Clinical trial NCT04002310
Conditions: Macular Degeneration
Sponsor: Boehringer Ingelheim
Start date: 2019-07-26; Completion date: 2022-08-09
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a study in adults with geographic atrophy, an advanced form of age-related macular degeneration. The purpose of this study is to find out how well different doses of BI 754132 are tolerated.

The participants are in the study for about 4 months. During this time, they visit the study site about 10 times. Participants receive 1 injection of BI 754132 directly into one of the eyes affected by geographic atrophy. In this study, BI 754132 is given to humans for the first time.

The doctors compare how well participants tolerate the different doses of BI 754132. The doctors also regularly check the general health of the participants.

Detailed description:

Arms: arm 1: 0.3 milligram (mg) BI 754132 powder for solution for injection 60mg/vial with solution of diluent was administered intravitreally as one single injection on Day 1. One patient was dosed first, and when the safety assessments through Day 4 showed no ophthalmological dose limiting events (DLEs) or systemic DLEs, the remaining patients were dosed. Single rising dose (SRD) part. arm 2: 1 mg BI 754132 powder for solution for injection 60mg/vial with solution of diluent was administered intravitreally as one single injection on Day 1. One patient was dosed first, and when the safety assessments through Day 4 showed no ophthalmological dose limiting events (DLEs) or systemic DLEs, the remaining patients were dosed. SRD part. arm 3: 3 mg BI 754132 powder for solution for injection 60mg/vial with solution of diluent was administered intravitreally as one single injection on Day 1. One patient was dosed first, and when the safety assessments through Day 4 showed no ophthalmological dose limiting events (DLEs) or systemic DLEs, the remaining patients were dosed. SRD part. arm 4: 6 mg BI 754132 powder for solution for injection 60mg/vial with solution of diluent was administered intravitreally as one single injection on Day 1. One patient was dosed first, and when the safety assessments through Day 4 showed no ophthalmological dose limiting events (DLEs) or systemic DLEs, the remaining patients were dosed. SRD part. arm 5: 6 mg BI 754132 powder for solution for injection 60mg/vial with solution of diluent was administered intravitreally as 3 injections, each separated by 4 weeks (that is, Day 1, Day 29 and Day 57). Multiple dose.
Interventions: intervention 1: BI 754132
Intervention descriptions: intervention 1: One single injection

Protocol documents:
Prot_000.pdf: 


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer-Ingelheim 
Protocol date
19 Mar 2019
Revision date
17 Feb 2022
BI trial number
1418-0001
Title of trial
Safety, tolerability and pharmacokinetics of single rising intravitreal 
doses and multiple intravitreal dosing of BI 754132 in patients with 
geographic atrophy secondary to age-related macular degeneration 
(open label, non-randomized, uncontrolled).
Coordinating 
Investigator
Trial site(s)
Multi-centre trial
Clinical phase
I
Trial rationale
Currently, there are no approved or effective treatments to prevent 
either onset or progression of GA. Both published data as well as in-
house preclinical studies showed that TrkB activation can protect 
photoreceptors in animal models of diabetes, retinal ischemia as well 
as the blue light-induced photoreceptor degeneration model. 
Therefore, stimulating TrkB signaling in the eyes of patients with 
GA might protect photoreceptors from degenerating thereby 
counteracting the loss of vision.
Trial objective(s)
To investigate the safety, tolerability and pharmacokinetics of single 
intravitreal doses and multiple intravitreal dosing of BI 754132
Trial endpoints
Primary endpoints:
SRD Part:
•
Number of patients with ocular (in the study eye) and systemic
dose limiting events (DLEs) from drug administration until end 
of trial (EOT)
MD part:
•
Number of patients with drug-related adverse events (AEs) from 
drug administration until EOT
Secondary endpoints:
SRD part:
•
Number of patients with drug-related adverse events from drug 
administration until EOT
•
Number of patients with any ocular adverse events in the study 
eye from drug administration until EOT
•
Cmax (maximum serum concentration of BI 754132 after a single 
intravitreal dose)


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•
AUC0-∞(area under the concentration-time curve of BI 754132 
in serum over the time interval from 0 extrapolated to infinity)
•
tmax (time from dosing to maximum serum concentration of 
BI 754132)
MD part:
•
Systemic exposure of BI 754132 after multiple IVT dosing by 
determination of Cmin,1 and Cmin,2 (trough levels before second 
and third administrations) and plasma concentrations 4, 8 and 14 
weeks after the third administration 
Trial design
This trial will consist of an SRD part followed by an MD part. Both 
parts will be open label, uncontrolled and non-randomized.
Total number of patients 
entered
Up to 24 in total; 18 patients (planned 15 plus 3 additional if DLEs 
occur) in the SRD part and 6 patients in the MD part.
Number of patients on 
each treatment
Planned: 3 per dose group and 6 at final dose in SRD part (actual 
numbers depending on the dose escalation decisions taken by the 
Safety Monitoring Committee (SMC)) and 6 at the dose of the MD 
part
Diagnosis
Patients with geographic atrophy secondary to age-related macular
degeneration 
Main in- and exclusion 
criteria
Inclusion: Men and women over the age of 50 with GA lesion at 
least 0.75 disk area in size and a best corrected visual acuity 
(BCVA) of 20/100 to 20/400 (SRD part) and 20/100 or lower (MD 
part) Snellen equivalent measured by the Early Treatment Diabetic 
Retinopathy Study protocol.
Exclusion: Additional eye disease that could compromise BCVA.
Test product(s)
BI 754132
dose
SRD part: 4 dose groups, 0.3 mg, 1 mg, 3 mg, 6 mg (single doses)
MD part: The highest dose (e.g. 6 mg) established as safe and 
tolerable dose during the SRD part
mode of 
administration
Intravitreal
Duration of treatment
SRD part: Single intravitreal dose
MD part: 3 intravitreal doses in 4-weekly intervals (q4w)
Statistical methods
Descriptive statistics will be provided for all endpoints.
The dose escalation in the SRD part will be guided by a Bayesian 
logistic regression model (BLRM) with overdose control that will be 
fitted to binary toxicity outcomes. The estimates of parameters will 
be updated as data are accumulated using the BLRM.


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FLOW CHART I (SINGLE RISING DOSE PART)
Trial Periods
Screening 
Period
Treatment 
Visit
Follow-up period
End of 
trial
Visit
1
2
3
47
5
6
7
8
9
10
Study Days
-3
1
4
8
15
22
29
56
84
100
Time window for 
visits (days)
-286,10
none
±1
±1
±2
±2
±2
±4
±4
±7
Informed consent
X
Demographics
X
Medical history
X
Physical examination
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Laboratory tests
X
X
X
X
X
X
X
X
X
12 lead-ECG
X
X2
X2
X2
X2
X2
X2
Review of in-
/exclusion criteria
X
X
Dose Assignment
X
IVT drug 
administration
X
PK Sampling
X3
X
X
X
X
X
X
X
ADA Sampling
X
X
X
X
Pharmacogenomics 
biomarker
X4
Visual Acuity 
Testing8
X
X
X
X
X
X
X
X
X
X
Fundus 
autofluorescence9
X
X
X
X
X
X
X
X
SD-OCT9
X
X
X
X
X
X
X
X
X
X
OCT Angiography9
X
X
X
X
X
X
ERG8
X
X
X
X
X
Color Fundus 
Photography9
X
X5
X5
X5
X5
X5
X5
X5
X5
X
Slit lamp and IOP8
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
Completion of 
patient participation1
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).


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(2)
Triplicate resting ECGs (see Section 5.2.6). For time points with PK sampling, the ECGs are to be recorded shortly 
before PK sampling (see time schedule in Appendix 10.3).
(3)
PK sampling see time schedule in Appendix 10.3.
(4)
One DNA sample for analysis of pre-specified genes will be collected at visit 2 (see Section 5.4.2). If not possible at 
Visit 2 (Day 1), this sample may also be collected at a later visit.
(5)
Only to be done if considered medically necessary by the principal investigator
(6)
Rescreening of eligible patients, see Section 6.2.1.1.
(7)
End of observation period for DLE´s for dose escalation process (SMC).
(8)
Before pupil dilation; at PI´s discretion, IOPcan be repeated after pupil dilation and after IVT injection.
(9)
After pupil dilation. If fixation does not allow for acquisition of good quality images, the examination may be 
considered optional.
(10)
If the screening visit performed earlier than 14 days before dosing visit, an additional visit for repeating of safety lab, 
vital signs, ECG and targeted physical examination has to be performed again, see Section 6.2.1.1.


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FLOW CHART II (MULTIPLE DOSING PART)
Trial Periods
Screening 
Period
Treatment Period
Follow-up period
End of trial
Visit
1
2
3
4
5
6
7
Study Days/Week
Duration
-3 to -28 
days5,6
1
29
Week 4
57
Week 8
85
Week 12
113
Week 16
155
Week 22
Time window for visits
(days)
none
±3
±3
±7
±7
±7
Informed consent
X
Demographics
X
Medical history
X
Physical examination
X
X
X
Vital signs
X
X
X
X
X
X
X
Laboratory tests
X
X
X
X
X
X
X
12 lead-ECG
X
X2,3
X2,3
X2,3
X2
X2
Review of in-/exclusion 
criteria
X
X
Dose Assignment
X
IVT drug administration
X
X
X
PK Sampling
X3
X3
X3
X
X
X
ADA Sampling
X3
X
X
Pharmacogenomics 
biomarker 
X4
Visual Acuity Testing7
X
X
X
X
X
X
X
Fundus autofluorescence9
X
X
X
X
X
X
X
SD-OCT9
X
X
X
X
X
X
X
OCT Angiography9
X
X
X
X
X
X
ERG7
X
X
X
X
Color Fundus Photography9
X
X
X
X
X
X
X
Slit lamp7, IOP7,8 and 
indirect ophthalmoscopy9
X
X
X
X
X
X
X
Post-injection 
assessments10
X
X
X
Adverse events
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
Completion of patient
participation1
X


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(1)
Completion of patient participation also needs to be completed if the patient withdraws prematurely following 
assignment to dose (see Section 3.3.4).
(2)
Triplicate resting ECGs (see Section 5.2.6). For time points with PK sampling, the ECGs are to be recorded shortly 
before PK sampling.
(3)
PK and ADA sampling as well as ECG measurement must be performed within 4 hours prior to the IVT drug 
administration, and each sampling and measurement timepoint has to be entered in the eCRF.
(4)
One DNA sample for analysis of pre-specified genes will be collected at visit 2 (see Section 5.4.2). If not possible at
Visit 2 (Day 1), this sample may also be collected at a later visit.
(5)
Rescreening of eligible patients, see Section 6.2.2.1.
(6)
If the screening visit performed earlier than 14 days before dosing visit, an additional visit for repeating of safety lab, 
vital signs, ECG and targeted physical examination has to be performed again, see Section 6.2.2.1.
(7)
Before pupil dilation.
(8)
IOP must be repeated 30 to 50 minutes after IVT injection at Visit 2, 3 and 4.
(9)
After pupil dilation. 
(10)
For details of post-injection assessments, see Section 6.2.2.2.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART I (SINGLE RISING DOSE PART)............................................................4
FLOW CHART II (MULTIPLE DOSING PART)..............................................................6
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................16
1.1
MEDICAL BACKGROUND.............................................................................16
1.2
DRUG PROFILE................................................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................20
1.4
BENEFIT - RISK ASSESSMENT.....................................................................21
1.4.1
Benefits.................................................................................................................21
1.4.2
Risks .....................................................................................................................21
1.4.2.1
Available clinical data on the MoA ......................................................................21
1.4.2.1.1
Trials evaluating native ligand (BDNF)................................................................21
1.4.2.1.2
Trials evaluating agonist antibodies targeting TrkB.............................................22
1.4.2.2
Available data from pre-clinical toxicity studies ..................................................22
1.4.2.2.1
IV administration of BI 754132............................................................................22
1.4.2.2.2
IVT administration of BI 754132..........................................................................22
1.4.2.2.3
Immunogenetic response in pre-clinical studies...................................................22
1.4.2.3
Risks related to intravitreal injection ....................................................................23
1.4.2.4
Risks related to blood sampling............................................................................23
1.4.2.5
Risks related to BI 754132 based on human clinical data ....................................23
1.4.2.6
Planned measures for monitoring and minimization the risks..............................24
1.4.2.7
Drug induced liver injury......................................................................................25
1.4.3
Discussion.............................................................................................................25
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................27
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........27
2.1.1
Main objectives....................................................................................................27
2.1.2
Primary endpoint(s)............................................................................................27
2.1.3
Secondary endpoint(s) ........................................................................................27
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................29
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................31
3.3
SELECTION OF TRIAL POPULATION .......................................................32
3.3.1
Main diagnosis for trial entry ............................................................................32


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3.3.2
Inclusion criteria .................................................................................................32
3.3.3
Exclusion criteria ................................................................................................33
3.3.4
Withdrawal of patients from treatment or assessments..................................34
3.3.4.1
Withdrawal from trial treatment ...........................................................................34
3.3.4.2
Withdrawal of consent to trial participation .........................................................35
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................35
3.3.5
Replacement of patients......................................................................................35
4.
TREATMENTS...................................................................................................37
4.1
INVESTIGATIONAL TREATMENTS ...........................................................37
4.1.1
Identity of the Investigational Medicinal Products..........................................37
4.1.2
Selection of doses in the trial and dose modifications......................................37
4.1.3
Method of assigning patients to treatment groups...........................................39
4.1.4
Drug assignment and administration of doses for each patient......................39
4.1.5
Blinding and procedures for unblinding...........................................................40
4.1.5.1
Blinding.................................................................................................................40
4.1.5.2
Unblinding and breaking the code ........................................................................41
4.1.6
Packaging, labelling, and re-supply...................................................................41
4.1.7
Storage conditions...............................................................................................41
4.1.8
Drug accountability.............................................................................................41
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................42
4.2.1
Other treatments and emergency procedures..................................................42
4.2.2
Restrictions ..........................................................................................................42
4.2.2.1
Restrictions regarding concomitant treatment ......................................................42
4.2.2.2
Restrictions on diet and life style..........................................................................42
4.2.2.3
Contraception requirements..................................................................................42
4.3
TREATMENT COMPLIANCE........................................................................43
5.
ASSESSMENTS..................................................................................................44
5.1
ASSESSMENT OF EFFICACY........................................................................44
5.2
ASSESSMENT OF SAFETY.............................................................................44
5.2.1
Dose limiting event..............................................................................................44
5.2.2
Physical examination ..........................................................................................45
5.2.3
Vital signs.............................................................................................................45
5.2.4
Ophthalmological examinations ........................................................................45
5.2.5
Safety laboratory parameters ............................................................................46
5.2.6
Electrocardiogram ..............................................................................................48
5.2.7
Other safety parameters.....................................................................................50
5.2.8
Assessment of adverse events.............................................................................50
5.2.8.1
Definitions of AEs ................................................................................................50
5.2.8.1.1
Adverse event........................................................................................................50
5.2.8.1.2
Serious adverse event............................................................................................50
5.2.8.1.3
AEs considered “Always Serious”........................................................................51
5.2.8.1.4
Adverse events of special interest.........................................................................51
5.2.8.1.5
Intensity (severity) of AEs....................................................................................51
5.2.8.1.6
Causal relationship of AEs....................................................................................52


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5.2.8.2
Adverse event collection and reporting ................................................................52
5.2.8.2.1
AE Collection........................................................................................................52
5.2.8.2.2
AE reporting to the sponsor and timelines............................................................53
5.2.8.2.3
Pregnancy..............................................................................................................53
5.2.8.2.4
Exemptions to SAE reporting ...............................................................................53
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................54
5.3.1
Assessment of pharmacokinetics .......................................................................54
5.3.2
Methods of sample collection .............................................................................54
5.3.2.1
Sampling for pharmacokinetic analysis ................................................................54
5.3.2.2
Sampling for ADA assessment .............................................................................54
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................55
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................55
5.4.1
ERG as physiological response biomarker.......................................................55
5.4.2
Biochemical and cellular biomarkers................................................................55
5.4.3
Pharmacogenomics biomarkers.........................................................................56
5.5
BIOBANKING ....................................................................................................56
5.6
OTHER ASSESSMENTS...................................................................................56
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................56
6.
INVESTIGATIONAL PLAN.............................................................................57
6.1
VISIT SCHEDULE.............................................................................................57
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................57
6.2.1
Single Rising Dose Part.......................................................................................57
6.2.1.1
Screening and run-in period(s) of SRD part .........................................................57
6.2.1.2
Treatment period(s) of SRD part ..........................................................................58
6.2.1.3
Follow-up period and trial completion of SRD part .............................................58
6.2.2
Multiple Dosing Part...........................................................................................59
6.2.2.1
Screening and run-in period(s) of MD part...........................................................59
6.2.2.2
Treatment period(s) of MD part............................................................................59
6.2.2.3
Follow-up period and trial completion of MD part...............................................60
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................61
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................61
7.2
PLANNED ANALYSES.....................................................................................61
7.2.1
General considerations .......................................................................................61
7.2.1.1
Dose escalation in the SRD part ...........................................................................61
7.2.1.2
Subject analysis sets..............................................................................................64
7.2.2
Primary endpoint analyses.................................................................................65
7.2.3
Secondary endpoint analyses .............................................................................65
7.2.5
Safety analyses.....................................................................................................65
7.2.6
Other Analyses ....................................................................................................66
7.2.7
Interim Analyses .................................................................................................66
7.3
HANDLING OF MISSING DATA ...................................................................67


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7.4
RANDOMISATION ...........................................................................................67
7.5
DETERMINATION OF SAMPLE SIZE .........................................................67
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........68
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................68
8.2
DATA QUALITY ASSURANCE ......................................................................69
8.3
RECORDS...........................................................................................................69
8.3.1
Source documents ...............................................................................................69
8.3.2
Direct access to source data and documents.....................................................70
8.3.3
Storage period of records ...................................................................................71
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................71
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........71
8.6
TRIAL MILESTONES.......................................................................................71
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................72
9.
REFERENCES....................................................................................................74
9.1
PUBLISHED REFERENCES............................................................................74
9.2
UNPUBLISHED REFERENCES......................................................................76
10.
APPENDICES.....................................................................................................77
10.1
INSTRUCTIONS FOR USE..............................................................................77
10.2
PHARMACOKINETIC METHODS AND ANALYSES................................77
10.3
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.........................................................................................................78
10.4
STATISTICAL APPENDIX..............................................................................79
10.5
BENEFIT-RISK ASSESSMENT IN CONTEXT OF COVID-19 
PANDEMIC FOR PATIENTS PARTICIPATION IN TRIAL 1418-0001 
INVESTIGATING BI 754132............................................................................85
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................87
11.1
GLOBAL AMENDMENT 1 ..............................................................................87
11.2
GLOBAL AMENDMENT 2 ..............................................................................88
11.3
GLOBAL AMENDMENT 3 ..............................................................................88
11.4
GLOBAL AMENDMENT 4 ..............................................................................90
11.5
GLOBAL AMENDMENT 5 ..............................................................................93
11.6
GLOBAL AMENDMENT 6 ..............................................................................97


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ABBREVIATIONS
ADA
Anti-drug antibodies
ADCC
Antibody-dependent Cell-mediated Cytotoxicity
ADME
Absorption, Distribution, Metabolism and Elimination/Excretion
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate (dimensions 
of data integrity)
ALS
Amyotrophic Lateral Sclerosis
ALT
Alanine Aminotransferase
AMD
Age-related Macular Degeneration
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BCVA
Best Corrected Visual Acuity
BDNF
Brain-derived Neurotrophic Factor
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
CA
Competent Authority
CDC
Complement-Dependent Cytotoxicity
CFP
Color Fundus Photography
CNV
Choroidal Neovascularisation
Cmax
Maximum Concentration
CRA
Clinical Research Associate
CRC
Central Reading Center
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CRP
C reactive Protein
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
DLE
Dose Limiting Event


