A Biomarker Evaluation Study in Patients With Geographic Atrophy Secondary to Age-related Macular Degeneration (AMD) Evaluating the Use of Microperimetry (Fundus-controlled Perimetry) and Swept Source-OCT in Assessing Changes in Retinal Sensitivity and Anatomy Over Time.
Conditions: Age-related Macular Degeneration
Sponsor: Boehringer Ingelheim

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Clinical Study Protocol
TITLE PAGE
Document Number:
c20065772-02
EudraCT No.:
EU Trial No:
NA
BI Trial No.:
0352-2110
BI Investigational 
Product(s):
NA
Title:
A biomarker evaluation study in patients with geographic atrophy 
secondary to age-related macular degeneration (AMD) evaluating 
the use of microperimetry (fundus-controlled perimetry) and 
Swept Source-OCT in assessing changes in retinal sensitivity and 
anatomy over time.
Lay Title:
Geographic Atrophy Biomarker Evaluation Study (GABiE)
Clinical Phase:
0
Trial Clinical Monitor:
Phone 
Fax 
Coordinating 
Investigator:
Tel: 
; Fax: 
E-mail: 
Status:
Final Protocol
(Revised Protocol (based on global amendment No. 1))
Version and Date:
Version: 2.0
Date: 21 Aug 2019
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Proprietary confidential information.
2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim Pharma GmbH & Co.KG
Finished product name
NA
Active ingredient name:
NA
Protocol date
26 Jul 2018
Revision date
21 Aug 2019
Trial number
0352-2110
Title of trial:
A biomarker evaluation study in patients with geographic atrophy 
secondary to age-related macular degeneration (AMD) evaluating the 
use of microperimetry (fundus-controlled perimetry) and Swept 
Source-OCT in assessing changes in retinal sensitivity and anatomy
over time.
Principal Investigator 
< for single-centre trial 
or > Coordinating 
Investigator< for multi-
centre trial if 
applicable >:
Tel: 
; Fax:
E-mail: 
Trial site(s):
Multi-center trial
Clinical phase:
0
Objective(s):
To investigate the use of microperimetry and SS-OCT in assessing 
the natural changes of retinal sensitivity and anatomy in the 
perilesional zone of geographic atrophy areas in patients with dry 
age-related macular degeneration.
Methodology:
Biomarker Evaluation Study
Number of patients 
entered: 
50
Number of patients on 
each treatment:
NA
Diagnosis :
Geographic atrophy in patients with dry age-related macular 
degeneration.

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Main in- and exclusion 
criteria
Inclusion criteria:

Best Corrected Visual Acuity (BCVA) of 20/63 or better (Snellen 
equivalent) using ETDRS charts at starting distance of 4 m

Well demarcated area(s) of GA secondary to AMD with no 
evidence of prior or active choroidal neovascularization (CNV)

At least one patch of GA more than 0.5 disc area (DA)

Sufficiently clear ocular media, adequate pupillary dilation, and 
fixation to permit quality fundus imaging
Exclusion Criteria:

GA in either eye due to causes other than AMD (for example, 
monogenetic macular dystrophies [e.g., Stargardt disease, cone 
rod dystrophy] or toxic maculopathies [e.g., 
chloroquine/hydroxychloroquine maculopathy])

Receiving active treatment in any studies of investigational drugs 
for GA/dry AMD
Test product(s):
NA
dose:
NA
mode of 
   administration:
NA
Comparator products:
NA
dose:
NA
mode of 
   administration:
NA
Duration of observation: 12 months
Endpoints
All of the following endpoints will be assessed for the study eye.
Primary:

Change from baseline in retinal sensitivity in the junctional zone 
and in the perilesional zone of the largest atrophic loci as assessed 
by microperimetry at week 12

Change from baseline in RPE layers thickness in the junctional 
zone and in the perilesional zone as measured by SS-OCT at week 
12

Change from baseline in photoreceptor layer thickness in the 
junctional zone and in the perilesional zone as measured by 
SS-OCT at week 12
Secondary:

Change from baseline in retinal sensitivity in the junctional zone 
and in the perilesional zone of the largest atrophic loci as assessed 
by microperimetry at week 24 and 48

