only if there are missing values.
Units of variables should be given in the titles or column/row descriptors in round brackets 
(e.g. (mg)).
Exclusion of PK parameters
The ADS ADPP (PK parameters) contains column variables APEX and APEXCO indicating 
inclusion/exclusion (APEX) of a PK parameter and an analysis flag comment (APEXCO). All 
analyses based on the PKS will include parameters if they are not flagged for exclusion that is 
APEX is equal to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEX or ACEXCO indicating inclusion/exclusion (ACEX) of a concentration and 
an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the analysis 
flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value will be 
excluded for all types of analyses based on concentrations. If ACEXCO is set to ‘DESC 
STATS’, the value will be excluded from descriptive evaluations per planned time point/time 
interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME DEVIATION’, 
the value can be used for further analyses based on actual times. If ACEXCO is set to ‘HALF 
LIFE’, the value will be excluded from half-life calculation (and, consequently, any 
calculation that relies on λz) only; the value is included for all other analyses.
Further details are given in 001-MCS-36-472 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (9).


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS. 
The data will be summarized by dose group/cohort and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the latest version of the coding system of the 
Medical Dictionary for Drug Regulatory Activities (MedDRA). Medications will be coded 
using the World Health Organization Drug Dictionary (WHO-DD). The coding version 
number will be displayed as a footnote in the respective output.
The diagnoses and medications will be listed. Patients without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
Previous and concomitant therapies will be presented per dose group/cohort without 
consideration of time intervals and treatment periods. In addition, the rescue medication will 
be presented separately for MRD part.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP:
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured sample concentrations 
will provide additional confirmation of compliance.
It is not intended to list the compliance separately. Exposure table/listing would quantify 
whether administration per dose was as per the protocol or not, to indicate any potential 
compliance issues. Any deviations from complete intake will be addressed in the MQRM/ 
RPM/DBLM and described in the CTR.
7.4
PRIMARY OBJECTIVE ANALYSIS
7.4.1
Main analysis 
Section 5.2.1 of the CTP:
For the SRD part and MRD cohort 1:
A DLE is defined as the occurrence of any of the following events in the study eye:

Development of sterile endophthalmitis and/or sterile inflammation of the vitreous 
grade 4+ according to standardization of Uveitis Nomenclature (SUN) working group 
(WG) grading scheme for anterior chamber cells (see CTP) 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


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
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).
[…]
DLE criteria are not applicable to MRD cohorts 2 and 3. Should an event involving
intraocular inflammation/signs of vascular occlusion, decreases in visual acuity, and/or
intraocular pressure occur, the event should only be reported as an AESI as described in CTP
Section 5.2.8.1, and not as a DLE.
Section 7.3.1 of the CTP:
SRD part:
The primary safety endpoint “Number of patients with ocular DLEs from drug administration 
till EOT” will be analysed descriptively, based on the TS.
[…]
MRD part:
The primary safety endpoint “Number of patients with drug related AEs from drug
administration till EOT” will be analysed descriptively, based on the TS.
Descriptive statistics will be provided by dose group/cohort and in total (more details 
regarding the analysis of AEs are described in Section 7.8.1).
7.4.4
Supplementary analysis
No supplementary analysis is planned.


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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 7.3.2 of the CTP:
In principle, all secondary endpoints specified in Section 5.2.2 will be analyzed descriptively, 
based on the TS. The analysis of percent change from baseline in CSFT in the study eye at 
week 12 (Visit 5) will be done by dose, based on the FAS.
Descriptive statistics for absolute values as well as changes from baseline (percent changes 
and changes in CSFT and changes in BCVA (study eye)) will be provided by dose 
group/cohort and in total. Time profiles of mean (±SD) absolute values and mean (±SD) 
changes from baseline by cohort as well as individual time profiles (absolute values and 
changes from baseline) per treatment group/cohort will be provided. For percent changes of 
CSFT, median and minimum/maximum values will be shown instead.
For those endpoints related to adverse events refer to Section 7.8.1.
Section 5.2.2 of the CTP:
Time to recurrence will be assessed in the MRD part, based on the TS, from last trial drug 
administration to occurrence of any of the following in the study eye, leading to the use of 
wAMD rescue medication as decided by the investigator:

Increase in CSFT ≥ 75 μm with a decrease in BCVA of ≥ 5 letters compared to Visit 5,
OR

Decrease in BCVA of > 5 letters compared to baseline (Visit 2), due to worsening 
wAMD activity,
OR

Decrease in BCVA of ≥ 10 letters compared to the best prior BCVA, due to worsening 
wAMD activity
From above criteria, if Visit 5 BCVA/CSFT assessment data is missing, BCVA/CSFT values 
available earlier than Visit 5 will be used. The last trial drug administration is strictly referring 
to the third injection, if a patient doesn’t complete three injections, the patient will not be 
evaluated for time to recurrence endpoint and will be censored as per Table 7.5.2:1. The 
details of censoring rules are listed in the table below. Kaplan-Meier curves will be estimated 
by cohort.