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DNA
Deoxyribonucleic Acid
EC
Ethics Committee
ECD
Extracellular Domain
ECG
Electrocardiogram
EEC
European Economic Community
eCRF
Electronic Case Report Form
EMA
European Medicines Agency
EOT
End of Trial
ERG
Electroretinography
ETDRS
Early Treatment Diabetic Retinopathy Scale
EU
European Union
EudraCT
European Clinical Trials Database
EWOC
Escalation With Overdose Control
FAF
Fundus Autofluorescence
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GA
Geographic Atrophy
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HA
Health Authority
HbA1c
Glycosylated haemoglobin
HCG
Chorionic Gonadotrophin
HR
Heart Rate
ICF
Informed Consent Form
IV
Intravenous
IVT
intravitreal
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medical Product
IOP
Intraocular Pressure
IQRM
Integrated Quality and Risk Management
iPDs
Important Protocol Deviations


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IRB
Institutional Review Board
ISF
Investigator Site File
ISO
International Organization for Standardization
IUS
Intrauterine Hormone-Releasing System
KD
Dissociation constant
LPLT
Last Patient Last Treatment
MD
Multiple Dosing
MedDRA
Medical Dictionary for Drug Regulatory Activities
MoA
Mode of Action
MTD
Maximum Tolerated Dose
∀g
Microgram (10-6 gram)
NBE
New Biological Entity
NOAEL
No Observed Adverse Effect Level
OCT
Optical Coherence Tomography
OCT-A
OCT Angiography
OPU
Operative Unit
PD
Pharmacodynamics
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter analysis set
P(OD)
Probability of over-dosing
PT
Prothrombin Time
P(TD)
Probability of target dosing
RPE
Retinal Pigment Epithelium
SAE
Serious Adverse Event
SD-OCT
Spectral Domain Optical Coherence Tomography
SMC
Safety Monitoring Committee
SOP
Standard Operating Procedure
SRD
Single Rising Dose
STZ
Streptozotocin
SUN
Standardization of Uveitis Nomenclature
SUSAR
Suspected Unexpected Serious Adverse Reactions
t1/2
Half Life Time
tmax
Timepoint of Maximum Plasma Concentration


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TMF
Trial Master File
TrkA
Tropomyosin-related Kinase Receptor Type A
TrkB
Tropomyosin-related Kinase Receptor Type B
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Level of Normal
VA
Visual Acuity
VEFG
Vascular Endothelial Growth Factor
WBC
White Blood Cells
WG
Working Group
WHO
World Health Organisation
WOCBP
Woman of childbearing potential
YAG
Yttrium Aluminium Granat


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1.
INTRODUCTION
Boehringer Ingelheim (BI) is planning to develop BI 754132, an agonistic humanized 
immunoglobulin G1 (IgG1) for the TrkB (tropomyosin-related kinase receptor type B) 
receptor. BI 754132 binds to the extracellular domain of TrkB and causes auto-
phosphorylation and induction of downstream signalling cascades, leading to increased glial 
cell and neuronal survival as well as potentially synaptogenesis, for treating geographic 
atrophy (GA) secondary to age-related macular degeneration (AMD).
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]. AMD is a medical 
condition which may result in blurred or no vision in the center of the visual field. It 
preferentially affects the central vision, which is needed for reading, driving, recognizing 
people’s faces and color vision.
Clinically, AMD is divided into dry and wet AMD. However, it is better to describe AMD as 
the early phase which is virtually asymptomatic, intermediate advanced phase with mild 
visual loss, which can then develop into geographic atrophy (GA) and / or neovascular (or 
wet) AMD. Highlighting the complexity of the disease, in some patients who are first 
diagnosed to have wet AMD and treated with anti-VEGF therapy, these patients can then 
develop GA even after the wet component is under control or stabilized.
The pathogenesis of AMD is not well understood, although significant progress has been 
made in recent years. Several theories have been put forward, including oxidative stress, 
mitochondrial dysfunction, choroidal perfusion dysfunction and inflammatory processes. The 
imbalance between production of damaged cellular components and degradation leads to the 
accumulation of intracellular lipofuscin and extracellular matrix material, commonly seen 
clinically as yellow deposits called drusen. Photoreceptor loss occurs overlying the drusen 
area. Incipient atrophy is demarcated by thinning or depigmentation of the retinal pigment 
epithelium (RPE), the supporting layer of the photoreceptors, in the macular area during early 
disease stages. In the advanced stages of AMD, atrophy of the RPE over a geographic area 
(GA) and/or development of neovascularization result in massive loss of photoreceptors and 
central vision loss.
In contrast to wet AMD, where loss of vision is typically acute and treatment leads to a 
relatively rapid reduction in retinal fluid and subsequent improvement in visual acuity (VA), 
disease progression and vision loss in GA is a gradual process. 
While neovascular AMD is effectively treated with anti-VEGF agents, no approved therapy 
is available to prevent either onset or progression of GA. However, in recent years, a number 
of new potential therapies has been tested. Recently, results from Phase III trials of 
Lampalizumab (Roche), an Anti-Complement Factor D Fab, showed no efficacy. Ongoing 
clinical trial evaluations include e.g. APL-2 (Apellis), an Anti-Complement C3 in Phase III 
development.


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A possible explanation for the recent failures evaluating new potential drugs for GA could be 
that, because this pathology includes different sub-types of diseases, trials need to better 
identify the target population based upon the mechanism of action of the compound [R18-
3147]. Moreover, there is uncertainty on which cell type is primarily affected in GA. Some 
studies indicate that the first alteration is in the RPE cells, followed by photoreceptors and 
choriocapillaris loss [R18-3146, R18-3150]. Some other investigations suggest that 
photoreceptors play a fundamental role in GA onset [R18-3148]. Photoreceptor loss is 
already observed in early and intermediate stages of AMD before progression to the more 
severe form of GA [P17-03129], and accompanied by additional functional changes of the 
inner retina downstream of photoreceptors [R18-3153]. Therefore, neuroprotection of the 
retina via TrkB activation, in particular of photoreceptors, could be a promising new 
therapeutic concept for GA.
1.2
DRUG PROFILE
Mode of action
BI 754132 is a human IgG1 with agonistic activity for the human TrkB receptor which leads 
to phosphorylation and induction of downstream signaling similar to that induced by the 
endogenous TrkB agonist, brain-derived neurotrophic factor (BDNF), resulting in an increase 
in cell survival and potentially synaptogenesis.
Key pharmacokinetic characteristics
BI 754132 demonstrated similar ocular pharmacokinetics as Avastin# in the rabbit after
intravitreal (IVT) administration (see Investigator`s Brochure (IB) Section 5.2 [c22785135]).
Human ocular PK of BI 754132 is expected to be similar to that of Avastin# (human vitreal 
t1/2 of 9.73 days). The predicted human efficacious dose of BI 754132 is 3 mg/eye 
administered every 3 months.
BI 754132 is a monoclonal antibody with a molecular weight of 146 KDa, which is above the 
renal filtration cut-off threshold (around 60 KDa). BI 754132 is not expected to have a 
significant renal filtration. It is expected to undergo protein catabolism therefore dedicated 
absorption, distribution, metabolism, and excretion studies have not been conducted for 
BI 754132.
Drug-Drug interactions:
BI 754132 is a therapeutic protein eliminated through protein catabolism. BI 754132 is not an 
immune modulator and is not expected to impact CYP450 enzymes. Therefore,
pharmacokinetic drug-drug interactions between BI 754132 and co-administered drugs are 
not likely.
Pharmacology:
BI 754132 is an agonistic IgG1 antibody that displays high affinity for human TrkB receptor
as determined by in vitro binding assessment. It binds with a binding affinity (KD) of
1.44 nM to the extracellular domain (ECD) of human TrkB receptor, which is identical to the
ECD in the cynomolgus TrkB receptor [n00262761-01]. Furthermore, BI 754132 does not 
exhibit activity regarding the induction of human TrkA or human TrkC receptor 
phosphorylation [n00255513-01].


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BI 754132 exhibits a pronounced species selectivity and is not active on mouse and rat TrkB 
receptors, precluding it from pharmaco-dynamics (PD) profiling in established rodent retinal 
disease models. In preclinical models, EX00077780, a TrkB agonistic antibody that is also 
active on rat and mouse TrkB receptors, was used as a surrogate. The in vivo efficacy of 
EX00077780 in rodent models of retinopathy, especially the neuroprotection and the 
improvement in neuronal function [n00254511-01], reflects the therapeutic potential of IVT 
TrkB activation for the treatment of retinal diseases, including GA.
Safety pharmacology
BI 754132 did not demonstrate any adverse effects on neurological or respiratory functions. 
In the 13 week IV toxicology study [n00259625-01], BI 754132 administration was 
associated with decreases (up to 0.6x) of mean values for blood pressure (systolic, diastolic, 
and mean arterial pressure) in females at ≥ 3 mg/kg on Days 22 and 85 compared to the 
control. Similar decreases were not noted in the males. BI 754132 did not cause changes in 
heart rate or electrocardiograms (ECGs) in the 13-week IV toxicology study.
Toxicology
The toxicology data suggest BI 754132 can be safely administered via IVT to humans for up 
to 13 weeks. Given that the tolerability and immunogenicity profiles in human may be 
different from those in cynomolgus monkey, the potential inflammatory and immunogenicity 
responses in human should be closely monitored. Escalation of doses in human should be 
based on the tolerability in the earlier cohorts and the maximum dose in human should not 
exceed 6 mg/eye. Potential systemic effects including body weight, heart rate, blood pressure 
and hematology should be monitored based on the findings in the cynomolgus studies (see 
Section 1.4.2 and IB [c22785135] Section 5.3 for further details).
BI 754132 is a human IgG1 carrying FcR-gamma receptor binding mutations for reducing
ADCC and CDC. BI 754132, an agonist for the TrkB receptor, binds to the extracellular
domain causing auto-phosphorylation and induction of downstream signaling cascades for
increased cell survival and synaptogenesis. Based on expected pharmacology and reduced Fc
effector function, the risk for cytokine release syndrome in humans is expected to be low.
There were no signs of cytokine release in the monkey studies.
Data from clinical studies
The first-in human trial, 1418-0001, an open-label, multicenter, Phase I study, investigates 
the safety, tolerability and pharmacokinetics of BI 754132 administered intravitreally in 
patients with GA secondary to AMD. The study has two parts: a single rising dose (SRD) and 
a multiple dose (MD) part. In the SRD part, 15 patients will be included (3 patients per dose 
cohort and additional 3 patients in the highest tolerated dose cohort) to test an increasing 
exposure to BI 754132 with 4 doses (0.3, 1, 3, 6 mg). The MD part will test the highest 
tolerated dose from the SRD part with 6 patients. Three doses of BI 754132 will be 
administered 4 weeks apart.
At the time of amending this CTP, 3 patients of Cohort 1 (0.3 mg), 3 patients of Cohort 2 (1.0 
mg), 3 patients of Cohort 3 (3.0 mg) and 6 patients of Cohort 4 (6 mg) had completed the 
SRD part of trial 1418-0001.


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Pharmacokinetics:
Systemic Pharmacokinetic (PK) samples of the first-in-human single-rising dose study 1418-
0001 were obtained from all patients of the SRD part. PK samples were collected before IVT 
injection and at 4, 72, 168, 336, 672, 1344, 2016, and 2352 h after injection. Cohort 1 (0.3 
mg) had no measurable BI 754132 serum concentrations. For Cohorts 2 and 3, detectable 
individual patient serum concentrations of BI 754132 were 26.2 μg/L 4 h post-dose in the 1.0 
mg dose and 6.38 μg/L 168 h post-dose in the 3.0 mg dose.
Patients in Cohort 4 (6.0 mg) showed systemic values ranging from 6.35 - 28.7 μg/L within 4 
to 168 h post IVT administration (for further details see current version of IB [c22785135]).
Ant-drug antibodies (ADAs):
As all patients in Cohorts 1 through 4 completed the study sera collected from all visits have 
been analyzed for ADA responses. Thus far, one positive patient titer (1:1280) was observed 
at study Visit 10 (EoT) in the 3.0 mg dose group.
Safety evaluations:
The safety evaluation of the SRD part includes surveillance of dose limiting events (DLEs), 
physical examination, vital signs, laboratory testing, 12-lead ECG, and AEs (including ocular 
AEs).
At the time amending this CTP, 15 patients were enrolled in the SRD part and treated with 
single doses of intravitreal BI 754132 (3, 3, 3 and 6 patients in the 0.3, 1.0, 3.0 and 6.0 mg 
dose groups, respectively). All fifteen patients completed the study up to the final end of trial 
(EoT) visit 10. 
Out of the15 patients treated with BI 754132, 9 patients across all dose cohorts were reported 
with an AE, (see Table 6.2.1: 1 in IB [c22785135]).
Two serious AEs (SAEs) were reported in which optic disc swelling was diagnosed as non-
arteritic anterior optic ischaemic neuropathy (AION).
The first case occurred in the study eye of a patient in the 0.3 mg dose cohort. The patient 
was subjectively asymptomatic and the optic disc swelling was most likely related to an 
anterior ischemic optic neuropathy and diagnosed as an incidental finding during a planned 
study visit (visit 9, 84 days after study drug administration). The event was classified by the 
investigator and BI as not drug- or procedure-related. The AE was of moderate intensity, and 
it was reported as resolved at the last follow-up visit. 
The second case occurred in the study eye of a patient in the 6.0 mg dose cohort. The patient 
was symptomatic and reported blurred vision and a visual field defect with an onset on day 
46 after study drug administration. The diagnosis was established at an unscheduled visit on 
day 52. The patient had a swelling of the optic disc and hemorrhages which were diagnosed 
as non-arteritic AION. The event was classified by the investigator as not drug- or procedure-
related and of moderate intensity. At the EoT visit the optic disc swelling had regressed and 
the visual field defect slightly improved. The AE was classified as ongoing.


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Non-arteritic AION has an incidence of ~1:10 000/year in the general population 50 years or 
older. 
No specific data on the non-arteritic AION incidence rate are available for patients with 
Geographic Atrophy. Based on the limited human exposure and the epidemiological data, the 
Safety Monitoring Committee (SMC) and the Sponsor concluded that the findings could be 
coincidental, but a causal relationship to the trial drug cannot be fully excluded. Accordingly, 
the second SAE was reported as a SUSAR.There were a total of 12 ocular AEs; 4 were 
considered study drug-related and 5 were considered procedure-related. All ocular AEs, 
except for the optic ischaemic neuropathies were of mild intensity. All ocular AEs related to 
study drug or procedure recovered, with the exception of the second AION case.
Overall, 20 systemic AEs were reported. None of these were considered study drug-related 
and all were of mild or moderate intensity.
No Adverse Events of Special Interest (AESIs), DLEs or deaths were reported, and there was 
no identifiable exposure/dose-AE relationship. There were no apparent patterns of any 
clinically significant abnormalities in the general (ECG, vital signs, lab safety parameters) or 
ophthalmological (IOP, slit lamp, BCVA, SD-OCT, FAF, CFP and OCT-A) safety
assessments.
For a more detailed description of BI 754132, please refer to the current IB [c22785135].
1.3
RATIONALE FOR PERFORMING THE TRIAL
There is no available treatment for GA, and given the degenerative nature of this disease, it is 
likely that the visual acuity in these patients will continue to worsen up to the stage of legal 
blindness.
As a transition from preclinical investigations to clinical development in this first-in human 
trial, safety, tolerability and pharmacokinetics of BI 754132 will be assessed in GA volunteer 
patients using single rising intravitreal doses and a multiple intravitreal dose in order to 
provide the basis for an ongoing clinical development of BI 754132 in the indication GA 
secondary to AMD.
This trial will include patients affected by GA with significant visual loss since because 
intravitreal injections in healthy subjects would not be considered ethically justifiable. 
This trial will consist of a single rising dose (SRD) and a multiple dosing (MD) part.
In the single rising dose parts, within each dose group, all intravitreally treated patients will 
receive the same BI 754132 dose. The next higher dose will only be administered to the next 
group, if the treatment in the preceding dose group was safe and showed acceptable 
tolerability. Plasma concentrations will be assessed to investigate the relationship between 
systemic drug exposure and potential observable systemic AEs.
In the MD part, one multiple dose cohort (6 patients) will be studies over a 22 week period. 
After an initial active treatment period of 12 weeks (3 injections in 4 weekly intervals) 


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patients will be followed up for an additional 10 weeks without further injections to study the 
tolerability and pharmacokinetics. This might also help to guide injection frequency intervals 
in later studies.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
GA is a progressive disease that leads to an irreversible loss in central vision because of 
degeneration of RPE and photoreceptors. People affected by this pathology may result in 
blurred or no vision in the center of the visual field, needed for reading, driving, recognizing 
people’s faces and color vision. There is no approved treatment for this disease, and usually 
patients can only be followed-up. 
TrkB receptors are abundantly expressed by retinal neurons and glial cells. In the normal 
retina, TrkB signaling counteracts cell stress and promotes cell survival. 
Both published data as well as in-house preclinical studies [n00254512-01, n00254511-01, 
n00255512-01] showed that TrkB activation can protect photoreceptors in animal models of 
diabetes, retinal ischemia as well as in the blue light-induced photoreceptor degeneration 
model. Furthermore, recent data show that levels of BDNF, the endogenous ligand of TrkB, 
are reduced in the eyes of AMD patients including GA [R18-3156], suggesting that reduced 
TrkB signaling might account for the loss of photoreceptors occurring in GA. 
Therefore, stimulating TrkB signaling in the eyes of patients with GA might protect 
photoreceptors from degenerating, thereby counteracting the loss of vision. 
1.4.2
Risks
1.4.2.1
Available clinical data on the MoA
1.4.2.1.1
Trials evaluating native ligand (BDNF)
Stimulation of TrkB receptor was previously tested in clinical trials with TrkB’s native 
ligand, BDNF. Recombinant methionyl human BDNF was developed for the indication 
amyotrophic lateral sclerosis (ALS) in a Phase 1-3 development. Based on supportive data 
from the Phase 1-2 trials, this phase 3 controlled trial evaluated the use of recombinant 
methionyl human BDNF in 1135 patients affected by ALS, with daily subcutaneous 
administration up to 9 months (25 or 100 μg/kg/day). The safety profile was considered 
acceptable [R17-1162]. 
In 2000 a phase 1/2 trial assessed the use of the same recombinant human BDNF 
administered by intra-thecal infusion for 12 weeks. The major adverse events were sensory 
disturbances, insomnia, behavioural effects, dry mouth, increased sweating and gustatory 
abnormalities [R19-0073].