Change from baseline in RPE layer thickness in the junctional 
zone and in the perilesional zone as measured by SS-OCT at week 
24 and 48

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
Change from baseline in photoreceptor layer thickness in the
junctional zone and in the perilesional zone as measured by 
SS-OCT at week 24 and 48

Change from baseline in the GA area as measured by FAF at 
week 12, 24 and 48

Change in BCVA score as assessed by ETDRS chart at a starting 
distance of 4 m at week 12, 24 and 48

Change in LLVA score as assessed by ETDRS chart under low 
luminance conditions at a starting distance of 4 m at week 12, 24 
and 48

Number of scotomatous points assessed by microperimetry at 
week 12, 24 and 48

Change from baseline in the area of choroidal non-perfusion as 
measured via OCT-A at week 12, 24 and 48
Safety criteria:
Adverse events
Statistical methods:
All endpoints will be evaluated descriptively.

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FLOW CHART
Trial Periods
Screening
Observation Period
Visit
1
2
(Baseline)
3
4
5
Weeks
-4 to -1
12
24
48
Time window for visits
±2 weeks
±2 weeks
±2 weeks
Informed consent
X
In/exclusion criteria
X
X
Demographics
X
Medical history
X
BCVA testing (starting at 4 m)
X
X
X
X
X
Low Luminance Visual Acuity
X
X
X
X
SD-OCT
X
X
X
X
X
SS-OCT with OCT-A
X
X
X
X
X
FAF and Near Infrared imaging
X
X
X
X
X
Microperimetry
X1)
X
X
X
X
Concomitant medication
X
X
X
X
X
Concurrent ocular procedures
X
X
X
X
X
1)
Microperimetry examination to be executed twice with few minutes of resting 
2)
Do be performed only after Microperimetry testing has been done in order to avoid that the microperimetry is 
influenced by the light used for Color Photography.
3)
Optional

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................6
ABBREVIATIONS..................................................................................................................9
1.
INTRODUCTION...............................................................................................10
1.1
MEDICAL BACKGROUND.............................................................................10
1.2
RATIONALE FOR PERFORMING THE STUDY ........................................10
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................11
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........11
2.1.1
Main objectives....................................................................................................11
2.1.2
Primary endpoints...............................................................................................11
2.1.3
Secondary endpoints...........................................................................................11
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS ..........................11
2.2.1
Further objectives ...............................................................................................11
2.2.2
Further endpoints ...............................................................................................12
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................13
3.1
OVERALL STUDY DESIGN AND PLAN ......................................................13
3.2
SELECTION OF STUDY POPULATION.......................................................13
3.2.1
Main diagnosis for study entry ..........................................................................13
3.2.2
Inclusion criteria .................................................................................................13
3.2.3
Exclusion criteria ................................................................................................14
3.2.4
Withdrawal of patients from study participation............................................15
3.2.4.1
Withdrawal of consent for study participation......................................................15
3.2.4.2
Discontinuation of the study by the sponsor.........................................................15
4.
TREATMENTS...................................................................................................16
4.1
INVESTIGATIONAL TREATMENTS ...........................................................16
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................16
4.2.1
Other treatments and emergency procedures..................................................16
4.2.2
Restrictions ..........................................................................................................16
4.2.2.1
Restrictions regarding concomitant treatment ......................................................16
4.2.2.2
Restrictions on diet and life style..........................................................................16
5.
ASSESSMENTS..................................................................................................17
5.1
ASSESSMENTS OF SAFETY...........................................................................17
5.1.1
Physical examination ..........................................................................................17
5.1.2
Safety laboratory parameters ............................................................................17
5.1.3
Assessment of adverse events.............................................................................17