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Table 7.5.2: 1 Censoring Rules for time to recurrence
No.
Scenario
Relative Day of Event or Censoring
Outcome
1
A patient meets more 
than one recurrence 
rule
Earliest day of recurrence
Event 
(Recurrence)
2
A patient completed 
the treatment and 
follow-up without 
recurrence
Last day of follow-up
Censored
3.
SAE after completion 
of three injection
Day of SAE
Censored
4.
Treatment 
discontinuation (not 
completing all three 
injections)
Time to censoring value is assigned to 
1 (day 1 = the first day after last 
injection)
Censored
 
 
 
 
 
 
 
 
 
 
 
 


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7.6.2
Pharmacokinetic/Pharmacodynamic endpoints
Descriptive statistics of plasma concentrations, ADA, PK and PD endpoints will be done by 
 
 and will be presented in 
Section 15.6,15.7 and 15.8 of the CTR.


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The analysis of PK & PD parameters as well as the tables and graphs for the pharmacokinetic 
non-compartmental analyses will follow specific definitions of this TSAP or, otherwise, the 
BI standard procedure “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics” [001-MCS-36-472] (4).
7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each patient.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
If not stated otherwise, the safety results will be sorted by dose group/cohort.
The safety data for treated patients who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1 Adverse Events
AEs will be coded with the most recent version of MedDRA. The version to be used will be
specified in RPM and will be displayed as a footnote in the respective output.
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in “Analysis and Presentation of Adverse Event Data from Clinical Trials – Display 
Template” [BI-KMED-BDS-HTG-0041] (7) and [BI-KMED-BDS-HTG-0066] (2).
All analyses of AEs will be based on the number of subjects with AEs and not on the number 
of AEs.
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs occurring between start of treatment and the EOT visit will be assigned to the 
respective treatment. All AEs occurring before first drug intake will be assigned to 
‘screening’. For details on the treatment definition, see Section 6.1.
Section 5.2.8.1.4 of the CTP:
All AEs meeting the criteria for a dose limiting event as defined in Section 7.4.1 are defined 
as AESIs for SRD and MRD cohort 1. 
For MRD cohorts 2 and 3, the AESIs are defined as following:
Ocular related events (applicable to MRD cohorts 2 & 3)

Intraocular inflammation events
o
Anterior chamber cells of grade 1+ according to the Standardization of 
Uveitis Nomenclature (SUN) working group (WG) grading scheme (see CTP
Table 5.2.1: 1)


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o
Sterile inflammation of the vitreous of 1+ according to the NEI Grading of 
vitreous haze (see CTP Table 5.2.8.1.4: 1)

Signs of vascular occlusion and inflammation (vasculitis) in the retina, including 
peripheral retinal hemorrhages in the area supplied by the occluded vessel 
(hemorrhage of the macula would not be included as this is a sign of wAMD disease)

Visual acuity decrease of more than 15 letters from the previous visit

Persistent IOP over 30 mmHg for 3 days after study treatment is administered, despite 
rescue treatment
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin≥2-fold ULN measured in the same blood draw sample, and/or

aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the eDC
system.
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.
According to ICH E3 (15), in addition to Deaths and serious adverse events, AEs classified as 
‘other significant’ 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 (including number of patients with any AE, DLEs (applicable for 
SRD part and MRD part cohort 1 only), drug related AEs, procedure related AEs, ocular AEs, 
AESIs, serious AEs and drug related serious AEs) will be presented.
The frequency of patients with AEs will be summarized by treatment group/cohort, primary 
system organ class (SOC) and preferred term (PT). Separate tables will be provided for 
patients with ocular AEs, for patients with DLEs, for patients with serious AEs, for patients 
with drug-related AEs, for patients with drug-related serious adverse events, for patients with 
AESIs, for patients with drug-related AESIs and for patients with study procedure related 
AEs. In addition, the frequency of patients with AEs will be summarized by worst intensity, 
treatment group/cohort, SOC and PT.
The system organ classes will be sorted alphabetically, PTs will be sorted by frequency 
(within SOC). 
In addition, frequencies of patients with non-serious AEs that have an incidence of > 5% for 
at least one treatment will be summarised by treatment, primary SOC and PT (both trial parts 
combined).


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For disclosure of adverse events on EudraCT the following three entries will be created, 
combined for both trial parts:

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] (8).
Descriptive statistics of laboratory data including change from baseline will be calculated by 
visit based on the worst value of the patient at that visit (Or assigned to that visit / planned 
time point).
Additionally, laboratory data will be analysed qualitatively via comparison of laboratory data 
to their reference ranges. Values outside the reference range as well as values defined as 
possible clinically significant will be flagged in the data listings. Dose groups will be 
compared descriptively with regards to distribution parameters as well as with regards to 
frequency and percentage of patients with abnormal values or possibly clinically relevant 
abnormal values.
Clinically relevant findings in laboratory data will be reported as adverse events if judged 
clinically relevant by the investigator and will be analyzed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significant 
abnormal or not (at the RPM/DBLM at the latest).
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure, pulse rate). In the vital signs listing, the difference from baseline will 
also be displayed.
For post-dose measurements of vital signs, descriptive statistics will be calculated by planned 
time point based on the first value of the subject at that planned time point (or assigned to that 
planned time point). For baseline value, the last measurement before drug administration will 
be used.
Body weight will be listed only. 
Clinically relevant findings in vital signs as judged by the investigator will be reported as 
AEs.