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1.4.2.1.2
Trials evaluating agonist antibodies targeting TrkB
In 2011, Pfizer terminated a phase I trial evaluating subcutaneous administration of TAM-
163, an agonist monoclonal antibody targeting TrkB, in patients affected by cachexia, due to 
the emergent safety concern of sensory symptoms 
(https://clinicaltrials.gov/ct2/show/NCT01262690?cond=TAM-163&rank=1). No data is 
available neither on dosages nor on the description and the severity of AEs observed in the 
trial. However, in a related paper on dose selection methodology employed for this trial, the 
authors indicated a hypothetical starting dose equal to 0.05 mg/kg, corresponding to 3 mg for 
a 60 kg human [R19-0077]. It should be noted that the expected systemic exposure in these 
clinical trials is much higher than the expected systemic exposure after intravitreal injection 
with the planned doses of BI 754132 (see IB [c22785135] Section 5.2).
1.4.2.2
Available data from pre-clinical toxicity studies
1.4.2.2.1
IV administration of BI 754132
BI 754132 was tested in pre-clinical studies in cynomolgus monkeys. IV administration of 
BI 754132 resulted in a reduction of lymphocytes in the spleen and in the thymus. The 
findings are not considered adverse because it was without effect on the peripheral 
lymphocyte count and did not result in apparent clinical effect on immune function. In IV 
study it was also observed an increase in body weight and a reduction of blood pressure. 
Increased body weight in cyno study was not considered adverse because it did not affect the 
well-being of the animals under the condition of the study. Decreased blood pressure did not 
result in any clinically relevant finding nor affect the well-being of the animals, therefore was 
considered non-adverse.
1.4.2.2.2
IVT administration of BI 754132
IVT administration of BI 754132 for 13 weeks in cynomolgus monkeys was well tolerated 
with minimal findings (increased plasma fibrinogen and microscopic decrease of
lymphocytes in the thymus). 
1.4.2.2.3
Immunogenetic response in pre-clinical studies
Following IVT injection, high incidence (11/22) of plasma anti-drug antibody (ADA) after 
the fourth administration at day 85 was detected in treated monkeys. In two animals ADA 
response was associated with intraocular inflammation (perivascular sheathing, vascular 
leakage and optic nerve leakage, hazy media). The inflammation generally resolved after 
each dose (with or without topical treatment via eye drops); even severe intraocular 
inflammation showed resolution after dosing cessation and ophthalmic treatment. 
Immunogenicity to humanized protein in animal studies does not usually predict clinical 
immunogenicity in human. Moreover, ophthalmic inflammatory response is easily detected 
and monitored in patients, and usually can be addressed and resolved with topic anti-
inflammatory therapy.


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1.4.2.3
Risks related to intravitreal injection 
Intravitreal injection has potential serious adverse events, but these are considered rare: 
clinical trials assessing efficacy and safety of EYLEA® intravitreal injections showed serious 
adverse reactions related to the injection procedure in <0.1%, including endophthalmitis, 
traumatic cataract, and increased intraocular pressure 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.pdf). Because the 
procedure of intravitreal injection of BI 754132 is the same, the expected adverse events 
related to the procedure are considered equal to what was observed with marketed drugs (e.g. 
EYLEA®).
BI recommends the use of material for intraocular drug delivery, which is according to 
standard medical practice. This material is not officially approved for intraocular drug 
delivery, with associated potential risks. Long-term experience as standard of medical care 
suggests a favourable risk-benefit profile. To the best of the sponsor´s knowledge, there is 
currently no comparable material 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 
considered low based on long-term experience with comparable material. 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 comparable material 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 material 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 754132.
1.4.2.4
Risks related to blood sampling
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to veinipuncture for blood sampling.
The total volume of blood withdrawn during the entire study per patient will not exceed the 
volume of a normal blood donation (appr. 500 mL). No health-related risk is expected from 
this blood withdrawal
1.4.2.5
Risks related to BI 754132 based on human clinical data
During the SRD part of this trial, two patients have experienced Non-Arteritic Anterior 
Ischemic Optic Neuropathy (AION) in the study eye with 0.3 and 6.0 mg BI 754132, 
respectively. Both events were classified as not related to study drug by the investigators, and 
patients had some predisposition including hypercholesterinaemia, hypertension and sleep 


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apnea. Non-arteritic AION is uncommon in the general population (incidence ~1:10 000/year
in adults aged 50 years or older). Based on the limited human exposure and the available 
epidemiological data, it was concluded that the events could be coincidental, but that a causal 
relationship to the trial drug cannot be fully excluded. Accordingly, the second SAE was 
reported as a SUSAR and additional safety measures have been implemented in the MD part 
of the trial (see Section 1.4.2.6).
1.4.2.6
Planned measures for monitoring and minimization the risks
Taking into consideration all the clinical (during SRD) and pre-clinical findings, the AEs 
reported in previous trials involving the same mode of action (MoA) of BI 754132, and the 
risks related to the intravitreal injection, the trial will include complete ophthalmic 
examinations at each timepoint. 
Patients will be evaluated with functional, imaging and systemic tests to identify any possible 
adverse event. Specifically, any signs of intraocular inflammation will be assessed by slit
lamp examination of anterior chamber, vitreous and posterior segment of the eye, to identify 
occurrence of flare or cells in the anterior chamber, deposits of material in the corneal 
endothelium, deposits on the anterior capsule of the crystalline lens, any signs of vitreous 
haze, vitreous cells, vitreous snowbanks/snowballs, signs of intraretinal edema or retinal 
thickening, signs of perivascular inflammation e.g. vessel walls sheathing, signs of incipient 
retinitis or intraretinal haemorrhages. 
Spectral domain optical coherence tomography (SD-OCT) will be used to evaluate any 
possible occurrence of intraretinal cystic edema or perivascular reaction. The same imaging 
modality together with fundus autofluorescence (FAF) will be used to evaluate early signs of 
cell toxicity (e.g. increased ellipsoid zone disruption, granular appearance of outer retinal 
layers, increase in intraretinal foci predominantly located in the outer nuclear layers, changes 
in areas of focal increased autofluorescence). 
Based on the safety data evaluation from the SRD part of the trial, the following measures are 
implemented in MD part of the trial:
•
Detailed clinical assessment of optic disc morphology using indirect ophthalmoscopy
Spectral Domain Optical Coherence Tomography (SD-OCT) and Color Fundus 
Photography (CFP)
•
Implementation of a “Sentinel” strategy for the MD part
•
Amendment of the inclusion and exclusion criteria to minimize the risk and impact for 
patients
•
Update informed consent (IC) to include the potential risk for AION.
Additionally, a systemic evaluation will be performed at the timepoints specified in the flow 
charts under physical examination, to assess any possible systemic reaction. This will 
include: body weight, blood pressure, and pulse rate. At the time points specified in the 
Flow Chart I and Flow Chart II, full blood cell count, C-reactive protein (CRP; MD part 
only), Glycosylated haemoglobin (HbA1c; MD part only), prothrombin time (PT) and 
fibrinogen will be determined, and ECGs will be recorded. All these evaluations will have to 


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be reported immediately for evaluating any possible safety issue related to the drug or to 
inflammatory response.
1.4.2.7
Drug induced liver injury
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety (see also Section 5.2.8.1.4, AEs of special interest).
1.4.3
Discussion
Considering the data available from previous non-BI clinical trials evaluating the same MoA
(see Section 1.4.2.1), and data from pre-clinical studies on BI 754132, in this trial extensive 
ophthalmic and systemic examinations are planned in all the visits. 
Blood tests and physical examination will evaluate potential changes in blood cell count and 
fibrinogen plasma levels, as well as in body weight and blood pressure. Ophthalmic physical 
examination will focus on the risks related to the procedure (e.g. endophthalmitis and retinal 
detachment), and the risks related to a potential immunologic response. Imaging and 
functional tests will further assess any possible signs of neurotoxicity after the administration 
of the drug.
Because of the agonistic mode of action of BI 754132, special attention will be applied to 
ensure the highest level of safety for patients selecting the starting dose, the dose escalation 
steps and the highest dose applied (see Section 4.1.2).
Based on the safety evaluation of the SRD part of this trial, additional assessments of the 
optic disc, an amendment of the inclusion and exclusion criteria as well as a sentinel 
recruitment strategy have been implemented in the MD part. 
In the trial design a sentinel approach will be used, according to EMA and ICH guidelines 
(EMA/CHMP/SWP/28367/07 Rev.1; EMA/CHMP/ICH/731268/1998): In the SRD part, for 
each cohort the first patient will be dosed and monitored to exclude acute AEs, before dosing 
the other patients of the same cohort. For the MD part each patient will be dosed on a sentinel 
approach using the 4 weeks data to decide upon the second injection of the same patient and 
to start the dosing of the next patient (see Section 3.1).
Moreover, the duration of observation will reflect the expected human PK of BI 754132, with 
a follow-up for all patients up to 100 days (i.e. the minimum observation period per patient is 
100 days), with appropriate ophthalmologic and systemic evaluations (see Section 3.1). The 
implications of the current Coronavirus pandemic (COVID-19) are summarized in 
Section 10.5.
Pre-clinical data show that BI 754132 can improve photoreceptor functionality, which holds 
promise to be beneficial in GA. However, because of the limited administration of BI 754132
during phase I and the long duration of the pathology of GA, long-term benefit for the 


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patients entered in this trial is unclear at this point of the development. Their participation in 
this trial, however, is of major importance to the development of BI 754132 to determine a 
safe dose for further clinical trials in this pre-selected patient population. Patients included in 
the trial will have progressed disease in the treatment eye, minimizing the effect of potential
adverse events
GA is the leading cause of blindness in western countries, with no treatment available. Given 
the urgent need to address this unmet medical need and based on available clinical safety data
analysis, SMC recommendations, as well as the added risk mitigation measures in the MD 
part, the benefit-risk of BI 754132 remains favorable and supports its continued use in this 
clinical trial.


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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 
pharmacokinetics of single intravitreal and multiple intravitreal administrations of BI 754132.
2.1.2
Primary endpoint(s)
SRD part: 
•
Number of patients with ocular (in the study eye) and systemic dose limiting events 
(DLEs) from drug administration until end of trial (EOT). For definition of DLEs, refer to 
Section 5.2.1.
MD 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 from drug administration until EOT
•
Number of patients with any ocular AEs in the study eye from drug administration until 
EOT
•
Cmax (maximum serum concentration of BI 754132 after a single intravitreal dose)
•
AUC0-∞(area under the concentration-time curve of BI 754132 in serum over the time 
interval from 0 extrapolated to infinity)
•
tmax (time from dosing to maximum serum concentration of BI 754132)
MD part:
•
Systemic exposure of BI 754132 after multiple IVT doses by determination of
Cmin,1 and Cmin,2 (trough levels before second and third administrations) and plasma 
concentrations 4, 8 and 14 weeks after the third administration 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The trial will consist of an SRD part followed by an MD part. Both parts will be conducted in 
a non-randomized, open-label, and uncontrolled manner.
SRD part:
Cohorts of patients will receive escalating doses of BI 754132, with the starting dose 0.3 mg. 
The other provisional dose levels are 1 mg, 3 mg, and the maximum planned dose 6 mg. Each 
cohort will consist of 3 newly enrolled patients. For each cohort, a single patient will be 
dosed on day 1, and the dosing investigator, coordinating investigator and 2 representatives 
of the sponsor who are involved in the trial will carefully evaluate all being available 
systemic (i.e. physical examinations, safety lab parameters, ECG and AEs) and 
ophthalmological (i.e. as defined in Section 5.2.1) safety data until day 4. If this patient 
neither has experienced an ophthalmological nor a systemic DLE, the remaining 2 patients 
will be dosed. Written minutes of this assessment are being distributed to all investigators 
participating in this trial part.
A Safety Monitoring Committee (SMC, see Section 8.7) will decide on the next dose level to 
be investigated, the size of the next cohort based on occurrence of DLEs and on additional 
information (systemic PK and patient profiles). Refer to Figure 3.1.1 for a schematic 
representation of the dose escalation.
A Bayesian logistic regression model (BLRM) based on a weakly informative prior 
distribution, and employing the escalation with overdose control (EWOC) principle will be 
used for guiding the dose escalation (see Section 7.2.1.1). After all patients in a cohort have 
either experienced a DLE or have been observed for at least the 7 days evaluation period
without experiencing a DLE (i.e. 7 days after drug administration, until Visit 4, will be 
evaluated per patient), the BLRM will be updated with the newly accumulated data. The 
BLRM provides estimates for the probability of observing a DLE for each planned dose.
Dose escalation will be permitted to the next planned dose which fulfils the EWOC criterion.
Note that this may also result in repeating the current dose level, or in going down to a lower 
dose level again.
For any dose-escalation cohort, at least 3 evaluable patients will be required. 
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.
As a sensitivity analysis, the BLRM might also be run again shortly before the SMC meeting, 
using all AE data available up to this time point.


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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 
that the MTD will likely be the highest feasible dose, 6 mg, rather than the highest tolerable 
dose in a strict sense. The SMC may decide on stopping the dose escalation after the criterion 
for MTD is fulfilled. Further patients may be included to confirm that the EWOC criterion is 
still fulfilled. 
In Figure 3.1: 1, the dose escalation process is depicted as planned, i.e., if no DLE occurs in 
the trial and dose escalation may proceed up to the highest dose level.
Figure 3.1: 1 Schematic representation of the dose escalation process in the SRD part 
MD part:
The MD part will consist of one dose cohort (6 patients). After the SRD part has been 
completed, the SMC will decide on the selection of the highest dose (e.g. 6 mg) established 
as safe and tolerable during the SRD part to be used in the MD part. Patients that had 
received a dose in the SRD part of the trial (regardless of the eye) will not be included. In the 
MD part, patients will receive three consecutive dose injections over a 3-month period 
(dosing every 4 weeks).
For the MD part, the first patient will receive one dose and will be monitored after four weeks 
to exclude acute AEs and especially adverse changes of the optic disc. Data will be assessed 
by the dosing investigator and 2 representatives of the sponsor who are involved in the trial.
The decision to continue will be based on pre-specified criteria and include certified gradings 
from the Central Reading Center (CRC). If no AEs or adverse changes of the optic disc are 
observed, the first patient can receive the second dose. The second patient can be dosed at 
least 7 days thereafter. The second to sixth patients will follow the same procedure as the first 
patient, with a safety review after 4 weeks. In addition, this safety review will include safety 
data from visit 4 of the previous patient (assessment 4 weeks after second injection) as well 
as all available safety data of the previous patients. Written minutes of this review are being 
distributed to all investigators participating in this trial part.


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In all patients included in the MD part of the trial, safety and pharmacokinetics will be 
studied to 98 days after the last injection.
Figure 3.1: 2 Schematic representation of the sentinel dosing in the MD part 
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This trial is designed to establish a safe and tolerable dose for further testing in phase II trials. 
The trial consists of separate SRD and MD parts. A comparison between the untreated versus 
the treated eye is considered adequate to derive a safe and tolerable dose and therefore neither 
parts of this trial will use a comparison to sham injection.
The SRD dose escalation is 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. 
The dose escalation and cohort size will be decided by the SMC, guided by a BLRM with 
overdose control. An EWOC design will increase the chance of treating patients at 
efficacious doses while reducing the risk of overdosing. The use of 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].
One MD cohort (3 injections in a 4-weekly interval) will be included after the SRD part. This 
part of the trial will generate additional safety data and plasma concentrations of BI 754132
after MD. These data will further support the definition of the injection frequency in later 
studies.


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3.3
SELECTION OF TRIAL POPULATION
This trial will recruit approximately up to 24 patients in total. The SRD part is expected to 
enrol 18 patients; the actual number may increase depending on the occurrence of DLEs; 
please refer to Section 7.5 and Appendix 10.4 for details and justification. The MD part is 
expected to enrol 6 patients.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is entered in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor has to be contacted immediately.
3.3.1
Main diagnosis for trial entry
This trial enrols patients with GA secondary to AMD as diagnosed by FAF and with 
significant visual loss selected based on BCVA.
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
1. Men and women with GA secondary to AMD: For the SRD part, the GA lesion in the 
study eye must be ≥1.9 mm2 disc area in size (approximately ≥0.75 disc area in size); for 
the MD part the total GA lesion size in the study eye must be ≥7.5 mm2 (approximately 
≥3 disc area in size). 
2. Fellow eye is not required to have GA
3. BCVA:
a.
SRD part: BCVA of 20/100 to 20/400 Snellen (corresponding to 19 to 53 letters in the 
ETDRS chart) in the study eye equivalent measured by the Early Treatment Diabetic 
Retinopathy Study (ETDRS) protocol
b.
MD part: BCVA score of  ≤53 letters (Snellen equivalent of 20/100) in the study eye
4. Age ≥ than 50 years
5. Best-corrected VA in the non-study eye must have a better best-corrected VA compared 
to the study-eye
6. Women of childbearing potential (WOCBP1) 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 in Section 4.2.2.3


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7. Signed informed consent consistent with ICH GCP guidelines and local legislation prior 
to participation in the trial, which includes medication washout and restrictions
8. Not under any administrative or legal supervision or under institutionalization due to 
regulatory or juridical order
(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. 
3.3.3
Exclusion criteria
1. GA in either eye because of causes other than AMD 
2. History of choroidal neovascularization (CNV) in the study eye and in the fellow eye
3. Previous treatment in the study eye for GA secondary to AMD within 6 months prior to 
screening visit (ongoing therapy with vitamin and mineral supplements is allowed)
4. Previous participation in other trials for treatment of GA receiving active drug in the 
study eye. For the MD part any patients that participated in SRD part of the trial 
(regardless of the eye).
5. Additional eye disease in the study eye that could compromise 
•
best corrected VA (BCVA) with visual field loss, 
•
uncontrolled glaucoma intraocular pressure (IOP>24), 
•
clinically significant diabetic maculopathy, 
•
history of ischemic optic neuropathy or retinal vascular occlusion,
•
symptomatic vitreomacular traction, 
•
genetic disorders such as retinitis pigmentosa); 
•
history of high myopia > 8 diopters in the study eye and
•
anterior segment and vitreous abnormalities in the study eye that would preclude 
adequate observation with SD-OCT
6. Any prior intraocular surgery in the study eye other than uneventful lens replacement for 
cataract within 3 months prior to screening
7. Aphakia or total absence of the posterior capsule. Yttrium aluminium granat (YAG) laser 
capsulotomy permitted, more than 3 months prior to enrolment in the study eye
8. 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)
9. Significant disease or other medical conditions (as determined by medical history, 
examination and clinical investigations at screening) that may, in the opinion of the 
investigator result in 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, e.g. cardiac 
(including tachycardia), gastro-intestinal, hepatic, renal, metabolic, dermatologic, 
neurological, haematological, oncological and psychiatric. 


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10. 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.
11. Known hypersensitivity to any of the ingredients used in the IMP formulation, or any of 
the medications used
12. Active intraocular inflammation in the study eye
13. Active infectious conjunctivitis in either eye
14. For the MD part: Unstable cardiovascular/metabolic disease (e.g. hypertension, diabetes 
mellitus, hypercholesterolemia) and/or not on stable medication for these conditions at 
least 3 months prior to inclusion
15. For the MD part: Any evidence for current or past giant cell arteritis
3.3.4
Withdrawal of patients from treatment or assessments
Patients may be withdrawn from trial treatment or withdraw consent to trial participation as a 
whole (“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1
and 3.3.4.2 below.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the 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 discontinue trial treatment, without the need to justify the decision.
•
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
•
The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
•
The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy). An AE or clinically significant laboratory 
change or abnormality occurred that the investigator judges to warrant discontinuation of 
treatment. 
Even if the patient is withdrawn from trial treatment, the patient remains in the trial and, 
given his/her agreement, will undergo the procedures for early treatment discontinuation and 
follow-up as outlined in the Flow Chart I and Flow Chart II and Section 6.2.


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3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to 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 be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
For the following scenario further enrolment and entering into the trial will be interrupted by 
the sponsor once the sponsor becomes aware (i.e. stopping rule):
•
A single serious adverse reaction (i.e. a single serious adverse event) or two severe 
adverse reactions in two different patients (regardless of the system organ class) 
confirmed by both the investigator and sponsor as having a reasonable causal relationship
to the IMP administration.
•
For the MD part: Occurrence of AION or relevant predisposing changes of the optic disc 
in the study eye after administration of BI 754132.
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 another reason than DLE or patients who miss any visit
between visits 2 and 4 are not evaluable for the occurrence of a DLE within 7 days after drug 
administration. These patients will be replaced until 3 evaluable patients are included.
Patients who come off study due to a DLE will not be replaced.