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5.1.3.1
Definitions of AEs ................................................................................................17
5.1.3.2
Adverse event collection and reporting ................................................................18
5.2
ASSESSMENT OF BIOMARKER(S) ..............................................................19
5.2.1
Biobanking...........................................................................................................20
6.
INVESTIGATIONAL PLAN.............................................................................21
6.1
VISIT SCHEDULE.............................................................................................21
6.2
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS ................21
6.2.1
Observation period .............................................................................................21
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................22
7.1
STATISTICAL DESIGN - MODEL.................................................................22
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................22
7.3
PLANNED ANALYSES.....................................................................................22
7.3.1
Primary endpoint analyses.................................................................................22
7.3.2
Secondary endpoint analyses .............................................................................23
7.3.3
Further endpoint analyses..................................................................................23
7.3.4
Safety analyses.....................................................................................................23
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................23
7.4
INTERIM ANALYSES ......................................................................................23
7.5
HANDLING OF MISSING DATA ...................................................................23
7.6
RANDOMISATION ...........................................................................................23
7.7
DETERMINATION OF SAMPLE SIZE .........................................................24
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........25
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................25
8.2
DATA QUALITY ASSURANCE ......................................................................26
8.3
RECORDS...........................................................................................................26
8.3.1
Source documents ...............................................................................................26
8.3.2
Direct access to source data and documents.....................................................26
8.3.3
Storage period of records ...................................................................................27
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................27
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........27
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................27
8.6
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................27
9.
REFERENCES....................................................................................................28
9.1
PUBLISHED REFERENCES............................................................................28
10.
APPENDICES.....................................................................................................29
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................30
11.1
GLOBAL AMENDMENT 1 ..............................................................................30

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11.2
GLOBAL AMENDMENT 2 ..............................................................................31

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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AMD
Age-related Macular Degeneration
BCVA
Best Corrected Visual Acuity
BI
Boehringer Ingelheim
CI
Confidence Interval
CNV
Choroidal Neovascularization
CRA
Clinical Research Associate
CRC
Central Reading Center
CRF
Case Report Form, paper or electrocic (sometimes referred to as “eCRF”)
CTR
Clinical Trial Report
DA
Disc Area
eDC
Electronic Data Capture
ETDRS
Early Treatment Diabetic Retinopathy Scale
EudraCT
European Clinical Trials Database
FAF
Fundus Autofluorescence
FDA
Food and Drug Administration
GA
Geographic Atrophy
GCP
Good Clinical Practice
IEC
Independent Ethics Committee
IMP
Investigational Medical Product
IRB
Institutional Review Board
IReST
International Reading Speed Test
ISF
Investigator Site File
LLD
Low Luminance Deficit
LLVA
Low Luminance Visual Acuity
MedDRA
Medical Dictionary for Drug Regulatory Activities
NEI VFQ-14
National Eye Institute Visual Function Questionnaire-14
OCT-A
Optical Coherence Tomography Angiography
PGx
Pharmacogenetics
RPE
Retinal Pigment Epithelium
SAE
Serious Adverse Event
SD
Standard Deviation
SD-OCT
Spectral Domain – Optical Coherence Tomography
SS-OCT
Swept Source – Optical Coherence Tomography
TSAP
Trial Statistical Analysis Plan
WHO
World Health Organization
YAG
Yttrium Aluminum Garnet

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
In the developed world, age-related macular degeneration (AMD) is the leading cause of 
blindness. 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. AMD is divided into dry and wet AMD. 
However, it is better to describe AMD as the early phase which is virtually asymptomatic, 
intermediate phase with mild visual loss, which can then develop into advanced phase 
defined as Geographic Atrophy (GA) and / or Neovascular (or wet) AMD leading to 
significant visual loss. Highlighting the complexity of the disease, in some patients who are 
first diagnosed to have wet AMD and be 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 the past few 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 deposit called drusen. Photoreceptor loss occurs 
overlying the drusen area. Incipient atrophy is demarcated by thinning or pigmentary changes
of the Retinal Pigment Epithelium (RPE), the supporting layer of the photoreceptors in the 
macular area during early disease stages. The interaction between the photoreceptors / RPE 
and the underlying choroid (the blood supply to the retina) in the disease state is unclear. In 
the advanced stages of AMD, atrophy of the RPE over a geographic area and/or development 
of neovascularization result in massive loss of photoreceptors and central vision loss.
1.2
RATIONALE FOR PERFORMING THE STUDY
GA secondary to AMD is an indication with high unmet medical need. Decision making in 
early clinical trials may be based on quantification of changes in retinal sensitivity or 
anatomical changes such as thinning of the photoreceptor layer. Retinal sensitivity in a 
specific area of the retina can be measured by fundus-controlled perimetry (microperimetry).
Anatomical changes of retinal or choroidal structures or the RPE can be analysed via OCT 
imaging, and correlated to changes in light sensitivity.
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking. If the patient agrees, banked samples may be used for 
future drug development projects, e.g. to identify patients that are more likely to benefit from 
a treatment or experience an adverse event (AE), and thereby better match patients with 
therapies.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this study is to investigate the use of microperimetry and Swept Source 
– Optical Coherence Tomography (SS-OCT) in assessing the natural changes of retinal 
sensitivity and anatomy in the retina of patients with GA.
2.1.2
Primary endpoints
All of the following endpoints will be assessed for the study eye.