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7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under ‘Relevant Medical History / Baseline 
Conditions’ or as AEs (if they occurred during treatment) and will be analyzed as such.
Categorical endpoints will also include morphological findings that might be attributable to 
treatment. In particular, new onsets of findings not present at baseline will be explored. A 
morphological finding observed on treatment that was not reported at baseline will be 
categorized as a ‘new onset’ of this finding.
7.9
OTHER ANALYSIS
Ophthalmological data
All the following endpoints will be listed and will be analyzed descriptively by dose 
group/cohort and in total.

The results of the IOP measurements as well as the corresponding changes from 
baseline at each time point for the study eye and the fellow eye (time profiles will be 
provided as well)

The results of the BCVA measurements as well as the corresponding changes from 
baseline at each time point for the study eye and the fellow eye (time profiles will be 
provided as well)

The results of the SUN grading for Anterior Chamber Cells (slit lamp) will be 
analyzed descriptively at each time point by number and percentages for the study eye 
and the fellow eye. (If no entries unequal 0/not evaluable are available, a listing will 
be sufficient.)
The following parameters will be listed only:

Other results of the Slit Lamp examination (categories defined in CRF: regarding 
eyelid, conjunctiva, cornea, anterior chamber cells, anterior chamber flare, hypopyon, 
iris, lens status, lens opacity, posterior capsule status, vitreous chamber cells, vitreous 
chamber flare, posterior vitreous detachment, optic disc, retinal tear, retinal 
detachment).

Color fundus photography (gradeability (yes/no), overall quality (good, fair, poor),
vitreous haze, additional CFP findings)

Categorical assessments from OCT (gradeability (yes/no), scans to be analysed (25 
line scan, 49 line scan, both), overall quality (good, fair, poor), CNV presence 
(present, absent), if present only: type of CNV, CNV involvement of the foveal center, 
IRF within the central 6mm of the macula (present, absent), , GA presence (present, 
absent), drusen (present, absent), PED (present, absent), of present only: type of PED, 
outer retinal tabulation (present, absent),correction of segmentation lines (yes, no), if 
yes only: level of segmentation, additional findings

Categorical and other assessments from OCT-A (gradability (yes/no), type of device 
used, overall quality (good, fair, poor), vessel flow density (Deep Capillary Plexus (% 
of area): foveal, parafoveal-superior, parafoveal-nasal, parafoveal-inferior, parafoveal-


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temporal, perifoveal-superior, perifoveal-nasal, perifoveal-inferior, perifoveal-
temporal, presence of CNV (present, absent), if present only: location of CNV (DCP, 
outer retina, choroid, DCP+outer retina, outer retina+choroid, DCP+outer 
retina+choroid), additional findings)
7.9.1
Biomarker analyses
Not applicable.
7.9.2
PK / PD analyses
Covered in Section 7.6.2.


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8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION
Not applicable due to open label handling of the trial as described in CTP section 4.1.6.1.


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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-KMED-BDS-HTG-0066: “Analysis and Presentation of AE data from clinical 
trials”, current version, KMED.
3.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, 
current version; KMED.
4.
001-MCS-36-472: “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics”, current version; KMED.
5.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; KMED.
6.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project
Summaries”, current version; KMED.
7.
BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from
Clinical Trials – Display Template”, current version; KMED.
8.
BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”,
current version; KMED.
9.
BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; KMED.
10.
001-MCS-40-413: Identify and Manage Important Protocol Deviations (iPD)”, 
current version, Group “Clinical Operations”, IDEA for CON.
11.
BI-KMED-BDS-QRC-0065: “Transition Plan for Implementing Protocol Deviation 
Process for Clinical Trials”, template, current version, KMED.
12.
BI-KMED-BDS-TMP-0059: “iPD specification document (sdtm-dv-domain-
specification)”, template, current version, KMED.
13.
BI-KMED-BDS-TMP-0083: “iPD for Reconciliation”, template, current version, 
KMED.
14.
001-MCS-40-135_RD-01: “Integrated Quality and Risk Management Plan”, current 
version, Group “Clinical Operations”, IDEA for CON.
15.
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.
16.
001-MCS-50-415_RD-03: “Clinical Trial Analysis Decision Log (template) 
Decision Log”, current version, Group “Biostatistics & Data Sciences”, IDEA for 
CON.


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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
07-DEC-2023
None
This is the final TSAP.
12JAN2024: Correction of 
version date in history table
2.0
02-FEB-2024
None
1. Changes requested by 
publishing check: 
a.
Update the 
document 
number from 
“c31147466-01”
to “c31147466-
02”.
b. Correct the table 
number on page 
23 to “Table 
7.5.2:1”.
c.
Remove extra 
space between 
table number and 
title for Table 
7.5.2:1 and 
6.7:1.
2. Change in History table.