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MD part:
If some patients do not complete the trial, the Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide if and how many patients will be 
replaced.
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
Table 4.1.1:1
BI 754132
Substance:
BI 754132
Pharmaceutical form:
powder for solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
60 mg/vial
Posology:
SRD part: One single injection
MD part: 3 injections, each separated by 4 weeks
Mode of administration:
Intravitreal
Table 4.1.1:2
Diluent 
Substance:
Diluent for reconstituted BI 754132 powder for 
solution for injection 60 mg/vial, 10 mL/vial
Pharmaceutical form:
Solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
n/a
Posology:
SRD part: One single injection
MD part: 3 injections, each separated by 4 weeks
Mode of administration:
Intravitreal
4.1.2
Selection of doses in the trial and dose modifications
Because of the agonistic mode of action of BI 754132 and potential species differences in 
activation of cyno vs. human TrkB, an efficient dose selection strategy is critical to the 
successful clinical development of BI 754132. The selection of doses that are too high may
lead to significant safety concerns, as exemplified by the case of TGN1412, an agonistic 
antibody against a T cell target [R19-0690]. Whereas a dose that is too low can lead to the 
need for clinical testing of a wide dose range and a higher number of patients exposed to the 
IMP. 
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 
patients 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 


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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.
The observed NOAEL in the 13-week IVT study in cynomolgus monkeys was 6 mg/eye. As 
the vitreous volume in humans is approximately two times of that in cynomolgus monkeys 
[R17-3647], therefore the vitreal concentration achieved in cynomolgus is equivalent to a 
vitreal concentration reached after ivt injection of a 12 mg/eye dose in humans. A safety 
factor of 40-fold was applied; 10-fold for extrapolation from animal to human, and an 
additional factor of 4-fold for the potency shift observed between cyno and human in the 
functional assay. These combined safety factors result in a maximum recommended starting
dose of 0.3 mg/eye.
The measurement of the ERG a-wave in the STZ rat model represents a reliable animal 
surrogate to evaluate the effect of TrkB activation on photoreceptor function supporting the 
therapeutic benefit in GA patients. In an-in-house study using such a model [n00254511-01]
the targeted efficacious dose for BI 754132 was calculated to be a trough EC50 of 6.38 nM 
based on the pharmacological data of EX00077780 (tool TrkB antibody that cross reacts to 
the rat TrkB receptor). The human dose estimation of BI 754132 was performed based on 
scaling the PK/PD of the tool antibody from rat to human and comparison of PK between 
BI 754132 and Avastin [n00264883-01, R18-2968]. Taking into consideration the vitreous 
humor volume, the estimated human intravitreal half-life (t1/2 = 9.73 days) and the 
Ctrough value, an injection of 3 mg/eye every 90 days would maintain intravitreal concentration 
above the required Cthrough of 6.38 nM. 
The proposed starting dose of 0.3 mg/eye is predicted to maintain the predicted minimal 
efficacious vitreal concentration of 6.38 nM for 60 days. Doses lower than 0.3 mg are also 
expected to induce PD effects in the eye, however the duration of the effect would be smaller 
and in the light to slow down/halt GA progression with special emphasis on photoreceptor 
degeneration this PD effect would not be long enough to justify a potential long term benefit 
to the patients.
For the 1 mg and 3 mg dose, the relative increase to the next dose is 233% and 200%,
respectively. These doses limit the dose steps and resulting number of trial related IVT 
injections. Before each subsequent dose is administered, an external safety monitoring
committee will be convened to determine if it is safe to proceed to the next dose. If all 
previous doses are clinically well tolerated, one additional dose of 6.0 mg will be tested, as 
one of the development objectives is to find a dose that provides extended drug exposure and 
therefore longer efficacy and less injection frequency. 
The provisional dose levels to be assigned to separate cohorts of patients are listed in 
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.


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Table 4.1.2: 1
Provisional dose levels for escalation
Dose level
Proposed dose
Relative increment from previous 
dose
1
0.3 mg
Starting dose
2
1 mg
233%
3
3 mg
200%
4
6 mg
100%
4.1.3
Method of assigning patients to treatment groups
Patients for this trial will be selected based on BCVA and the presence of GA as diagnosed 
by FAF, SD-OCT and color fundus photography.
Recruitment of the trial will be started with the lowest dose group of the SRD part. The MD 
part will recruit patients only after the SRD part has been completed and safety of the 
selected dose has been endorsed by SMC.
In the SRD part, the doses are planned to be escalated in cohorts at the pre-defined 
provisional dose levels; see Table 4.1.2: 1. 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 the next dose is considered safe 
based on (the BLRM model and) the clinical course, the recruitment of the next higher dose 
group may be started. Therefore, the recruitment of subjects for the dose groups will neither 
be influenced by the trial personnel nor by any characteristics of the patients, but only by 
temporal availability.
The highest dose (e.g. 6 mg) established as safe and tolerable during the SRD part will be 
used in the MD part after the SRD part has been completed.
4.1.4
Drug assignment and administration of doses for each patient
BI 754132 solution for injection will be administered intravitreally.
The drug product “BI 754132, powder for solution for injection, 60 mg/vial” and the diluent 
“Diluent for reconstituted BI 754132 powder for solution for injection” will be provided by 
BI. A site pharmacist will prepare the BI 754132 solution for injection according to the 
instruction provided in the ISF and provided handling instructions of the IMP. 


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Table 4.1.4: 1
Planned doses and treatment schedule for the SRD part
Dose group 
(mg)
Visit 2 
Day 1
0.3
X
1.0
X
3.0
X
6.0
X
To determine the dose regimen for the next cohort, the available toxicity information 
(including DLEs and AEs that are not DLEs), PK, as well as the recommendations from the 
BLRM will be evaluated by the SMC members at the dose escalation meeting. The parties 
must reach a consensus whether further dose escalation is appropriate, or whether de-
escalation and/or expanded recruitment into particular cohorts is appropriate. Minutes from 
these meetings will be prepared and circulated to the trial team and each investigator for 
comment prior to finalization. The next dose group will only be initiated after further dose 
escalation is considered appropriate by the SMC (see Section 4.1.2 for details on dose 
rationale and escalation concept).
Table 4.1.4: 2
Planned doses and treatment schedule for the MD part
Dose group 
(mg)
Visit 2 
Day 1
Visit 3 
Day 29
Visit 4
Day 57
MD dose 
X
X
X
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. After administration of BI 754132, patients will be monitored according to 
standard practice and at least for 1 hour. In this minimum post-dose observation period, 
systemic and ocular conditions will be monitored according to local practice for such 
procedures.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
In this open-label trial, treatment allocation will not be concealed throughout the trial. The 
CRF will contain information on treatment.


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Within the central ECG lab, readers involved with interval measurements will be blinded 
with respect to treatment, visit and demographic information collected.
4.1.5.2
Unblinding and breaking the code
If an interim safety analysis of ECG data is required, a part of the staff of the central ECG lab 
may be unblinded.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP).
For details of packaging and the description of the label, refer to the ISF.
4.1.7
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 (as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:
•
Approval of the clinical trial protocol by the IRB / 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 
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial


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patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the investigator or designee must verify that no remaining 
supplies are in the investigators possession or have been destroyed.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
There is no available therapy for GA, therefore no concomitant therapy is possible. In case of 
CNV or occurrence of any other retinal disease/complication, as per judgment of the 
investigator, administration of local standard of care treatment such as Intravitreal Treatment 
(IVT) or peribulbar injections, or laser or other surgical treatment is allowed.
Any 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) are not allowed in the trial.
4.2.2.2
Restrictions on diet and life style
None.
4.2.2.3
Contraception requirements
WOCBP (partner of a trial participant, for the definition please refer to Section 3.3.2) and men 
able to father a child (trial participant) must use two medically approved methods of birth 
control throughout the trial (from Visit 1 until Visit 10) one barrier method, and one highly 
effective non-barrier method. 
Men (trial participant) must use a condom (regardless of vasectomy) if their sexual partner is 
a WOCBP. 


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WOCBP (partner of a trial participant) must use a highly effective method of birth control per 
ICH M3 (R2) throughout the trial (from Visit 1 until Visit 10) that results in a low failure rate 
of less than 1% per year when used consistently and correctly if their sexual partner is a man 
able to father a child:
•
Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal). 
•
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable). 
•
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS). 
•
Bilateral tubal occlusion.
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
Not applicable since not expected after a single or triple (q4w) intravitreal applications and 
the long-term progression of the disease.
5.2
ASSESSMENT OF SAFETY
5.2.1
Dose limiting event
A dose limiting event (DLE) is defined as the occurrence of any of the following events as 
ocular DLE (in the study eye):
•
Development of sterile endophthalmitis and/or sterile inflammation of the vitreous 
grade 3+ according to Standardization of Uveitis Nomenclature (SUN) working group 
(WG) grading scheme for anterior chamber cells measured by slit lamp (see 
Table 5.2.1: 1 below) and a duration of 5 or more days 
•
Visual loss of more than 15 letters at any given timepoint due to treatment effect in
the study eye confirmed on consecutive visits
•
Persistent IOP over 30 mmHg for 3 days
•
Signs of vascular occlusion in the retina, including peripheral retinal haemorrhage 
(haemorrhage of the macula would not be included as this is a possible sign of CNV 
occurrence; peripheral retinal haemorrhage may be a sign of vascular occlusion)
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.
or as systemic DLE:
•
Drug-related AEs of moderate and severe intensity according to CTCAE [R18-1357] out 
of the following:
o
Self-reporting paraesthesia, dysgeusia, taste abnormality, taste disorder, 
hyposmia [R19-0073]
o
Diarrhea, cough [R17-1162]
Each DLE needs to be reported as AESI (see Section 5.2.8.1.4).


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5.2.2
Physical examination
A complete physical examination will be performed at the time points specified in the Flow 
Chart I and Flow Chart II. It includes at a minimum general appearance, neck, lungs, 
cardiovascular system, abdomen, extremities skin, and measurement of height (only at 
Visit 1) and body weight. 
The results must be included in the source documents available at the site. 
5.2.3
Vital signs
Vital signs will be evaluated at the time points specified in Flow Chart I and Flow Chart II
prior to blood sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. Prior to the blood 
pressure measurement, the PI should ensure that the subject has taken his or her blood 
pressure medications (if any) as usual at home. If the measurement results are to be doubted 
for example because of preceding great exertion of the subject, a new measurement should be 
taken after half an hour in a resting position and only this stable value has to be entered in the 
eCRF.
5.2.4
Ophthalmological examinations
As described in Section 1.4.2.6, the trial will include the following ophthalmologic
examinations on both eyes for safety considerations at the timepoints indicated in 
Flow Chart I and Flow Chart II:
Ophthalmologic examination
A complete ophthalmologic examination of both eyes including slit lamp examination, IOP 
measurement and dilated binocular indirect ophthalmoscopy (MD part only) will be 
performed by qualified persons. This examination will be performed at the timepoints defined 
in Flow Chart I and Flow Chart II.
Color Fundus Photography (CFP)
Seven-field or modified 4-field digital fundus photographs will be obtained from both eyes 
by a qualified person according to the imaging manual. This examination will be performed 
at the timepoints defined in Flow Chart I and Flow Chart II.
SD-OCT/OCT-Angiography (OCT-A)
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. 


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OCT images will be sent to an independent Central Reading Center (CRC) for evaluation. A 
detailed manual for OCT image acquisition and data transmission will be provided.
Fundus autofluorescence (FAF)
FAF is a non-invasive imaging technology for the morphological assessment of GA. The 
fluorescence signal predominantly originates from fluorescent material within RPE cells. In 
eyes with GA, distinctly dark areas are observed where the atrophy of RPE cells leaves an 
absence of fluorescent signal allowing for a quantification of the size of atrophic regions. The 
assessment is also performed by a qualified person, and only specified device(s) will be used. 
FAF images will be sent to an independent CRC for evaluation. A detailed manual for FAF 
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.
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. 
Centrally collected ophthalmological data (CFP, FAF, SD-OCT/OCT-A) will be transferred 
from the 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 safety 
assessments during the study, it will be reported as AE in the eCRF (please also refer to 
Section 5.2.8).
In the MD part, special attention should be payed to relevant adverse changes of optic disc 
morphology (e.g. new swelling or hemorrhage, change of cup-to-disc ratio, relevant changes 
of thickness of the peripapillary retinal nerve fibre layer as assessed by a circular OCT scan) 
or function (e.g. loss of BCVA or impaired vision). Relevant changes should be reported 
immediately to the Sponsor.
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 Flow Chart I and Flow Chart II. Patients do not have to be 
fasted for the blood sampling for the safety laboratory.
All analyses will be performed by a central laboratory, 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 adverse events (please refer to Section 5.2.8).
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 ISF System).


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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.
Table 5.2.5: 1 
Safety laboratory parameters – whole blood, serum or plasma
Hematology
•
Haematocrit
•
Haemoglobin
•
Glycosylated Hemoglobin 
(HbA1c)
•
MCV, MCH, RDW, MCHC
•
Red Blood Cells (RBC) / 
Erythrocytes
•
WBC / Leukocytes (number of B and 
T-cells)
•
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)
•
C-reactive protein (CRP)
•
CK-MB, troponin I (reflex tests if CK 
is elevated)
•
Lactate dehydrogenase (LDH)
•
Lipase
•
Magnesium 
•
Phosphate 
•
Potassium
•
Protein total 
•
Prothrombin time
•
Sodium
•
Urea (BUN)
•
LDL/HDL and total cholesterol
•
Triglycerides
•
TSH
•
Folate
•
Fibrinogen


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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)
5.2.6
Electrocardiogram
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph at the time points given in the Flow Chart I and 
Flow Chart II. Electrode placement will be performed according to the method of Wilson, 
Goldberger and Einthoven modified by Mason and Likar (hips and shoulders instead of 
ankles and wrists). As an optional procedure, precise electrode placement will be marked 
with an indelible mark on the skin to allow reproducible placement throughout the study.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality.
ECGs will be recorded as triplicate ECGs (i.e. three single ECGs recorded within 180 sec) as 
indicated in Flow Chart I and Flow Chart II.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. These can be done as single ECGs. For 
repetition within triplicate ECGs, the time window of 180 sec applies as well. The repeat 
ECGs are assigned to the respective scheduled time point.
Additional (unscheduled) ECGs may be recorded for safety reasons.


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


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Any ECG abnormalities will be monitored carefully and, if necessary, the subject will be 
removed from the trial and will receive the appropriate medical treatment. 
5.2.7
Other safety parameters
Not applicable.
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.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
•
Worsening of the underlying disease or of other pre-existing conditions 
•
Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
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,
•
is life-threatening, which refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe,
•
requires inpatient hospitalisation or prolongation of existing hospitalisation
•
results in persistent or significant disability or incapacity,
•
is a congenital anomaly / birth defect,
•
is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement which may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 


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5.2.8.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the ISF system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described above.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.8.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”.
5.2.8.1.4
Adverse events of special interest
The term adverse event of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.8.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
•
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or
•
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 ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
All AEs meeting the criteria for a dose limiting event (DLE) as defined in Section 5.2.1 are 
defined as AESIs for this trial.
5.2.8.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:


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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 whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
•
The event is consistent with the known pharmacology of the drug.
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced.
•
No medically sound alternative aetiologies that could explain the event (e.g. pre-existing
or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).
•
Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation 
(e.g. situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
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.


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The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial: 
all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should only 
report any occurrence of cancer and trial treatment related SAEs and trial treatment 
related AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form (see 
Section 5.2.8.1.1), but not on the CRF.
5.2.8.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process contact details will be provided in the 
ISF). The same timeline applies if follow-up information becomes available. In specific 
occasions, the investigator could inform the sponsor upfront via telephone. This does not 
replace the requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
5.2.8.2.3
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.
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.
5.2.8.2.4
Exemptions to SAE reporting
Not applicable.


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points
indicated in Flow Chart I and Flow Chart II. The actual sampling times will be recorded in 
the CRFs and used for determination of pharmacokinetic parameters. Sampling should be 
done at the timepoints listed in the flow-chart I and II and within 4 hours prior to the IVT 
drug administration. It is important to ensure that the exact time of the assessment of 
pharmacokinetics is recorded. Planned time points for systemic pharmacokinetic samples are 
listed in Appendix 10.3.
5.3.2
Methods of sample collection 
5.3.2.1
Sampling for pharmacokinetic analysis
For quantification of BI 754132 serum concentrations, approximately 3.0 mL of blood will be 
taken from a forearm vein into a serum collection tube at the time points listed in 
Appendix 10.3 under PK sampling.
Samples will be stored in a freezer set at the analytical laboratory until the finalization of the 
clinical trial report (CTR). Samples may be used for further methodological investigations, 
(e.g. for stability testing), however, only data related to the analyte will be generated by these 
additional investigations. The study samples will be discarded after completion of the 
additional investigations but not later than 5 years upon the final study report has been 
signed.
5.3.2.2
Sampling for ADA assessment
For the determination of anti-drug antibodies (ADA), approximately 3.0 mL of blood will be 
taken from a forearm vein into serum blood-drawing tube at the time points listed in 
Flow Chart I and Flow Chart II under ADA and in Appendix 10.3.
Samples will be stored in a freezer set at the analytical laboratory until they are analyzed. The 
samples may be used for further methodological investigations, e.g. for stability testing, 
however only data related to the anti-drug antibodies will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations but not later than 5 years after the final study report has been signed.


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5.3.4
Pharmacokinetic – pharmacodynamic relationship
In order to characterize BI 754132´s exposure-response relationship a pharmacometric 
population PKPD analysis may be performed. The pharmacometric analysis will not be part 
of the CTR but will be reported separately.
5.4
ASSESSMENT OF BIOMARKER(S)
5.4.1
ERG as physiological response biomarker
For assessing potential efficacy effects after single dose IVT administration, ERG b-wave 
implicit times will be recorded under photopic condition as exploratory physiological 
response biomarker. The ERG b-wave is a positive depolarizing response predominantly 
originating from bipolar cells, and the b-wave implicit time is defined as the time needed 
after a light stimulus (such as a light flash) to reach the peak of the b-wave. In principle, the 
b-wave implicit time is a measure for the speed of the light-induced electrical response in the 
retina, predominantly on the level of bipolar cells and photoreceptor-to-bipolar cell synaptic 
transmission. 
It was shown that the b-wave implicit time can be measured robustly and conveniently in 
humans [e.g. R19-0308], and that patients with early or intermediate stage AMD as well as 
GA have significantly delayed b-wave implicit times [R19-0306; P17-03129; R18-3153; 
R19-0307]. Based on available preclinical data, a single IVT administration of a TrkB
activating antibody can improve delayed ERG b-wave implicit times in a disease-related
model of retinal dysfunction (reference to IB [c22785135], or to study report n00254511-01).
Therefore, ERG b-wave implicit times will be recorded in both eyes at baseline visit prior to 
IVT administration, and at follow-up visits as specified in Flow Chart I and Flow Chart II.
ERGs will be evoked by brief light flashes of different intensities and flickering light stimuli 
of different mean light intensities. An improvement of the b-wave implicit time (together 
with a potential dependency of this effect on the escalating doses) will provide evidence that 
BI 754132 can induce a meaningful physiological response within the patients’ eyes at the 
dose range tested. 
As further exploratory biomarker, ERG a- and b-wave amplitudes, flicker b-wave amplitude 
and flicker b-wave implicit time will be determined.
5.4.2
Biochemical and cellular biomarkers
No biochemical or cellular biomarkers relevant to the MoA will be assessed.