Change from baseline in retinal sensitivity in the junctional zone and in the perilesional 
zone of the largest atrophic loci as assessed by microperimetry for the evaluation of 
macular functional response at week 12

Change from baseline in RPE layer thickness in the junctional zone and in the perilesional 
zone as measured by SS-OCT at week 12

Change from baseline in photoreceptor layer thickness in the junctional zone and in the 
perilesional zone as measured by SS-OCT at week 12
2.1.3
Secondary endpoints
All of the following endpoints will be assessed for the study eye.

Change from baseline in retinal sensitivity in the junctional zone and in the perilesional 
zone of the largest atrophic loci as assessed by microperimetry at week 24 and 48

Change from baseline in RPE layer thickness in the junctional zone and in the perilesional 
zone as measured by SS-OCT at week 24 and 48

Change from baseline in photoreceptor layer thickness in the junctional zone and in the 
perilesional zone as measured by SS-OCT at week 24 and 48

Change from baseline in the GA area as measured by Fundus Autofluorescence (FAF) at 
week 12, 24 and 48

Change in Best Corrected Visual Acuity (BCVA) score as assessed by Early Treatment 
Diabetic Retinopathy Scale (ETDRS) chart at a starting distance of 4 m at week 12, 24 
and 48

Change in Low Luminance Visual Acuity (LLVA) score as assessed by ETDRS chart 
under low luminance conditions at a starting distance of 4 m at week 12, 24 and 48

Number of scotomatous points assessed by microperimetry at week 12, 24 and 48

Change from baseline in the area of choroidal non-perfusion as measured via Optical 
Coherence Tomography Angiography (OCT-A) at week 12, 24 and 48
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS
2.2.1
Further objectives

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2.2.2
Further endpoints

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL STUDY DESIGN AND PLAN
This is a US / Europe, multi-center observational study with an enrollment target of 
50 patients with GA secondary to AMD who are not receiving treatment for GA. 
The observational period is dependent on the potential future availability of approved 
treatments for GA; in the absence of an approved therapy, this observational study may 
extend to 12 months. Visual function and anatomic measures will be collected at baseline, 
3 months, 6 months, and 12 months. The study will consist of a screening period of up to 
28 days (Days 28 to 1) and an observation period of maximally 12 months.  
Enrolled patients must satisfy all eligibility criteria at both the screening period and the
Day 1 visit.  As part of the screening process, the Central Reading Center (CRC) will 
evaluate color fundus photographs, FAF images, to provide an objective assessment of 
patient eligibility.  Patients must also meet BCVA and other eligibility criteria. Screen-failed 
patients can rescreen up to two additional times to qualify for study participation. One eye 
will be chosen as the study eye.  If both eyes are eligible, the eye with the better visual 
function (as determined by the investigator and the patient) will be the study eye; if both eyes 
have the same visual function, the eye with the larger area of GA will be selected as the study 
eye (data will be collected on both eyes but analysed for the study eye only).
3.2
SELECTION OF STUDY POPULATION
Screening of patients for this study is competitive, i.e. screening for the study 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 study.
3.2.1
Main diagnosis for study entry
Patients with GA secondary to AMD who are not receiving treatment for GA and have not 
previously receiving active treatment in clinical trials in the indication under invesitigation 
will be enrolled and followed for up to 12 months. Please refer to section 8.3.1 (Source 
Documents) for the documentation requirements pertaining to the in- and exclusion criteria.
3.2.2
Inclusion criteria
1. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the study
2. Age 60 years
3. Ability (including a sufficient general health status according to investigators judgement) 
and willingness to undertake all scheduled visits and assessments including predefined 
methodology and standards utilizing microperimetry 

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4. GA secondary to AMD with no evidence of prior or active choroidal neovascularization
(CNV) in the study eye
5. GA lesion in the study eye must reside completely within the FAF imaging field (Field 2-
30 degree image centered on the fovea)
6. BCVA of 20/63 or better (Snellen equivalent) using ETDRS charts at starting distance of 
4 m in the study eye
7. Well demarcated area(s) of GA secondary to AMD with no evidence of prior or active 
CNV in the study eye
o
The total GA lesion size 1.2 mm2 (approximately 0.5 disc area [DA]) and 
17.78 mm2 (approximately 7 DA) and must reside completely within the FAF 
imaging field (Field 230 degree image centered on the fovea)
o
If GA is multifocal, at least 1 focal lesion must be 1.2 mm2
(approximately 0.5 DA)
8. Sufficiently clear ocular media, adequate pupillary dilation, and fixation to permit quality 
fundus imaging in the study eye
3.2.3
Exclusion criteria
1. GA in either eye due to causes other than AMD (for example, monogenetic macular 
dystrophies [e.g., Stargardt disease, cone rod dystrophy] or toxic maculopathies [e.g., 
chloroquine/hydroxychloroquine maculopathy])
2. Receiving active treatment in any studies of investigational drugs for GA/dry AMD in the 
study eye
3. Mean sensitivity difference > 3 dB between the two microperimetry examinations in the 
screening visit.
4. History of vitrectomy surgery, submacular surgery, or other surgical intervention for 
AMD in the study eye
5. Previous laser photocoagulation for CNV, diabetic macular edema, retinal vein occlusion, 
and proliferative diabetic retinopathy in the study eye
6. Prior treatment with Visudyne, external-beam radiation therapy, or transpupillary 
thermotherapy in the study eye
7. History of prophylactic subthreshold laser treatment for AMD in the study eye
8. Previous intravitreal drug delivery in the study eye (e.g., intravitreal corticosteroid 
injection, anti-angiogenic drugs, anti-complement agents, or device implantation). A 
single intraoperative administration of a corticosteroid during cataract surgery for cystoid 
macular edema prophylaxis at least 3 months prior to screening is permitted.
9. RPE tear that involves the macula in either eye
10. Any concurrent ocular or intraocular condition in the study eye (e.g., cataract or diabetic 
retinopathy) that, in the opinion of the investigator, could do either of the following:
o
Require medical or surgical intervention during the study period to prevent or treat 
vision loss that might result from that condition
o
If allowed to progress untreated, could likely contribute to loss of at least 
two Snellen equivalent lines of BCVA during the study period
11. Previous violation of the posterior capsule in the study eye unless it occurred as a result of 
Yttrium Aluminum Garnet (YAG) laser posterior capsulotomy in association with prior 
posterior chamber intraocular lens implantation

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12. Spherical equivalent of the refractive error in the study eye demonstrating 6 diopters of 
myopia
13. For patients who have undergone prior refractive or cataract surgery in the study eye, the 
preoperative refractive error in the study eye should not have exceeded 6 diopters of 
myopia.
14. Intraocular surgery (including cataract surgery) in the study eye within 3 months 
preceding Day 1
15. History of glaucoma-filtering surgery in the study eye
16. History of corneal transplant in the study eye
17. Major surgery (major according to the investigator’s assessment) performed within 
12 weeks prior to randomization or planned within 12 months after screening, e.g. hip 
replacement
18. Previous enrolment in this study
19. Currently enrolled in another investigational device or drug trial, or less than 30 days 
since ending another investigational device or drug trial(s), or receiving other 
investigational treatment(s)
3.2.4
Withdrawal of patients from study participation
3.2.4.1
Withdrawal of consent for study participation
Patients may withdraw their consent for study 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 
study and negative implications for the scientific value may be the consequence. Furthermore 
it may mean that further patient follow up on safety cannot occur.
If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for study participation and explain the 
options for continued follow up after withdrawal from study treatment, please see 
section 3.2.4.1 above.
3.2.4.2
Discontinuation of the study by the sponsor
Boehringer Ingelheim (BI) reserves the right to discontinue the study overall or at a particular 
study site at any time. 
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of studytermination (except in case of the third reason).