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5.4.3
Pharmacogenomics biomarkers
For subjects who consent in the study, one mandatory pharmacogenomics sample will be 
collected for DNA extraction and exploratory genotyping of genes related to the disease or 
the targeted pathway, such as BDNF. These data will be part of the clinical trial report.
In addition, this blood sample may also be used for exploratory analysis of variants of genes 
involved in Absorption, Distribution, Metabolism and Excretion (ADME) of drugs in case of 
unexplainable variability in pharmacokinetic parameters in patients or healthy volunteers. It 
is not intended to include these data in the final report. However, the data may be part of the 
report if necessary. All remaining samples will be destroyed no later than three years after the 
end of the trial.
Procedures and timing: Approximately 8.5 mL blood will be taken in a PAXgene Blood 
DNA tube at day 1 (Visit 2) only. If not feasible at Visit 2, the sample can also be taken at a 
later visit or day. Detailed instructions for sampling, handling and shipment of samples are 
provided in the ISF/Laboratory Manual.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor patients’ safety and to determine pharmacokinetic parameters
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The systemic safety assessments are standard, are accepted 
for evaluation of safety and tolerability of an intravitreally administered drug and are widely 
used in clinical trials. Within the ophthalmological examinations, colour fundus photography,
SD-OCT, FAF, slit lamp, indirect ophthalmoscopy (MD part only) and IOP are considered 
standard, whereas OCT-A and ERG are of exploratory nature. The pharmacokinetic 
parameters and measurements outlined in Section 5.3 are generally used assessments of drug 
exposure. The functional and pharmacogenomics biomarkers as outlined in Section 5.4 and 
5.5 are of exploratory nature only.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
For visit schedule, refer to Flow Chart I and Flow Chart II. The acceptable time windows for 
visits are given in Flow Chart I and Flow Chart II. For planned individual plasma 
concentration sampling times, refer to Appendix 10.3.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures and assessments to be performed at each visit are listed in Flow Chart I and 
Flow Chart II, and in Appendix 10.3. Additional details regarding visit procedures are 
provided below.
All ophthalmic examinations will be performed in both eyes and should be performed in 
specific order described below.
Before pupil dilation: BCVA assessment, slit lamp examination, ERG and ocular tonometry
(for determination of IOP).
After dilation: slit lamp examination, SD-OCT, OCT-A, colour fundus photography, fundus 
autofluorescence angiography. For the SRD part, IOP can be repeated after pupil dilation and 
after IVT injection on discretion of the investigator. For the MD part, IOP must be taken 
before pupil dilation and then repeated 30 to 50 min after IVT injection at Visit 2, 3 and 4.
6.2.1
Single Rising Dose Part
6.2.1.1
Screening and run-in period(s) of SRD part
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.
In case of closed dose groups no further rescreening activities for a screened and eligible 
patient are required within 12 weeks after completed screening visit. If the screening visit 
performed earlier than 14 days before dosing visit, an additional visit for repeating of safety 
lab, vital signs, ECG and targeted physical examination has to be performed again.
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.


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Any abnormal clinical significant findings observed during ophthalmological examinations 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.
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 the initial screening visit, can be re-
screened up to one time. For re-screening a new patient number will be assigned, and the 
patient must sign a new Informed Consent Form (ICF). Imaging of retina (SD-OCT, 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(s) of 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 ophthalmological assessments in Flow Chart I have been 
performed (please see Section 4.1.4 for details). After administration of BI 754132, patients 
will be monitored according to standard practice and at least for 1 hour. In this minimum 
post-dose observation period, systemic and ocular conditions will be monitored according to 
local practice for such procedures. An additional tonometry could be performed after IVT 
injection to monitor IOP.
6.2.1.3
Follow-up period and trial completion of SRD part
Patients must continue to be followed according to the visit schedule (unless they withdraw 
consent for further follow-up) in order to collect data up to 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 visits 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 ocular 
inflammation during the follow-up period as deemed medically appropriate.
Visit 10/End of Trial:
The Visit 10/EOT will be performed 16 days after the Visit 9 (see Flow Chart I). 
The Visit 10/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 9 should be scheduled as soon as possible, and also Visit 10/EOT 
should be performed to assess for safety and if patient agrees.


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If patient refuses to participate at a Visit 9 or Visit 10, the trial completion page of the eCRF 
has to be filled in.
6.2.2
Multiple Dosing Part
6.2.2.1
Screening and run-in period(s) of MD part
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.
If the screening visit has been performed earlier than 14 days before the dosing visit, an 
additional visit for repeating of safety lab, vital signs, ECG and targeted physical examination 
has to be performed again.
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 examinations
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.
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 the initial screening visit, can be re-
screened up to one time. For re-screening, a new patient number will be assigned, and the 
patient must sign a new ICF. Imaging of retina (SD-OCT, 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.
6.2.2.2
Treatment period(s) of MD 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 ophthalmological assessments in 
Flow Chart II have been performed (please see Section 4.1.4 for details). 


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Post-injection assessments:
After study drug administration a gross visual function test (e.g. finger counting/hand motion) 
will be performed within 15 minutes. IOP will be measured between 30-50 minutes after the
injection. Patients will be monitored according to standard practice and at least for 1 hour. In 
this minimum post-dose observation period, systemic and ocular conditions will be monitored
and treated according to local practice for such procedures.
6.2.2.3
Follow-up period and trial completion of MD part
Patients must continue to be followed according to the visit schedule (unless they withdraw 
consent for further follow-up) in order to collect data up to 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 visits 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 
ocular inflammation during the follow-up period as deemed medically appropriate.
Visit 7/End of Trial:
The Visit 7/EOT will be performed 42 days after the Visit 6 (see Flow Chart II). 
The Visit 7/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, the investigator should offer the possibility to continue the trial without 
further treatment until Visit7/EOT. If patient disagrees to continue under these circumstances, 
Visit 6 should be scheduled as soon as possible, and also Visit 7/EOT should be performed to 
assess for safety.
If patient refuses to participate at a Visit 6 or Visit 7, the trial completion page of the eCRF 
has to be filled in.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The main objective of this trial is to investigate ocular and systemic safety and tolerability as 
well as pharmacokinetics of single intravitreal and multiple intravitreal administrations of BI 
754132. This will be assessed by calculating descriptive statistics for safety and PK 
parameters, which will be compared between the treatment groups.
7.1
NULL AND ALTERNATIVE HYPOTHESES
No confirmatory testing is performed and hence no null and alternative hypotheses are 
defined. A discussion of the sample size is provided in Section 7.5.
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Dose escalation in the 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 and systemic DLE rate is above 0.25. The 
BLRM will not be used for the analysis of the primary endpoint.
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* = 6 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 233% from the previous dose up to doses of 3 mg, 
and to a maximum of 100% from the previous dose from dose 3 mg onwards. Dose escalation 
will continue up to the 6 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 an additional number of patients at this dose level.


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Since a Bayesian approach is applied, a prior distribution f(θ) for the unknown parameter 
vector θ needs to be specified. This prior distribution will be specified as a mixture of three 
multivariate normal distributions, i.e.
f(θ) = a1f1(θ) + a2f2(θ) + a3f3(θ)
with ai, i = 1, 2, 3 the prior mixture weights (a1+ a2+ a3 = 1), and fi(θ) = MVN(μi, Σi), the 
multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, where 
Σ = 
	
,
 , ,		
 , ,		
	
,		
.
Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.
For the current study, no relevant information in the form of human data 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 0.3 mg would equal 0.01, and the median DLE rate at the 
maximum feasible dose of 6 mg would equal 0.10. This yields μ1 = (-2.197, -0.223). 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. 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 0.3 mg would equal 0.10, and 
the median DLE rate at 6 mg would equal 0.40. These assumptions yield μ2 = (-0.405, 
-0.514). 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 0.3 mg would equal 0.001, and 
the median DLE at 6 mg would equal 0.01. These assumptions yield μ3 = (-4.595, -
0.259). 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 7.2.1.1: 1. Additionally, the prior 
probabilities of DLEs at different doses, as well as the corresponding probability of targeted 
and overdosing, are shown in Table 7.2.1.1: 2. Graphically, the prior medians with 
accompanying 95% credible intervals are shown in Figure 7.2.1.1: 1. As can be seen from 
both Table 7.2.1.1: 2 and Figure 7.2.1.1: 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 


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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 10.4.
Table 7.2.1.1: 1
Summary of prior distribution
Prior Component
Mixture Weight
Mean Vector
SD Vector
1: Weakly inf.
0.900
-2.197  -0.223
2.00  1.00
2: High Tox.
0.050
-0.405  -0.514
2.00  1.00
3: Low Tox.
0.050
-4.595  -0.259
5.00  0.01
Table 7.2.1.1: 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%
0.3
0.917
0.083
0.067
0.151
0.000
0.007
0.599
1
0.876
0.124
0.096
0.179
0.000
0.017
0.704
3
0.799
0.201
0.147
0.214
0.000
0.048
0.810
6
0.696
0.304
0.212
0.249
0.001
0.101
0.882
Figure 7.2.1.1: 1
Prior medians and 95% credible intervals 


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The prior may be updated once the trial has started in case new data that can be used will be 
available. Only 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.
7.2.1.2
Subject analysis sets
The main analysis populations are defined below. In the TSAP, further analysis data sets may 
be defined. Patients will be analysed according to the assigned treatment, unless otherwise 
specified. 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. IPDs will be identified no later than in the Report Planning 
Meeting, and the iPD categories will be updated as needed. 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 754132.
Pharmacokinetic parameter analysis set (PKS)
This set includes all subjects in the TS who provide at least one plasma sample for 
determination of PK parameters that was not excluded due to a protocol violation relevant to 
the evaluation of PK or due to PK non-evaluability (as specified below).
The pharmacokinetic parameters listed in Sections 2.1.3 and 2.2.2 for BI 754132 will be 
determined according to the relevant SOP of the Sponsor (001-MCS-36-472). 
Plasma concentration data and parameters of a subject will be included in the PK analyses if 
they are not flagged for exclusion due to a protocol violation relevant to the evaluation of PK 
(to be decided no later than in the Report Planning Meeting) or due to PK non-evaluability 
(as revealed during data analysis, based on the criteria specified below). Exclusion of a 
subject’s data will be documented in the CTR.
Relevant protocol violations may be
•
Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to
•
Incorrect dose of trial medication taken
•
Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example, there were missing samples/concentration data at important phases of PK 
disposition curve.
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses.


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Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format as in the bioanalytical report (that is 
to the same number of decimal places provided in the bioanalytical report).
7.2.2
Primary endpoint analyses
SRD part:
The primary safety endpoint “Number of patients with ocular (in the study eye) and systemic 
DLEs from drug administration till EOT” will be analysed descriptively, based on the TS.
For the definition of DLEs, please refer to Section 5.2.1.
MD 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.
7.2.3
Secondary endpoint analyses
All secondary safety endpoints defined in Section 2.1.3 will be analysed descriptively, based 
on the TS.
SRD part:
The PK endpoints Cmax, AUC0-∞, and tmax specified in Section 2.1.3 will be analysed 
descriptively, based on the PKS. Dose proportionality will be explored descriptively for the 
PK endpoints AUC0-∞and Cmax if feasible.
MD part:
Systemic exposure of BI 754132 after multiple IVT doses by determination of Cmin,1 and 
Cmin,2 (trough levels before second and third administrations) and plasma concentrations 4, 8 
and 14 weeks after the third administration will be determined in the MD part along with 
descriptive statistics, based on the PKS.
7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. For BI 754132, the 
residual effect period (REP) after IVT administration is not known. Therefore, all AEs with 


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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 planned dose group.
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 adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and the EOT visit.
Adverse events that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
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.
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, PR, QRS, RR, and further derived ECG endpoints. 
The baseline value of an ECG variable is defined as the mean of the ECG measurements prior 
to drug administration. The derivation of the quantitative and qualitative ECG endpoints and 
their analyses will be described in the TSAP.
7.2.6
Other Analyses
Not applicable.
7.2.7
Interim Analyses
The sponsor will continuously monitor the safety. The dose escalation design of the SRD part 
foresees that the sponsor and the SMC perform regular safety evaluations. These evaluations 
will be unblinded to dose.
An exploratory PK analysis will be performed after each dose group of the SRD part to check 
the systemic exposure of BI 754132.


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7.3
HANDLING OF MISSING 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.
7.4
RANDOMISATION
No randomisation will be performed. Patients will be assigned to escalating dose groups of 
the SRD part or to the MD part by order of admission into the trial.
7.5
DETERMINATION OF SAMPLE SIZE
SRD part:
If no DLE occurs, 15 DLE evaluable patients will treated in this trial part, based on the 
planned number of dose levels that are tested and on the requirement to have 6 DLE 
evaluable patients in the last dose group (see Section 3.1). However, the actual number of 
patients will depend on the actual number of dose cohorts tested and on the occurrence of 
DLEs. Based on the simulation study to evaluate operating characteristics of the BLRM (see 
Appendix 10.4), about 17 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.
MD part:
It is planned to include a total of 6 patients in this trial part. The planned sample size is not 
based on a power calculation but is in general considered as sufficient for the evaluation of 
multiple dose safety and pharmacokinetics of drugs with intravitreal route of administration.


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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 Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014 and other relevant regulations. Investigators and site 
staff must adhere to these principles. Deviation from the protocol, the principles of ICH GCP 
or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the 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 Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As per the project publication strategy, interim cohort data may 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 Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
The investigator or delegate 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. 


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The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or his delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent:
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. 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 the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 


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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 copies of source documents (please see Section 8.3.2). Before sending or 
uploading those copies, 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.
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
•
Adverse events and outcome events (onset date (mandatory), and end date (if available))
•
Serious adverse events (onset date (mandatory), and end date (if available))
•
Concomitant therapy (start date, changes)
•
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)
•
Completion of 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 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.


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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.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.


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Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI). A Coordinating Investigator is 
responsible to coordinate investigators at the different sites participating in this trial. Tasks 
and responsibilities are defined in a contract. 
An extended SMC composed of participating investigators, members of the BI trial team and 
two trial independent external ophthalmological experts will be established for both SRD and 
MD parts. The primary responsibility of the SMC is to ensure and protect the safety and well-
being of the patients participating in the trial. In the SRD part, the SMC will 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. After completion of the SRD part, the SMC will decide on 
the selection of the highest dose established as safe and tolerable (during SRD part) and its 
continuing evaluation in the MD part of the trial.
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 (CT Leader), responsible for coordinating all 
required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.


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The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service will be used in this trial. Details will be provided in Central 
Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P17-03129
Yang S, Zuo C, Xiao H, Mi L, Luo G, Xu X, et al. Photoreceptor 
dysfunction in early and intermediate age-related macular degeneration 
assessed with mfERG and spectral domain OCT. Doc Ophthalmol 2016. 
132:17-26
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 
Rockville: U.S.Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER) 2005
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
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005). 
2005
R13-1509
Eye Diseases Prevalence Research Group. Prevalence of age-related macular 
degeneration in the United States. Arch Ophthalmol (Chicago) 2004. 
122:564-572
R13-4803
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
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http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/u
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and Drug Administration 2012
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E14 Implementation Working Group. ICH E14 guideline: the clinical 
evaluation of QT/QTc interval prolongation and proarrhythmic potential for 
non-antiarrhythmic drugs: questions & answers (R3) (current version dated 
10 December 2015). 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/E
fficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2015); 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 2015
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BDNF Study Group (Phase III). A controlled trial of recombinant 
methionyl human BDNF in ALS. Neurology 1999. 52(7):1427-1433
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Vezina M. Comparative ocular anatomy in commonly used laboratory 
animals. https://link.springer.com/chapter/10.1007/978-1-62703-164-6_1 
(access date: 24 October 2017); In: Weir AB, Collins M, editors. Assessing 
ocular toxicology in laboratory animals. (Molecular and Integrative 
Toxicology) New York: Springer 2013:1-21
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Trusko B, Thorne J, Jabs D, Belfort R, Dick A, Gangaputra S, et al, 
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clinical evidence base utilizing informatics tools and techniques. Methods 
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(access date: 9 April 2017); U.S. Department of Health and Human 
Services, National Institutes of Health, National Cancer Institute 2017
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Hutton-Smith LA, Gaffney EA, Byrne HM, Maini PK, Schwab D, Mazer 
NA. A mechanistic model of the intravitreal pharmacokinetics of large 
molecules and the pharmacodynamic suppression of ocular vascular 
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related macular degeneration. Arch Ophthalmol (Chicago) 2002. 120:1435-
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Holz FG, Sadda SR, Busbee B, Chew EY, Mitchell P, Tufail A, et al, 
Chroma and Spectri Study Investigators. Efficacy and safety of 
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al. Brain-derived neurotrophic factor in patients with age-related macular 
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mechanistic modeling to enable preclinical to clinical translation and guide 
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Multimodal assessment of microscopic morphology and retinal function in 
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electroretinograms before and after intravitreal ranibizumab injection in 
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e468
9.2
UNPUBLISHED REFERENCES
c22785135
BI 754132 Investigator’s Brochure, Current Version
n00255512-01
Effects of EX00077780 on regain of retinal function in the 
oxygen-induced retinopathy mouse model. 11 April 2017
n00255513-01
 Characterization of TrkB agonists regarding 
signalling in CHO cells overexpressing the TrkB, TrkA or TrkC receptors. 
21 April 2017
n00254511-01
. Effects of EX00077780 on regain of retinal function after
hyperglycemia-induced neuronal damage in the retina of rats. 11 April 2017
n00254512-01
 Effects of EX00077780 and insulin on retinal function in the 
STZ-induced diabetic rat model. 10 April 2017
n00259625-01
. BI 754132: A 13-Week Intravenous Injection (Bolus)
Toxicity and Toxicokinetic Study in Cynomolgus Monkeys with a 13-Week 
Recovery Phase. 11 January 2019
n00262761-01
 Binding Kinetics of BI 754132 Binding to human TrkB. 23 
October 2018
n00264883-01
 Prediction of BI 754132 vitreal 
pharmacokinetics and therapeutic dose in Humans. 16 Jan 2019


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10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
Not applicable.
10.2
PHARMACOKINETIC METHODS AND ANALYSES
Not applicable.


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10.3
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING
Table 10.3: 1
Time schedule for PK and ADA blood sampling and ECG recording
during SRD part
Course
Visit
Day
Planned Time 
Planned Time 
[h]
PK 
BI 754312
ADA
ECG3
1
V2
1
Before drug administration of 
BI 754132
-0:301, 2
X
X
X
Drug administration
0:00
V2
1
4h after drug administration
4:004
X
  X
V3
4
(+/- 1 
day)
3 days after drug 
administration
72:00
X
X
V4
8
(+/- 1
days)
1 week after drug 
administration
168:00
X
X
V5
15
(+/- 2 
days)
2 weeks after drug 
administration
336:00
X
X
X
V6
22
(+/- 2 
days)
3 weeks after drug 
administration
504:00
V7
29
(+/- 2 
days)
4 weeks after drug 
administration
672:00
X
X
X
V8
56
(+/- 4
days)
8 weeks after drug 
administration
1344:00
X
V9
84
(+/- 4
days)
12 weeks after drug 
administration
2016:00
X
End of 
trial
V10
100
(+/- 7
days)
14 weeks after drug 
administration
2352:00
X
X
X
(1)
The -0:30 sample can be taken between 1h and 5min before drug administration.
(2) 
Time points are also required for sample identification.
(3)
Time points with triplicate resting ECG, shortly before PK sampling.
(4) 
A time window of +/- 15 min for sample drawing is allowed here.