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
No treatments will be administered in this biomarker evaluation study.
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
Patients should not be included in an interventional trial for the condition under investigation 
while being part of this study. There are no other restrictions regarding concomitant treatment 
to be followed.
4.2.2.2
Restrictions on diet and life style
There are no restrictions regarding diet and lifestyle to be followed.

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5.
ASSESSMENTS
5.1
ASSESSMENTS OF SAFETY
5.1.1
Physical examination
NA
5.1.2
Safety laboratory parameters
No safety laboratory parameters will be determined.
5.1.3
Assessment of adverse events
5.1.3.1
Definitions of AEs 
AE reporting to sponsor and timelines
This study will not use a BI Investigational Medical Product (IMP). All AEs should be 
collected on the appropriate Case Report Form (CRF) page only.
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical study subject 
and which does not necessarily have to have a causal relationship with this study.
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 study procedures.
Serious Adverse Event (SAE)
A 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 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect, or

is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement which may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 

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AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in section 5.1.3.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI has set up a list of further AEs, which by their nature, can always be considered to be 
“serious” even though they may not have met the criteria of an SAE as defined above.
The latest list of “Always Serious AEs” can be found in the electronic Data Capture (eDC)
system. A copy of the latest list of “Always Serious AEs” will be provided upon request.  
These events should always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
No AESIs have been defined for this study.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Yes: 
There is a reasonable causal relationship between a study procedure and the AE.
No: 
There is no reasonable causal relationship between a study procedure and the AE.
5.1.3.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until the individual patient’s end of study: 
-all AEs (serious and non-serious).

After the individual patient’s end of study: 
the investigator does not need to actively monitor the patient for AEs but should only 
report related SAEs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should however, not be reported in the CRF.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages. The investigator should determine the causal relationship to the study 
procedures.
If such abnormalities already pre-exist prior to study inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only.

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5.2
ASSESSMENT OF BIOMARKER(S)
This section describes the exploratory biomarkers which will be measured in the study.
For all biomarker endpoint, baseline is defined as the value at Visit 2; if not measured at 
Visit 2 then baseline is the value at Visit 1. All ophthalmologic examinations will be 
performed on in the study eye only, as described below.
Centrally collected ophthalmological data (microperiometry, color fundus photography, 
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.
Microperimetry
Microperimety is a psychophysical technique allowing for a detailed assessment of function 
across specific areas of the retina such as the macula. Specific standardized patches of the 
retina are stimulated with points of light, and the test subject presses a button when he is able 
to perceive the light spot. In order to assess the light sensitivity at each test location, the 
stimulus intensity is lowered gradually. The fundus is monitored through an infrared camera 
and the fixation point is continuously tracked, thereby allowing for mapping the sensitivities 
of the test spots to the fundus and to images obtained with e.g. FAF imaging.
SS-OCT / SD-OCT-Angiography
The retinal layers and their thickness can be visualized and measured by SS-OCT (for direct 
comparison SD-OCT imaging will be performed). The assessment will be performed by a 
qualified person, and only specified OCT equipment will be used. OCT-A is a non-invasive
imaging technique that provides high-resolution volumetric blood flow information without 
the use of dye. The assessment is also performed by a qualified person, and only specified 
device(s) will be used. OCT images will be sent to an independent CRC for evaluation. A 
detailed manual for OCT image acquisition and data transmission will be provided.
Visual Acuity measured by ETDRS letter charts
BCVA will be determined by using the ETDRS visual acuitychart 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.
FAF and Near Infrared imaging
FAF is an 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. Furthermore, 
FAF may support the prediction of the progression rate of GA via imaging the appearance of 
the hyperfluorescent junctional zone (i.e., the boundary between dead and surviving RPE 
regions, which is likely to represent RPE and/or photoreceptor cells which are more likely to 
become atrophic). Specifically, retinae with junctional zones of the banded or diffuse type are 
more likely to progress than retinae with focal junctional zones. Therefore, the type of the 
junctional zone appearance in the FAF can be utilized to define inclusion criteria for this 
clinical study. 

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Low Luminance Visual Acuity (LLVA)
To determine visual acuity under low luminance condition, the amount of light transmitted is 
reduced by neutral density filters placed over the eye to be tested, and the subject is asked to 
read the letters of a ETDRS visual acuity chart which normally illuminated. Because of the 
filter-reduced luminance, LLVA scores are lower than for BCVA (the magnitude of the 
difference between BCVA and LLVA is defined as Low Luminance Deficit (LLD). LLVA 
measurments reveal visual function abnormalities not apparent by measuring standard BCVA 
alone and might be a more sensitive indicator for the risk of visual decline than assessing 
only standard BCVA.
5.2.1
Biobanking

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All study visits should take place is pointed out in the Flow Chart and all patients are to 
adhere to the visit schedule as specified in the Flow Chart.
If any visit has to be rescheduled, subsequent visits should follow the original visit date 
schedule.
6.2
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS
Patients must sign Informed Consent before any study related procedures are performed.
Signing of the Informed Consent is not necessarily the start of the screening visit.
Once Visit 1 procedures are complete inclusion/exclusion criteria must be reviewed. If 
patient meets inclusion/exclusion criteria, patient should be contacted to schedule next visit.
If patient does not meet inclusion/exclusion criteria the patient must be recorded in CRFs as a 
screen failure.
6.2.1
Observation period
Assessments should be performed as mentioned in Flow Chart, the respective protocol 
sections and in the imaging manual.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
The main objective of this longitudinal observational study is to investigate the use of 
microperimetry and SS-OCT in assessing the natural changes of retinal sensitivity and 
anatomy in patients with GA. In addition, changes in several other ophthalmologic 
measurements over time will be examined.
To this end, point estimates and confidence intervals (CIs) for the primary and secondary 
endpoints will be determined. Correlations between interesting pairs of outcome measures 
will be assessed. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in a confirmatory sense. All statistical 
analyses are exploratory even if they use confirmatory methods.
7.3
PLANNED ANALYSES
All subjects entering the study will be included in the analyses. Protocol violations will be 
defined in TSAP. A per-protocol set will be defined accordingly thereafter.
7.3.1
Primary endpoint analyses
For each primary endpoint (see section 2.1.2), baseline is defined as the measurement 
obtained at Visit 2.
The following descriptive statistics will be calculated for the measurements related to the 
primary endpoints at each time point, as well as for the changes from baseline: N, arithmetic 
mean, Standard Deviation (SD), minimum, median, maximum, percentiles, arithmetic 
coefficient of variation.
Correlations (both Pearson and rank-based) of the changes from baseline of retinal sensitivity 
in the junctional zone and in the perilesional zone, respectively, of the largest atrophic loci as 
measured by microperimetry to the following endpoints will be estimated:

Change from baseline in RPE layer thickness in the junctional zone and in the perilesional 
zone, respectively, as measured by SS-OCT and by SD-OCT

Change from baseline in photoreceptor layer thickness in the junctional zone and in the 
perilesional zone, respectively, as measured by SS-OCT and by SD-OCT

Changes from baseline in GA area as measured by FAF

Change from baseline in the area of choroiocapillaris flow deficits as measured via 
OCT-A at week 12, 24 and 48

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Individual data as well as summary statistics will be visualised in respective graphical
presentations, e.g. scatter plots or box-plots.
Correlations between the primary endpoints and continuous baseline characteristics will be 
investigated if necessary.
7.3.2
Secondary endpoint analyses
The secondary endpoints (see Section 2.1.3) will be analysed descriptively.
Correlations between the secondary endpoints and continuous baseline characteristics will be 
investigated if necessary.
7.3.3
Further endpoint analyses
7.3.4
Safety analyses
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
Standard BI summary tables and listings will be produced.
AEs recorded prior to Visit 2 will be assigned to the screening period, and AEs occurring 
after Visit 1 but prior to the study termination date will be assigned to the observation period.
Note that AEs occurring after the last per protocol contact but entered before database lock 
will not be captured in the trial database.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
NA
7.4
INTERIM ANALYSES
No formal interim analysis is planned.
For BI internal decision making, preliminary exploratory analyses will be performed on an 
ad-hoc basis at selected time points of interest (based on the availability of pre-defined 
proportions of 12 weeks and 24 weeks data, respectively) before the final database lock. Each 
of these preliminary analyses will be based on a database snapshot. Details on the analyses 
will be described in the cumulative statistical analysis plan. Results of these evaluations will 
be distributed to the project team. No formal preliminary report will be written.
7.5
HANDLING OF MISSING DATA
Missing data will not be imputed.
7.6
RANDOMISATION
NA