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Table 10.3: 2
Time schedule for PK and ADA blood sampling and ECG recording 
during MD part
Course
Visit
Day
Planned Time 
[h]
Planned 
Time [h]
PK 
BI 754132
ADA
ECG3
1
V2
1
Before 1st drug 
administration 
of BI 754132
-4:001,2
X
X
X
1st drug 
administration
0:00
V3
29
(+/- 3 
days)
Before 2nd
drug 
administration 
of BI 754132
671:551,2
X
X
2nd drug 
adminstration
672:00
V4
57
(+/- 3 
days)
Before 3rd
drug 
administration 
of BI 754132
1343:551,2
X
X
3rd drug 
administration
1344:00
Follow 
up 
period
V5
85
(+/- 7
days)
12 weeks after 
first drug 
administratio
2016:002
X
X
X
V6
113
(+/- 7 
day)
16 weeks after 
first drug 
administration
2688:002
X
End of 
Trial
V7
155
(+/- 7 
day)
22 weeks after 
first drug 
administration
3360:002
X
X
X
(1)
PK and ADA sampling as well as ECG measurement must be performed within 4 hours prior to the IVT drug 
administration, and each sampling and measurement timepoint has to be entered in the eCRF.
(2)
Time points are also required for sample identification.
(3)
Time points with triplicate resting ECG, shortly before PK sampling.
10.4
STATISTICAL APPENDIX
A BLRM with overdose control will be used to guide dose escalation in the SRD part of this 
study. The BLRM is introduced in Section 7.2, 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 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


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Section 3.1) under various dose-toxicity relationships through computer simulation. These 
results are summarized in Table 10.4: 3. In addition, recommendations of the next dose level 
by the BLRM with overdose control principle are provided under various hypothetical 
outcome scenarios, to show how it facilitates on-study dose-escalation decisions (see 
Table 10.4: 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 10.4: 1. These scenarios reflect potential on-
study data constellations and related escalation as allowed by the model and the planned dose 
groups. It is assumed that each cohort has exactly three patients who are all evaluable. For 
each scenario, the probability of overdose for the current dose, as well as the next potential 
dose and related probabilities of target dosing and over-dosing are shown (probability of 
over-dosing: P(OD), probability of target dosing: P(TD)).
For example, scenario 1 represents the case that no DLE is observed in 3 patients at the 
starting dose of 0.3 mg. In this case, the next planned dose permitted by the model and the 
233% escalation rule is 1 mg. In contrast, scenario 2 assumes that there is one DLE observed 
in the first dose group. This would mean overtoxicity from the beginning, i.e., all planned 
dose levels are not considered safe. 
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. If no further DLE occurs in the trial, dose escalation would 
proceed to the 6 mg dose, with an additional cohort at that dose level at the end of the SRD 
part, i.e. overall 15 patients (scenario 3b).
In scenario 4, the first DLE occurs in dose group 1 mg. Then the recommendation would be 
to treat an additional cohort of 3 patients at the same dose level. If no new DLE occurs then, 
scenario 4b shows that the next recommended dose level would still be 1 mg. Thus, the 1 mg 
dose would be declared as MTD and the SRD part of the trial would stop (after 9 patients). 
However, if (after repeating dose group 1 mg according to the recommendation from scenario 
4) there was another DLE in the second cohort for dose group 1 mg (as in scenario 5), then 
the recommendation would be to go back to dose 0.3 mg. If there was no further DLE then 
(scenario 5b), one could go up again to dose 1 mg. If there was no further DLE then, the SRD 
part of the trial would stop after 15 patients, declaring 1 mg as MTD (scenario 5c).
Scenario 6 shows the case where the first DLE occurs in the 3 mg dose group. Then an 
additional cohort of 3 patients would have to be treated at this dose level. If these 3 patients 
have no further DLE, the next recommended dose would still be 3 mg. Thus, 3 mg would be 
declared as MTD, after 12 patients (scenario 6b).
In scenario 7, there is the first DLE in the first cohort of the 6 mg dose group. Then the dose 
would have to be reduced to 3 mg for the next cohort. In case of no further DLE, the SRD 
part of the trial could stop after 18 patients overall (scenarios 7b, 7c).


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In contrast, if the first DLE occurs only in the second cohort of dose group 6 mg (scenario 8), 
then the SRD part of the trial could still be completed with a total of 15 patients. However, if 
there were 2 DLEs in the highest dose group, then the model would recommend to return to 
dose 3 mg (scenario 9).
Table 10.4: 1
Hypothetical data scenarios
Scenario
Dose 
(mg/eye)
# 
Pat.
# 
DLE
Current Dose: 
P(OD)
Next recomm. Dose
(mg/eye)
Next dose:
P(TD)
P(OD)
1
0.3
3
0
0.015
1
0.960
0.040
2
0.3
3
1
0.309
N/A
N/A
N/A
3
0.3
1
3
3
0
0
0.012
3
0.963
0.064
3b
0.3
1
3
6
3
3
3
6
0
0
0
0
0.013
6
0.987
0.013
4
0.3
1
3
3
0
1
0.202
1
0.798
0.202
4b
0.3
1
3
6
0
1
0.077
1
0.923
0.077
5
0.3
1
3
6
0
2
0.313
0.3
0.894
0.106
5b
0.3
1
6
6
0
2
0.047
1
0.776
0.224
5c
0.3
1
6
9
0
2
0.109
1
0.891
0.109
6
0.3
1
3
3
3
3
0
0
1
0.218
3
0.782
0.218
6b
0.3
1
3
3
3
6
0
0
1
0.088
3
0.912
0.088
7
0.3
1
3
6
3
3
3
3
0
0
0
1
0.253
3
0.960
0.040
7b
0.3
1
3
6
3
3
6
3
0
0
0
1
0.016
6
0.806
0194


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Table 10.4: 1
Hypothetical data scenarios (cont’d)
Scenario
Dose 
(mg/eye)
# 
Pat.
# 
DLE
Current Dose: 
P(OD)
Next recomm. Dose
(mg/eye)
Next dose:
P(TD)
P(OD)
7c
0.3
1
3
6
3
3
6
6
0
0
0
1
0.085
6
0.915
0.085
8
0.3
1
3
6
3
3
3
6
0
0
0
1
0.113
6
0.887
0.113
9
0.3
1
3
6
3
3
3
6
0
0
0
2
0.364
3
0.944
0.056
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 10.4: 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


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Table 10.4: 2
Assumed true dose-toxicity scenarios
Scenario
Dose (mg)
0.3
1
3
6
1: Prior Med
DLE rate, P(DLE)
0.007
0.017
0.048
0.101
2: Prior Mean
0.067
0.096
0.147
0.212
3: High Tox
0.100
0.150
0.400
0.600
4: Low Tox
0.001
0.005
0.010
0.100
5: Non-Logistic
0.050
0.010
0.200
0.500
6: Low-High
0.010
0.050
0.400
0.600
For each of these scenarios, 1000 trials were simulated. Each cohort consisted of 3 patients 
and dose escalation complied with the following rule:
Escalate to the maximum dose which satisfies the overdose criterion and is ≤ 234% 
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. The maximum allowed 
patient number for each trial was chosen as 18 or 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 10.4: 3.


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Table 10.4: 3
Simulated operating characteristics
Scenario
Max. allowed    
# Patients
% of trials declaring a MTD with 
true DLE rate in
% of stopped 
trials**
# Patients
# DLEs
[0, 0.25)
target dosing
[0.25,1]
overdosing
Mean (Min-
Max)
Mean
(Min-Max)
1*
18
87.3
0.7
12.0
16.5 (3-18)
1.99 (0-6)
2*
18
67.9
0.1
32.0
12.2 (3-18)
1.79 (0-6)
3
18
60.1
9.0
30.9
11.5 (3-18)
2.17 (1-6)
4*
18
85.7
1.9
12.4
17.6 (3-18)
1.91 (0-6)
5
18
69.7
3.6
26.7
13.1 (3-18)
1.97 (0-6)
6
18
73.5
15.0
11.5
13.3 (3-18)
2.27 (1-6)
1*
21
96.8
0.5
2.8
16.7 (3-21)
2.01 (1-7)
2*
21
77.0
0.2
22.8
12.7 (3-21)
1.86 (1-7)
3
21
65.8
9.1
25.1
12.2 (3-21)
2.33 (0-7)
4*
21
97.8
1.4
0.8
17.9 (3-21)
1.95 (0-6)
5
21
76.7
4.7
18.6
13.8 (3-21)
2.06 (0-6)
6
21
77.4
14.1
8.5
13.8 (3-21)
2.40 (0-6)
*
Due to technical reasons, scenarios 1,2, and 4 could only be calculated with one additional dose level with assumed 
true DLE rate in the overdose range. As additional dose level, a dose of 15mg was chosen with the following assumed 
true toxicity probabilities: scenarios 1,2: 0.7, scenario 4: 0.6. 
**
The stopped trials include early stopped trials (stopped due to too much toxicity), as well as trials that stopped because
the maximum allowed patient number was reached before an MTD was found.
Maximum number of patients =21
The case when the maximum number of patients is chosen as 21 allows the model to 
appropriately perform in most cases and for finding an MTD within the target dosing range 
with very high probability. 
In scenario 1, which reflects the case that the true dose-toxicity is aligned with prior medians,
96.8% of the simulated trials declared a dose as MTD with true DLE rate in the targeted 
toxicity range. Note that 2.8% of the simulated trials stopped either because there was no 
MTD determined after 21 patients had been observed (0.5%) or because of too high toxicity 
for the planned doses (2.3%). This latter is mostly due to the cases that 1 DLE is observed out 
of 3 patients at the starting dose of 0.3 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 23%). In this case, about 77% of the trials 
would end with an estimated MTD within the targeted toxicity range, and 0.2% in the 
overdosing range.
In Scenario 3 (high-toxicity scenario), only 65.8 % of the trials declared a dose as MTD with 
true DLE rate in the targeted toxicity range. In 9.1% of the trials, the estimated MTD was in 


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the overdosing range. Scenario 4 (low-toxicity scenario) shows the best results, i.e. the lowest 
number of stopped trials and the highest number of trials with estimated MTD in the target 
range, as would be expected. 
Scenarios 5 and 6 showed reasonable operating characteristics, given the quite large 
deviations of the assumed true dose-toxicity curve from the assumptions underlying the 
BLRM. 
The mean patient numbers range from 12.2 patients (Scenario 3) to 17.9 patients (Scenario 
4), 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.
Maximum number of patients =18
If the maximum number of patients is chosen as 18, an early stopping of the trial would be 
more often required than above. In most cases, this would be due to reaching the maximum 
number of patients before an MTD could be determined. Still, the resulting operating 
characteristics are reasonable.
The mean patient numbers range from 11.5 patients (Scenario 3) to 17.6 patients (Scenario 
4), and the maximum number of patients was 18. Again, the patient numbers are as expected 
and increase when moving away from the high-toxicity scenario.
Overall, by reviewing the metrics presented in Table 10.4: 3, it can be seen that the model is 
generally conservative due to the overdose control criteria. In all scenarios, the probabilities 
of recommending a dose with true DLE rate being at least 25%, P(DLE ≥ 25%), as MTD are 
much smaller than the probabilities of recommending a dose with true P(DLE) < 25% as 
MTD.
R version 3.5.1 was used for data scenarios and simulations.
10.5
BENEFIT-RISK ASSESSMENT IN CONTEXT OF COVID-19 
PANDEMIC FOR PATIENTS PARTICIPATION IN TRIAL 1418-0001 
INVESTIGATING BI 754132
Study population
GA secondary to AMD is affecting elderly population. Approximately 10% of individuals 
aged 65 to 74 years, and 30% of those aged 75 to 85 years, show signs of AMD. Even though 
few studies identified examined non-ophthalmic comorbidities among patients with GA, 
because of the old age, and potential concomitant diseases, this population is considered 
fragile and potentially at higher risk for complications following COVID-19 infection.
Benefits and risks conclusions and recommendations
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. 
BI 754132 is administered intravitreally using standard aseptic technique.


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Therefore, no change on the Benefit-Risk assessment of the compound in the context of the 
COVID-19 pandemic is foreseen.
The current study population is potentially at higher risk of COVID-19 infection due to 
background or concomitant diseases. Enrollment will re-start when the local situation allows 
and appropriate risk mitigation measures (e.g. use of personal protective equipment) will be 
implemented in line with local instructions and recommendations. 
The investigators will take the totality of information related to each single patient and the 
local COVID-19 situation into consideration when performing the individual benefit-risk 
assessment on a case-by-case basis. Considering all aspects, the investigator will decide upon 
each patient’s (continued) participation in the trial. BI as the sponsor, where required, will 
support the investigator in their decision finding. It is acknowledged that the investigator may 
decide to implement protocol deviations where this protects the safety, wellbeing and/or is in 
the best interest of the patient.
Details of the trial procedures at selected visits
In situations where an individual patient is unable or unwilling to attend a clinic visit, the 
investigator must assess the risk-benefit for the individual patient and may decide to perform 
a visit remotely if this is in the best interest of the patient and if agreed with the sponsor. All 
COVID-19 related deviations from the original schedule of visits and procedures will be 
documented and the implications considered for the analysis of the trial data. No trial specific 
SARS-CoV-2 testing will be performed. Testing will be performed in line with local standard 
procedures. In case of a confirmed infection appropriate measures e.g. for monitoring and 
quarantine will be implemented.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
22 May 2019
EudraCT number
EU number
2018-004125-92
BI Trial number
1418-0001
BI Investigational Medicinal 
Product(s)
BI 754132
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising intravitreal doses of BI 754132 in patients 
with geographic atrophy secondary to age-related 
macular degeneration (open label, non-
randomized, uncontrolled).
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
3.1
Description of change
Criteria of sentinel dosing, decision-maker and 
way of communication have been described.
Rationale for change
Authority feedback
Section to be changed
1.4
Description of change
The minimum observation period per patient has 
been specified.
Rationale for change
Authority feedback
Section to be changed
3.1; 3.3.5
Description of change
Increase to 3 evaluable patients for dose-
escalation.
Rationale for change
Authority feedback
Section to be changed
Synopsis; 2.1.2; 3.1; 5.2.1; 7.2.1.1; 7.2.2
Description of change
The criteria for DLEs have been expanded to also 
address systemic effects.
Rationale for change
Authority feedback
Section to be changed
4.2.2.3
Description of change
The duration of contraception in male participants 
(and their partners) has been defined and the need 
of condom use has been expanded to 
vasectomized participants. The inconsistency of 
contraception advice of WOCBP (not to include
in trial) has been resolved by defining them as 
partners of trial participants.
Rationale for change
Authority feedback
Section to be changed
3.3.4.3


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Description of change
A single serious adverse reaction or two severe 
adverse reactions (regardless of system organ 
class) have been specified as stop criteria for 
enrolment.
Rationale for change
Authority feedback
11.2
GLOBAL AMENDMENT 2
Date of amendment
04 Jun 2019
EudraCT number
EU number
2018-004125-92
BI Trial number
1418-0001
BI Investigational Medicinal 
Product(s)
BI 754132
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising intravitreal doses of BI 754132 in patients 
with geographic atrophy secondary to age-related 
macular degeneration (open label, non-
randomized, uncontrolled).
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
4.1.4 and 6.2.2
Description of change
The minimum immediate post dose observation 
period and the including specific assessments 
required for each patient have been specified.
Rationale for change
Authority feedback
11.3
GLOBAL AMENDMENT 3
Date of amendment
04 Jul 2019
EudraCT number
EU number
2018-004125-92
BI Trial number
1418-0001
BI Investigational Medicinal 
Product(s)
BI 754132
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising intravitreal doses of BI 754132 in patients 
with geographic atrophy secondary to age-related 
macular degeneration (open label, non-
randomized, uncontrolled).
Global Amendment due to urgent safety reasons
Global Amendment


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Section to be changed
Protocol Synopsis
Description of change
Safety Monitoring Committee has been spelled
Rationale for change
The abbreviation SMC was used in the synopsis 
without prior explanation
Section to be changed
Flow Chart & 10.3 (Table 10.3:1)
Description of change
ECG recording has been taken out at Visit 6 (day 
22) since no PK sampling is planned at that visit
Rationale for change
For the exposure-response (PK-QT) analysis, 
ECG recordings are needed only at time points of 
PK sampling
Section to be changed
Flow Chart and Table 10.3
Description of change
Add ADA sampling Visit 7 (day 29)
Rationale for change
Authority (FDA) feedback
Section to be changed
Flow Chart
Description of change
Add "resting" before term “ECG” into footnote 
(2)
Rationale for change
To emphasize the need of resting conditions for 
the ECG recordings
Section to be changed
Flow Chart
Description of change
Deletion of Footnote 9 from table line description 
“slit lamp and IOP”
Rationale for change
Footnote 9 text inappropriate for both 
ophthalmologic examinations 
Section to be changed
1.4.2.5
Rationale for change
Correction w.r.t. the timepoints of safety lab and 
ECG recordings
Section to be changed
3.3.3
Description of change
Exclusion criteria No.4 changed to "Previous 
participation in other trials for treatment of GA 
receiving active drug in the study eye"
Rationale for change
Feedback by Co-ordinating Investigator
Section to be changed
4.1.5
Description of change
Blinding and unblinding requirement added for 
ECG evaluations
Rationale for change
Feedback central ECG reading vendor
Section to be changed
4.2.2.3
Description of change
Rephrasing of contraception requirements of men 
able to father a child (trial participants) 
Rationale for change
Clarification that male trial participants are not 
required to have vasectomy but are required to 
use a condom (regardless of vasectomy) if their 
sexual partner is WOCBP.
Section to be changed
5.2.1
Description of change
Rephrasing of DLE descriptions


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Rationale for change
Integration of ocular and systemic DLEs as 
AESIs and of CTCAE assignment for systemic 
DLEs
Section to be changed
5.2.6
Description of change
Rephrasing of the description of ECG recording 
and evaluation
Rationale for change
Feedback central ECG reading vendor
Section to be changed
6.2 
Description of change
Add ERG measurement before pupil dilation
Rationale for change
Feedback from ERG vendor
11.4
GLOBAL AMENDMENT 4
Date of amendment
13 Oct 2020
EudraCT number
EU number
2018-004125-92
BI Trial number
1418-0001
BI Investigational Medicinal 
Product(s)
BI 754132
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising intravitreal doses of BI 754132 in patients 
with geographic atrophy secondary to age-related 
macular degeneration (open label, non-
randomized, uncontrolled).
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Title page; Synopsis; Flow Chart; 1.2; 1.3;
1.4.2.5 ; 2.1.1; 2.1.2; 2.1.3; 2.2.2; 3.1; 3.2; 3.3; 
3.3.2; 3.3.5, 4.1.1;4.1.3; 4.1.4; 5.1; 5.2.2; 5.2.3; 
5.2.4; 5.2.5; 5.2.6; 5.3.2.1; 5.3.2.2; 5.4.1; 6.1; 6.2; 
6.2.1; 6.2.2; 7; 7.2.1.1; 7.2.1.2; 7.2.2; 7.2.3; 7.2.7; 
7.4; 7.5; 8.7; appendices 10.3; 10.4
Description of change
The term, content and design of the MD part 
including an additional flow chart and timetable 
for PK, ADA sampling and ECG recording has 
been included. Where appropriate the text has 
been subdivided into SRD and MD part and the 
citation of the respective flow charts (I and II) 
have been added.
Rationale for change
As the intravitreal clinical development of 
BI 754132 is aiming for a safe drug with a 
preferable long lasting effect (e.g. allowing 2- or 
3-monthly treatment) only the highest dose of the 
SRD is expected to provide sufficient eye 


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exposure and efficacy to be selected assessing the 
safety, tolerability and pharmacokinetics after 
multiple dosing.
The inclusion of 6 patients (as required for the 
last dose group in SRD part) out of an almost 
identical patient population and applying the same 
safety assessments during treatment and extended 
follow-up period is considered as sufficient to 
justify the amendment of the SRD with a multiple 
dosing part using the same route of 
administration.
Section to be changed
Flow Chart I (SRD part) and 6.2; 6.2.1.2
Description of change
Extension of text in footnote 8 with “at PI´s 
discretion, IOP can be repeated after pupil 
dilation and after IVT injection”; addition of 
footnote 8 to IOP. Wording in 6.2 and 6.2.1.2
adapted accordingly.
Rationale for change
For clarity and safety reasons based on PIs
feedback to allow IOP measurement after pupil 
dilation and after IVT injection.
Section to be changed
Flow Chart I (SRD part) and 6.2.1.1
Description of change
Addition of footnote 10 and changed wording in 
6.2.1.1 to “If the screening visit performed earlier 
than 14 days before dosing visit, an additional 
visit for repeating of safety lab, vital signs, ECG 
and targeted physical examination has to be 
performed again.”
Rationale for change
For clarity and insertion of footnote based on PIs
feedback
Section to be changed
1.2
Description of change
Description of interim PK and safety data of dose 
cohort 1 and 2 of SRD part and reference to actual 
IB.
Rationale for change
Update of available data and for transparency 
Section to be changed
1.4 and Appendix 10.5
Description of change
Benefit Risk Assessment in context of COVID-19 
pandemic for patients participating in trial 
1418-0001 investigating BI 754132
Rationale for change
Clarification
Section to be changed
Synopsis, 2.1.3
Description of change
Deletion of eye disorders
Rationale for change
For clarity
Section to be changed
2.2.1
Description of change
Change spelling to ophthalmological
Rationale for change
Based on PI feedback


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Section to be changed
2.2.2; 3.1; 5.2.4; 5.7; 6.2.1.1; 6.2.1.2; 6.2.2.1; 
6.2.2.2; 7.2.4; 8.7
Description of change
OCT-A has been spelled; GA assessment has 
been specified; missing ERG readouts have been 
added
Rationale for change
For clarity and completeness
Section to be changed
3.1
Description of change
Deletion of “and on” in first sentence of third 
paragraph
Rationale for change
Correction
Section to be changed
3.3.2; Inclusion criteria #3
Description of change
Separation and differentiation of BCVA inclusion 
criteria between SRD and MD part; addition of 
Snellen equivalent in ETDRS letter chart.
Rationale for change
Lower visual acuity in MD part should result in 
better recruitment, EDTRS letter chart based on 
PI feedback.
Section to be changed
3.3.3
Description of change
Exclusion of patients in the MD part that 
participated in the SRD part
Rationale for change
For safety reasons
Section to be changed
5.2.1
Description of change
Extension and precision of term vascular 
occlusion
Rationale for change
For clarity and better differentiation versus CNV
Section to be changed
5.2.2
Description of change
Measurement of height only at Visit 1
Rationale for change
For Clarity
Section to be changed
5.2.6
Description of change
Description of precise ECG electrode placement 
as optional procedure; specify that single ECG 
recordings are only allowed in case of repetitions 
due to quality reasons
Rationale for change
For clarity and based on PI feedback
Section to be changed
5.2.8.2.2
Description of change
Deletion to fax the SAE form 
Rationale for change
According to site standards and revised sponsor 
process
Section to be changed
5.4.1
Description of change
Missing ERG readouts have been added
Rationale for change
For clarity and completeness
Section to be changed
5.4.3
Description of change
Deletion of randomization
Rationale for change
Correction; non-randomized trial


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Section to be changed
6.2
Description of change
Insertion of “slit lamp examination” and “ocular 
tonometry (for determination of IOP)” under 
assessments before pupil dilation
Rationale for change
Correction and to correspond to footnote 8 in 
Flow Chart I (SRD)
Section to be changed
7.2.1.2
Description of change
Deletion of “The subject experienced emesis that 
occurred at or before two times median tmax of
the respective treatment (Median tmax is to be 
determined excluding the subjects
experiencing emesis)” 
Rationale for change
For clarity as not considered relevant for an 
intravitreally administered IMP
Section to be changed
8.7
Description of change
Addition of primary responsibility of SMC within 
trial and specification of objectives for SRD and 
MD part 
Rationale for change
Dose selection based on SRD outcome and 
decision to continue with MD part
Section to be changed
10.3
Description of change
Addition of footnote (4) to define time window 
for PK sampling at V2
Rationale for change
Based on PI feedback
11.5
GLOBAL AMENDMENT 5
Date of amendment
12 Oct 2021
EudraCT number
EU number
2018-004125-92
BI Trial number
1418-0001
BI Investigational Medicinal 
Product(s)
BI 754132
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising intravitreal doses of BI 754132 in patients 
with geographic atrophy secondary to age-related 
macular degeneration (open label, non-
randomized, uncontrolled).
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Flow Chart II Multiple Dosing Part
Description of change
a) Addition of “indirect ophthalmoscopy” to slit 
lamp and IOP assessments


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b) Deletion of footnote 5 (CFP; “only be done if 
considered medically necessary by the 
principal investigator”)
c) Renumbering of subsequent footnote numbers 
5 to 10
d) Deletion of “at PI´s discretion, IOP can be 
repeated after pupil dilation and after IVT 
injection“ in footnote 7 and addition of 
footnote 8: “OP must be repeated 30 to 50 
minutes after IVT injection at Visit 2, 3 and 
4.”
e) Deletion of “If fixation does not allow for 
acquisition of good quality images, the 
examination may be considered optional” in 
footnote 9
f)
Addition of “Post-injection assessments” 
Rationale for change
a) In accordance with sections 1.4.2.6 and 5.2.4.
b) In accordance with sections 1.4.2.6 and 5.2.4.
c) To fit with the flow chart content sequence
d) In accordance with section 6.2 with the aim to 
better monitor IOP changes after IVT 
injections in MD part
e) FAF, SD-OCT and CFP considered 
mandatory in accordance with sections 
1.4.2.6, 5.2.4 and 5.7
f)
In accordance with insertion of post-injection 
assessments in section 6.2.2.2
Section to be changed
Abbreviations
Description of change
Addition of CFP, CRP, HbA1c and OCT-A
Rationale for change
Required due to additions into sections 1.2, 1.4.2, 
5.2.4 and 5.2.5
Section to be changed
1.1
Description of change
Addition of: “However, in recent years, a number 
of new potential therapies has been tested. 
Recently, results from Phase III trials of 
Lampalizumab (Roche), an Anti-Complement 
Factor D Fab, showed no efficacy. Ongoing 
clinical trial evaluations include e.g. APL-2 
(Apellis), an Anti- Complement C3 in Phase III 
development”
Rationale for change
To reflect the correct status of competitor´s trial 
outcomes
Section to be changed
1.2; sub-headings: Data from clinical studies, 
Pharmacokinetics, Anti-drug antibodies and 
Safety evaluations


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Description of change
Description of all safety & PK data and addition 
of ADA data of SRD part
Rationale for change
Update of all available SRD data, description of 
all observed ocular and systemic AEs & SAEs 
and to reference the actual version of IB
Section to be changed
1.4
Description of change
Rearrangement of introductory part into section 
1.4.3 (Discussion)
Rationale for change
To avoid redundancy and to better discuss the 
newly added content of sections 1.4.2.5 and 
1.4.2.6
Section to be changed
1.4.2.3
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 
favourable risk-benefit profile. To the best of the 
sponsor´s knowledge there is currently no 
comparable material 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 effect like 
vitreous floaters or intraocular inflammation. The 
overall risk for such events is considered low 
based on long-term experience with comparable 
material. However, patients should be made 
aware of this risk, as reflected in the ICF. To the 
best of the sponsor´s knowledge there is currently 
no comparable material 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 material from certain manufacturers and 
leaves 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 754132.”
Rationale for change
Following release of a caution statement by 
Becton Dickinson (BD), who supply materials for 


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use in this trial, a risk-benefit evaluation and 
associated mitigation steps was performed and 
incorporated into the trial protocol. This insertion 
has been requested and recently approved by 
MHRA on the basis of a local amendment. 
Implementation on the basis of a global 
amendment will lead to harmonization across all 
trial sites.
Section to be changed
1.4.2.5; addition of this section
Description of change
Description of both SAEs; PI´s & sponsor´s
assessments, reporting and recommended safety 
measures to be implemented in the MD part 
Rationale for change
For clarity and transparency
Section to be changed
1.4.2.6
Description of change
Addition of “minimizing” to section title. 
Description of the safety measures to be 
implemented in the MD part. Addition of CRP 
and HbA1c collection to the safety laboratory 
parameters in accordance with sections 3.3.3 and 
5.2.5
Rationale for change
Based on SMC and sponsor internal safety 
assessments & recommendations
Section to be changed
1.4.3
Description of change
Additions, update and edition of discussion 
section reflecting the content of previously added 
data described in sections 1.2, 1.4.2.5 and 1.4.2.6
Rationale for change
To better include and discuss all relevant safety 
data of SRD part
Section to be changed
3.1, sub heading: MD part and Figure 3.1:2
Description of change
Criteria of the sentinel dosing process for the MD 
part, decision making and communication
Rationale for change
Based on sponsor internal safety assessment and 
recommendation
Section to be changed
3.3.2; inclusion criteria 1., 3. and 5.
Description of change
1. Specification of GA lesion size (in mm2 and 
disc area size), reference to study eye and 
differentiation between SRD and MD part
3. Restatement of BCVA criteria in MD part
5. Deletion of “if both eyes are eligible and have 
identical VA the investigator may select the 
study eye”
Rationale for change
Based on sponsor internal safety assessment and 
recommendation
Section to be changed
3.3.3
Description of change
Addition of exclusion criteria 14 and 15 for MD 
part


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Rationale for change
Based on SMC and sponsor internal safety 
assessment and recommendation
Section to be changed
5.2.4; section title and content
Description of change
a) Change of section title to “Ophthalmological 
Examination”
b) Reorganization of section, additions (to MD 
part) and specification of ophthalmological 
examinations
Rationale for change
For clarity and to reflect content of sections 
1.4.2.6 and 1.4.3
Section to be changed
5.2.5
Description of change
Addition of HbA1c and CRP into safety 
laboratory parameters
Rationale for change
To reflect content of sections 1.4.2.6 and 3.3.3
Section to be changed
5.7
Description of change
Reassignment of certain ophthalmology 
examinations (SD-OCT, FAF and indirect 
ophthalmology) to “standard”
Rationale for change
For safety reasons and in accordance with 
sections 1.4.2.6, 1.4.3 and 5.2.4 for MD part
Section to be changed
6.2
Description of change
Different procedures of IOP measurements during 
SRD and MD part
Rationale for change
For safety reasons and in accordance with Flow 
Chart I (SRD part) and II (MD part)
Section to be changed
6.2.2.2
Description of change
Addition and description of “post-injection 
assessments”
Rationale for change
For safety reasons and to reflect added assessment 
in Flow Chart II (MD part)
Section to be changed
8
Description of change
Addition of “As per the project publication 
strategy, interim cohort data may be published as 
available, while full results will be published after 
CTR finalization”
Rationale for change
For transparency and in harmonization with other 
sponsor conducted retinopathy trials
11.6
GLOBAL AMENDMENT 6
Date of amendment
17 Feb 2022
EudraCT number
EU number
2018-004125-92
BI Trial number
1418-0001
BI Investigational Medicinal 
Product(s)
BI 754132


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Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising intravitreal doses of BI 754132 in patients 
with geographic atrophy secondary to age-related 
macular degeneration (open label, non-
randomized, uncontrolled).
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Page 6-7: Flow chart II (multiple dosing part)
Description of change
Change of footnotes 2 and 3 in and under the 
table:
(2)…before PK sampling (see time schedule in 
Appendix 10.3)…
(2)…before PK sampling.
(3) PK sampling see time schedule in Appendix 
10.3 
(3) PK and ADA sampling as well as ECG 
measurement must be performed within 4 hours 
prior to the IVT drug administration, and each 
sampling and measurement timepoint has to be 
entered in the eCRF.
Rationale for change
New time-window for PK & ADA sampling and 
ECG measurement to improve feasibility (based 
on PI feedback)
Section to be changed
Page 19: 1.2 Drug profile / Pharmacokinetics:
Description of change
…collectedbefore…injection.Cohort…
…collected before…injection. Cohort
Rationale for change
Missed space in former versions
Section to be changed
Page 19: 1.2 Drug profile / Safety evaluations:
Description of change
…non-arteric…
…non-arteritic…
Rationale for change
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…case occured…was subjectivly…
…case occurred…was subjectively…
Rationale for change
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and minimization the risks
Description of change
Amendment…patientsUpdate…
• Amendment…patients.
• Update informed consent (IC)…
Rationale for change
Insertion of missing bullet point
Section to be changed
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and minimization the risks
Description of change
…monitoring and mimimization…


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…monitoring and minimization…
and
…Additionally , a systemic evaluation will be 
performed at each timepoint, to assess…
…Additionally, a systemic evaluation will be 
performed at the timepoints specified in the flow 
charts under physical examination, to assess…
Rationale for change
Typo and wording correction.
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Description of change
…continuative use in this clinical trial…
…continued use in this clinical trial…
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…drug releated…
…drug-related…
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…Cmax…
…Cmax…
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…investigated,the…
…investigated, the…
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…occurance…
…occurrence…
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Description of change
Additional text: Prior to the blood pressure 
measurement, the PI should ensure that the subject 
has taken his or her blood pressure medications (if 
any) as usual at home. If the measurement results 
are to be doubted for example because of 
preceding great exertion of the subject, a new 
measurement should be taken after half an hour in 
a resting position and only this stable value has to 
be entered in the eCRF.
Rationale for change
Better explanation of how to improve blood 
pressure measurments. Addtionally, instruction for 
the study centers to remind their patients to take 
all necessary medication before their visits at 
home.
Section to be changed
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Description of change
…photographswill…
…photographs will…
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…documents.If…
…documents. If…
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…determination of pharmacokinetic parameters. 
Planned time points for systemic pharmacokinetic 
samples are listed in Appendix 10.3
…determination of pharmacokinetic parameters. 
Sampling should be done at the timepoints listed 
in the flow-chart I and II and within 4 hours prior 
to the IVT drug administration. It is important to 
ensure that the exact time of the assessment of 
pharmacokinetics is recorded.
Rationale for change
New time-window for PK & ADA sampling and 
ECG measurement to improve feasibility (based 
on PI feedback)
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completion of MD part
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ADA blood sampling and ECG recording during 
MD part
Description of change
Planned time for V1 was changed to -4:00h;
Footnotes changed in and under the table:
(1) A time window of +/- 15 min for sample 
drawing is allowed here. 
(1) PK and ADA sampling as well as ECG 
measurement must be performed within 4 hours 
prior to the IVT drug administration, and each 
sampling and measurement timepoint has to be 
entered in the eCRF.
Rationale for change
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ECG measurement to improve feasibility (based 
on PI feedback)
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trial 1418-0001 investigating BI 754132
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…conclusions and and…
…conclusions and…
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Section to be changed
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of covid-19 pandemic for patients participation in 
trial 1418-0001 investigating BI 754132
Description of change
…COVID-19 releated…
…COVID-19 related…
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…Synopis…
…Synopsis…
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…visual acquity…in case of repetitons…
…visual acuity…in case of repetitions…
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…tmax…
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…decribed…
…described…
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…implanted…
…implemented…
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APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Boehringer Ingelheim 
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Meaning of Signature  
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SAP_001.pdf: 


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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...........................................................13
6.1
TREATMENTS...................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED ...........................................................................15
6.5
POOLING OF CENTRES..................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................17
7.
PLANNED ANALYSIS ......................................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........20
7.2
CONCOMITANT DISEASES AND MEDICATION......................................20
7.3
TREATMENT COMPLIANCE ........................................................................20
7.4
PRIMARY ENDPOINTS ...................................................................................20
7.5
SECONDARY ENDPOINTS .............................................................................21
7.5.1
Key secondary endpoints ....................................................................................21
7.5.2
Secondary endpoints ...........................................................................................21
7.7
EXTENT OF EXPOSURE .................................................................................23
7.8
SAFETY ANALYSIS..........................................................................................23
7.8.1
Adverse Events ....................................................................................................23
7.8.2
Laboratory data...................................................................................................25
7.8.3
Vital signs.............................................................................................................25
7.8.4
ECG ......................................................................................................................25
7.8.5
Others ...................................................................................................................26
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............28
9.
REFERENCES ....................................................................................................29


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11.
HISTORY TABLE..............................................................................................33


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR .........................................................13
Table 6.3: 1
Subject sets analysed ........................................................................................16
Table 11: 1
History table .....................................................................................................33


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC0-tz
Area under the concentration-time curve of BI 754132 in serum over the 
time interval from 0 to the last quantifiable drug concentration
AUC0-∞
Area under the concentration-time curve of BI 754132 in serum over the 
time interval from 0 extrapolated to infinity
BCVA
Best Corrected Visual Acuity
BLRM
Bayesian Logistic Regression Model
BMI
Body mass index
CI
Confidence Interval
Cmax
Maximum serum concentration of BI 754132 after a single intravitreal dose
CV
Arithmetic Coefficient of Variation
DBLM
Database Lock Meeting
DILI
Drug induced liver injury
DLE
Dose Limiting Event
ENR
Enrolled set
ERG
Electroretinography
ES
Entered set
FAF
Fundus autofluorescence
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
IVT
intravitreal
IQRMP
Integrated Quality and Risk Management Plan
Max
Maximum
Min
Minimum
N
Number non-missing observations
NAION
Nonarteritic anterior optic ischaemic neuropathy 
OCT
Optical Coherence Tomography
P10
10th percentile


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Term
Definition / description
P90
90th percentile
PKS
PK parameter analysis set
Q1
1st quartile
Q3
3rd quartile
q4w
4-weekly interval
RAGe
Report Appendix Generator system
REP
Residual Effect Period
SD
Standard Deviation
SMC
Safety Monitoring Committee
tmax
Time from dosing to maximum serum concentration of BI 754132
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal


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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 trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
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 6.3 or higher, 
).
The statistical analyses will be performed within the validated working environment CARE, 
including SAS® (current Version 9.4, by 
), and a number of 
SAS®-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP. The following changes compared to the protocol will be made:
- The additional analysis set ‘Enrolled set’ was defined, which is used for disposition tables 
and listings, see Section 6.3.
- The additional analysis set ‘Entered set’ was defined, which is used in disposition tables and 
listings, see Section 6.3.
- The additional analysis set ‘DLE evaluable set’ was defined for the SRD part, which is used 
for SMC outputs related to the BLRM, see Section 6.3.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP:
SRD part:
∀
Number of patients with ocular (in the study eye) and systemic dose limiting events 
(DLEs) from drug administration until end of trial (EOT). 
For definition of a DLE, refer to Section 7.4.
MD 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 from drug administration until EOT
∀
Number of patients with any ocular AEs in the study eye from drug administration 
until EOT
∀
Cmax (maximum serum concentration of BI 754132 after a single intravitreal dose)
∀
AUC0-∞(area under the concentration-time curve of BI 754132 in serum over the time 
interval from 0 extrapolated to infinity)
∀
tmax (time from dosing to maximum serum concentration of BI 754132)
MD part:
∀
Systemic exposure of BI 754132 after multiple IVT doses by determination of Cmin,1
and Cmin,2 (trough levels before second and third administrations) and serum
concentrations 4, 8 and 14 weeks after the third administration
The pharmacokinetic parameters listed in Section 2.1 of the CTP for drug BI 754132 will be 
calculated according to the BI Standard Operating Procedure (SOP) ‘Standards and processes 
for analyses performed within Clinical Pharmacokinetics/Pharmacodynamics’ [BI-KMED-
TMCP-HTG-0025] (7). General note: PK parameters (planned as secondary or further 
endpoints) are determined only if sufficient data is available.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatment and selection 
of doses, please see CTP, Section 4.
The study will be performed as a non-randomized, open-label trial in an uncontrolled manner. 
It is planned that up to 24 patients (in SRD part it is expected to enrol up to 18 patients
(planned 15 plus 3 additional if DLEs occur), in MD part it is expected to enroll 6 patients)
with geographic atrophy secondary to age-related macular degeneration participate in this 
study, according to 4 sequential groups comprising 3 patients per group and 6 at final 
treatment group (SRD part) and 6 in MD treatment group. 
For details of dosage and formulation see Table 6.1:1 below.
Table 6.1: 1
Labels for treatments for use in the CTR 
Part
Treatment 
group
Treatment
Short label
SRD
1
A
BI 754132, injection, 0.3 mg
BI 0.3mg
SRD
2
B
BI 754132, injection, 1 mg
BI 1mg 
SRD
3
C
BI 754132, injection, 3 mg
BI 3mg 
SRD
4
D
BI 754132, injection, 6 mg
BI 6mg 
MD
5
E
BI 754132, injection, 6 mg, q4wk
BI 6mg q4wk
CTP Section 7.2.5:
For BI 754132, 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 following separate study phases will be defined for the analyses of AEs:
∀
Screening (ranging from 0:00h (midnight) on day of informed consent until first 
administration time of BI 754132)
∀
On treatment
o
BI treatment (separately for each treatment, ranging from the time of first 
administration of BI 754132 until 0:00h (midnight) on the day after trial 
completion date)
Please note that all AEs reported between start of trial drug administration and the last per-
protocol contact will be considered on treatment (i.e. no follow-up period is considered in this 
trial).


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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). Screening will not be included in this analysis. 
The following totals will be provided in addition in Section 15.3:
∀
a total over all on treatment phases included in this analysis ("Total") (SRD part only)
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.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewers guide. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated patients.
Section 7.2.1.2 of the CTP: Important protocol deviations (iPDs) will be defined in the 
Integrated Quality and Risk Management (IQRM) plan. iPDs will be identified no later than 
in the Report Planning Meeting, and the iPD categories will be updated as needed.
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting and database lock meeting
(RPM/DBLM). At this meeting, all manual deviations identified at the sites by the CRAs and 
deviations too complex to program will be reviewed by the trial team to decide which are 
considered important. For definition of important protocol deviations (iPD), and for the 
process of identification of these, refer to the Boehringer Ingelheim (BI) SOP "Identify and 
Manage Important Protocol Deviations (iPD)" (2).
IPDs will be identified no later than in the Report Planning Meeting. If any iPDs are 
identified, they are to be summarised into categories and will be captured in the RPM/DBLM
minutes (decision log) and in the iPD specification file (3). The iPD categories in the iPD
specification file will be updated as needed. The decision on exclusion of subjects from 
analysis sets will be made after discussion of exceptional cases and implications for analyses.
The iPD specification file (e.g. the DV domain specifications) will be stored within the TMF
in EDMS.
The iPDs will be summarised and listed.


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6.3
SUBJECT SETS ANALYSED
∀
Enrolled set (ENR):
This subject set includes all patients who were enrolled in the study (i.e. signed informed 
consent) regardless of whether they were treated or not. The ES is used for the disposition 
table / listing.
∀
Entered set (ES):
This subject set includes all patients who signed informed consent and were entered in 
the study regardless of whether they were treated or not. The ES is used in the disposition 
table / listing.
∀
Treated set (TS):
The TS will consist of all patients who were treated with at least one dose of BI 754132.
This is the full analysis set population in the sense of ICH-E9 (1). It is used for 
demographics, baseline characteristics, and safety analyses including ECG, as well as for 
the description of biomarkers.
∀
PK parameter analysis set (PKS):
The PK parameter analysis set (PKS) includes all patients from the TS receiving 
BI 754132 who provide at least one serum sample for determination of PK parameters 
that was not excluded due to a protocol deviation relevant to the evaluation of PK or due 
to PK non-evaluability (as specified below).
It is used for the descriptive analyses of PK parameters.
∀
DLE evaluable set (SRD part only):
The DLE evaluable set includes the patients from the TS who continued in the trial for at 
least 7 days after study drug administration and who attended Visits 2, 3, and 4, and the 
patients from the TS who were withdrawn from the trial before Visit 4 due to a DLE. It is 
used for the SMC outputs.
Section 7.2.1.2 of the CTP: 
Serum concentration data and parameters of a patient will be included in the PK analyses if 
they are not flagged for exclusion due to a protocol deviation relevant to the evaluation of PK 
(to be decided no later than in the Report Planning Meeting) or due to PK non-evaluability 
(as revealed during data analysis, based on the criteria specified below). Exclusion of a 
patient’s data will be documented in the CTR.
Relevant protocol deviations may be
∀
Incorrect trial medication taken, i.e. the patient received at least one dose of trial
medication the patient was not assigned to
∀
Incorrect dose of trial medication taken
∀
Use of restricted medications
Serum concentrations and/or PK parameters of a patient will be considered as non-evaluable, 
if for example there were missing samples/concentration data at important phases of PK 
disposition curve.


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Serum concentration data and PK parameters of a patient which is flagged for exclusion will 
be reported with its individual values but will not be included in the statistical analyses.
Only concentration values within the validated concentration range and actual sampling 
times will be used for the calculation of pharmacokinetic parameters. Concentrations used in 
the pharmacokinetic calculations will be in the same format as in the bioanalytical report 
(that is to the same number of decimal places provided in the bioanalytical report).
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
in Section 7.
Table 6.3: 1
Subject sets analysed
Class of endpoint
ES
TS
PKS
Primary endpoints and further safety
assessments (incl. ECG)
X
Analysis of biomarker
X
Analysis of PK endpoints (secondary and 
further)
X
ADA analysis
X
Demographic/baseline parameters
X
Important protocol deviations
X
Disposition
X
Exposure
X
6.5
POOLING OF CENTRES
Due to the limited number of patients, all patients will be pooled without using different 
weights for centres.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.3.
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 (4)).
Missing data and outliers of PK data are handled according to BI standards (see BI-KMED-
TMCP-MAN-0014 (5)).


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Missing baseline laboratory values will be imputed by the respective values from screening.
If single cardiac cycles of an ECG (out of the generally four) are missing, the arithmetic mean 
for this single ECG will be computed with the reduced (1, 2 or 3) number of cardiac cycles.
If replicate ECG recordings are missing, the arithmetic means per time point will be computed 
with the reduced number (1 or 2) of recordings.
For the classification of the on treatment QTc/QT intervals into ‘no new onset’ / ‘new onset’ 
categories, the handling of missing value is described in Appendix Section 10.1.2.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value for laboratory data, vital signs data and ophthalmological data is defined as 
the last measurement before first administration of BI 754132 (= value at V2, in case no 
actual time is given in data). 
Section 5.2.4 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 Charts.
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.
Unscheduled measurements of laboratory data, ophthalmologic 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.
Section 5.2.6 of the CTP: Central ECG lab evaluation will be performed for all ECGs 
indicated in the CTP Flow Charts. For all ECGs, this will include the intervals RR, PR, QRS 
and QT measured semi-automatically. The screening ECGs will be checked for abnormalities. 
[…].
At Visit 1, single ECGs will be recorded. At Visit 2-10, triple ECGs will be recorded (three 
single ECGs within 180 sec).
Section 7.2.5 of the CTP: The baseline value of an ECG variable is defined as the mean of 
the ECG measurements prior to drug administration on visit 2. The screening ECGs will not 
be included in calculation of baseline.




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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 eCRF and will display the number of observations in a category, as well as the percentage 
(%) for each treatment group. Percentages will be rounded to one decimal place and will be 
based on all patients in the respective subject set whether they have non-missing values or 
not. The category 'missing' will be displayed only if there are actually missing values.
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 only 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, as a consequence, any 
calculation that relies on λz) only; the value is included for all other analyses.
Further details are given in BI-KMED-TMCP-MAN-0014 “Noncompartmental
Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies” (5) and BI-KMED-
TMCP- MAN-0010: “Description of Analytical Transfer Files and PK/PD Data Files” (11).


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised by treatment group (SRD and MD part) and in total (SRD part 
only). 
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the latest version of the coding system of the 
Medical Dictionary for Drug Regulatory Activities (MedDRA). Medications will be coded 
using the latest version of the World Health Organization Drug Dictionary (WHO-DD). The 
coding version number will be specified during RPM. 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.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre 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. Any deviations from complete intake will 
be addressed in the RPM/DBLM (see Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
SRD part:
Section 5.2.1 of the CTP: A dose limiting event (DLE) is defined as the occurrence of any of 
the following events as ocular DLE (in the study eye):
∀
Development of sterile endophthalmitis and/or sterile inflammation of the vitreous 
grade 3+ according to Standardization of Uveitis Nomenclature (SUN) working group 
(WG) grading scheme for anterior chamber cells measured by slit lamp and a 
duration of 5 or more days
∀
Visual loss of more than 15 letters at any given time point due to treatment effect in 
the study eye confirmed on consecutive visits
∀
Persistent IOP over 30 mmHg for 3 days
∀
Signs of vascular occlusion in the retina (haemorrhage of the macula would not be 
included as this is a possible sign of CNV occurrence; peripheral retinal haemorrhage 
may be a sign of vascular occlusion)
[…]


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or as systemic DLE:
∀
Drug-related AEs of moderate and severe intensity according to CTCAE (14) out of 
the following:
o
Self-reporting paraesthesia, dysgeusia, taste abnormality, taste disorder,
hyposmia (15)
o
Diarrhea, cough (16)
Each DLE needs to be reported as AESI.
Descriptive statistics (number and percentage of patients with ocular (in study eye) and 
systemic DLEs) will be provided by treatment group and in total, based on the TS.
The results of the final BLRM after completion of the SRD part will be provided based on the 
TS, and based on the DLE evaluable set in case the DLE evaluable set and the TS differ.
MD part:
Descriptive statistics (number and percentage of patients with drug-related AEs) will be 
provided, based on the TS.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been specified in the 
protocol.
7.5.2
Secondary endpoints
All secondary safety endpoints defined in Section 5.2.2 will be analysed descriptively, based
on the TS (refer to TSAP Section 7.8.1 Adverse events for details).
SRD part:
The PK endpoints Cmax, AUC0-∞, and tmax specified in Section 5.2.2 will be analysed 
descriptively, based on the PKS. Dose proportionality will be explored descriptively for the 
PK endpoints AUC0-∞and Cmax if feasible.
MD part:
Systemic exposure of BI 754132 after multiple IVT doses by determination of Cmin,1 and
Cmin,2 (trough levels before second and third administrations) and serum concentrations 4, 8 
and 14 weeks after the third administration will be determined in the MD part along with 
descriptive statistics, based on the PKS.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each patient.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
If not stated otherwise, the safety results will be sorted by treatment group.
The safety data for treated patients who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
Per the European Union (EU) Regulation 536/2014 (Annex V, Point 4) (17), the following 
information will be included in Appendix 16.1.13.1 of CTR:
∀
number of patients included by country
∀
number of patients inside (member states) and outside the EU (third countries)
∀
frequency of serious drug-related AEs by treatment, primary system organ class and 
preferred term.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA. The 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] (8).
The standard AE analyses will be based on the number of patients 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 will be assigned to ‘screening’ or ‘on treatment’ phases as defined in Section 6.1.
According to ICH E3 (9), in addition to Deaths and serious adverse events, ‘other significant’ 
AEs need to be listed in the clinical trial report. These will be any non-serious adverse event 


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that led to an action taken with study drug (e.g. discontinuation or dose reduced or 
interrupted). 
An overall summary of adverse events (including number of patients with any AE, DLEs, 
drug related AEs, ocular AEs, AESIs, serious AEs, other significant AEs and drug related 
serious AEs) will be presented.
The frequency of patients with AEs will be summarised by treatment, primary system organ
class (SOC) and preferred term (PT). Separate tables will be provided for patients with serious 
AEs, for patients with drug-related AEs, for patients with drug-related serious adverse events, 
for patients with ocular AEs, for patients with DLEs and for patients with AESIs. In addition, 
the frequency of patients with AEs will be summarised by treatment, worst intensity, primary 
system organ class (SOC) and preferred term (PT).
The SOCs will be sorted by default alphabetically, PTs will be sorted by frequency (within 
SOC).
According to the clinical study protocol, adverse events of special interest (AESI) will be
analysed:
Section 5.2.8.1.4 of the CTP: The following are considered as AESIs:
∀
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. 
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab 
results (ALT, AST, total bilirubin) available, the Investigator should make sure that 
these parameters are analysed, if necessary in an unscheduled blood test. Should the 
results meet the criteria of hepatic injury alert, the procedures described in the DILI 
checklist should be followed.
All AEs meeting the criteria for a dose limiting event (DLE) […] are defined as AESIs for this 
trial.
In addition, non-serious AEs that were reported at a frequency of > 5% (at PT level) for 
patients in at least one treatment group will be summarised by treatment, primary SOC and 
PT.
For disclosure of adverse events on EudraCT additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:


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∀
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] (10).
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possibly
clinically significant will be flagged in the data listings. 
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as adverse events (during the trial) if judged clinically relevant by the 
investigator, and will be analysed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significantly
abnormal or not (at the RPM/DBLM at the latest).
Descriptive statistics of laboratory data (normalised values) including change from baseline 
will be calculated by time point based on the worst value of the patient at that time point (or 
assigned to that planned time point).
7.8.3
Vital signs
For vital signs (blood pressure, pulse rate and body weight), descriptive statistics including 
change from baseline will be calculated by treatment group and by planned time point based 
on the first value of the patient at that planned time point (or assigned to that planned time 
point). In the listing the difference from baseline will also be displayed.
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
Continuous safety ECG monitoring (by investigator)
Clinically relevant abnormal findings will be reported as adverse events.
No separate listing or analysis of continuous ECG monitoring will be prepared.
12-lead ECG
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during the 
trial) if judged clinically relevant by the investigator.  
All evaluations of ECG data will be based on the TS.


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Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR only listings will be provided. Occurrences of notable findings will be flagged.
Comments regarding the ECGs will be listed.
Categorical endpoints
For the categorical endpoints frequency tables will be provided.
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.
For all patients with any notable finding in ECG intervals, a separate listing will be created as 
end-of-text display (based on the same display template as in Appendix 16.2), and the 
corresponding time profiles will be shown.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the absolute 
values and changes from baseline over time of QTcF, QT, HR, PR and QRS. The time 
profiles of mean and SD for the changes from baseline on treatment will be displayed 
graphically by treatment.
7.8.5
Others
Physical examination
Physical examination findings, including general appearance, neck, lungs, cardiovascular 
system, abdomen, extremities, and skin will be reported as relevant medical history/baseline 
condition (i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such.
No separate listing or analysis of physical examination findings will be prepared.
Ophthalmological data
The following endpoint will be listed and will be analysed descriptively by treatment group
(SRD and MD part) and in total (SRD part only):
-
The results of the IOP measurements as well as the corresponding changes from 
baseline for each time point and the study eye / fellow eye
All of the following endpoints will be listed only (for the study eye / fellow eye):
-
The results of the SUN grading for Anterior Chamber Cells (slit lamp) 


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-
Other results of the Slit Lamp examination / Indirect ophthalmoscopy (categories 
defined in eCRF) 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, cup to disc ratio, central retina, retinal periphery, retinal tear, retinal 
detachment).
-
Color fundus photography (evidence of GA (present, absent, cannot determine), GA 
distribution (single lesion, multifocal, cannot determine), GA Foveal Involvement 
(minimal, moderate, complete, cannot determine), choroidal neovascular membrane 
(yes, no, cannot determine), drusen (present, absent, cannot determine), reticular 
pseudo drusen (present, absent, cannot determine), intraretinal hemorrhage (yes, no, 
cannot determine), subretinal hemorrhage (yes, no, cannot determine), CFP additional 
findings,
additionally for MD part: hemorrhage (yes, no, cannot determine), optic disc pallor 
(yes, no, q, cannot determine), cup to disc ratio (%), optic disc margin (well defined, 
ill defined, cannot determine))
-
Categorical assessments from OCT (overall quality (good, fair, poor), volume (uL), 
geographic atrophy (yes, no), GA foveal involvement (no GA, minimal or no, 
moderate, complete, cannot determine), drusen (yes, no), hyper reflective drusen spots 
(no drusen, yes, no), subretinal drusen deposits (yes, no), choroidal neovascular 
membrane (yes, no), intraretinal fluid (yes, no), outer retinal tabulation (yes, no), 
ellipsoid zone disruption (yes, no, cannot determine), disruption compare to previsit 
(no EZ disruption outside GA, progressed, regressed, no change, newly observed), 
granularity (yes, no, cannot determine), granularity compare to previsit (no os 
granularity outside GA, progressed, regressed, no change, newly observed), correct 
segmentation lines (yes, no), segmentation lines were off level (no off lines, mild,
moderate, severe), other findings,
additionally for MD part: evidence of optic disc swelling (yes, no, cannot determine), 
retinal nerve fiber layer total volume, retinal nerve fiber layer superior temporal, 
retinal nerve fiber layer temporal, retinal nerve fiber layer inferior temporal, retinal 
nerve fiber layer inferior nasal, retinal nerve fiber layer nasal, retinal nerve fiber layer 
superior nasal,  )
-
Categorical and other assessments from OCT-A (presence of CNV neovascularisation 
(yes, no), location of CNV (no CNV, involving foveal center, subfoveal but not 
involving foveal center, extrafoveal), additional findings)
-
Categorical assessments from FAF (definitely decreased autofluorescence AR 
(present, absent), lesion distribution (DDAF absent, single lesion, multifocal), foveal 
region involvement in DDAF (DDAF absent, no involvement, minor, moderate, major 
involvement), junctional zone pattern (DDAF absent, focal banded, patchy, diffuse 
trickling, diffuse reticular, other diffuse pattern, no increased AF, CD), background 
autofluorescence (normal, homogenously increased, homogenously decreased, 
reticular pseudo-drusen, other), que. decreased autofluorescence (present, absent), 
QDAF present (QDAF absent, surrounding areas of DDAF, isolated from areas of 
DDAF, both, no DDAF areas), other findings)


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be loaded into the trial database after completion of enrolment.


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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.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, IDEA for CON
3.
BI-KMED-BDS-TEMP-0059: "iPD specification document (sdtm-dv-domain-
specification)", template, current version; KMED
4.
BI-KMED-BDS-HTG-0035: "Handling of Missing and Incomplete AE Dates", 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-TMCP-HTG-0025: "Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics", current version; KMED.
8.
BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
9.
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
10. BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; KMED.
11. BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; KMED.
12. Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. J Pharmacokin Pharmacodyn 2017 [R18-0143]
13. Ring A. Statistical models for heart rate correction of the QT interval. Stat Med 2010 
[R10-2920]
14. U.S. Department of Health and Human Services. Common terminology criteria for 
adverse events (CTCAE) version 5.0 (published: November 27, 2017).
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v 
5_Quick_Reference_8.5x11.pdf#search=%22CTCAE%22 (access date: 9 April 2017); 
U.S.Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute 2017 [R18-1357]
15. Ochs G, Penn RD, York M, Giess R, Beck M, Tonn J, et al. A phase I/II trial of 
recombinant methionyl human brain derived neurotrophic factor administered by 
intrathecal infusion to patients with amyotrophic lateral sclerosis. Amyotroph Lateral 
Scler Other Motor Neuron Disord 2000. 1(3):201-206 [R19-0073]
16. BDNF Study Group (Phase III). A controlled trial of recombinant methionyl human 
BDNF in ALS. Neurology 1999. 52(7):1427-1433 [R17-1162]
17. REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF 
THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, 
and repealing Directive 2001/20/EC, European Commission webpage.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1 
08-SEP-22
None
This is the final TSAP