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7.7
DETERMINATION OF SAMPLE SIZE
The chosen number of 50 patients with GA is assumed to be sufficient for the purpose of 
investigating the distribution of the microperimetry measurements and their short-term 
changes in this patient population.
In particular, for this trial a precision (the half-width of the 95% CI) of 0.3 dB for the mean 
change from baseline in retinal sensitivity has been considered sufficient by the project team. 
Table 7.5: 1 provides an overview of numbers needed for obtaining a 95% CI for the mean 
change from baseline in retinal sensitivity with a given half width with at least 90% 
probability, under various assumptions for the underlying SD. For example, assuming an SD 
of 0.9, the trial will need 47 patients in order to achieve two-sided 95% CIs for the given 
precision with a probability of 90%. For an SD of 0.7, the required sample size would be 31. 
Note that the SD for longitudinal changes from baseline of the retinal sensitivity in 8 patients 
with GA as seen in Wu et al. [R17-1097] was about 0.62.
Table 7.5: 1
Number of patients needed for obtaining a 95% CI for the mean 
change from baseline of retinal sensitivity with a given half width 
with at least 90% probability, for different SD values
Half-width of CI [dB]
Assumed SD
0.60
0.7
0.8
0.9
0.20
47
61
77
96
0.25
33
42
53
64
0.30
24
31
39
47
The calculation was performed as described by Julious [R11-5230, Chapter 8] using R 
Version 3.3.2.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The study will be carried out in compliance with the protocol and the ethical principles laid 
down in the Declaration of Helsinki.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor with regard 
to publication of the results of this trial are described in the investigator contract. As a rule, 
no trial results should be published prior to finalization of the Clinical Trial Report (CTR).
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the Investigator Site File (ISF).
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This study 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) 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 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 must give a full explanation to study patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 
The patient must be given sufficient time to consider participation in the study. The 
investigator 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 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.

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8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor.
8.3.1
Source documents
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
8.3.2
Direct access to source data and documents
No regular on-site monitoring visits will be performed. The frequency of site monitoring will 
be kept to a minimum 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 Clinical Research Associate (CRA), auditor 
and regulatory inspector (e.g. Food and Drug Administration (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 Good Clinical Practice (GCP).
The investigator /institution will allow on-site trial-related monitoring, audits, IRB/IEC 
review and regulatory inspections. Direct access should be granted to all source documents 
(paper and e-records) including progress notes, copies of laboratory and medical test results
The CRA and auditor may review all CRFs and informed consents. The accuracy of the data 
will be verified by direct comparison with the source documents described in section 8.3.1.

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8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
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
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with the 
Principles of GCP as outlined in 'Note For Guidance On GCP (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analysing biological samples and data from clinical 
trial participants as well as the laboratories' activities for clinical trials sponsored by BI
are regularly audited. The analytical groups and the banking facilityare therefore assessed 
to be qualified for the storage and use of biological samples and data collected in clinical 
trials.

Samples and data are used only if an appropriate informed consent is available.
8.6
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The study is financed by 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. 

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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R11-5230  
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group 2010  
R17-1097
Wu et al. Longitudinal Changes in Microperimetry and Low Luminance 
Visual Acuity in Age-Related Macular Degeneration. JAMA Ophthalmol. 
2015;133(4):442-448.

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10.
APPENDICES
Not applicable

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
21 Aug 2019
EudraCT number
EU number
NA
BI Trial number
0352-2110
BI Investigational Product(s)
NA
Title of protocol
A biomarker evaluation study in patients with 
geographic atrophy secondary to age-related 
macular degeneration (AMD) evaluating the use of 
microperimetry (fundus-controlled perimetry) and 
Swept Source-OCT in assessing changes in retinal 
sensitivity and anatomy over time.
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
X
Section to be changed
3.3.2. Inclusion criterion #7
Description of change
Well demarcated area(s) of GA secondary to AMD 
with no evidence of prior or active CNV in the 
study eye
o
The total GA lesion size 2.54 mm2
(approximately 1 disc area [DA]) and 
17.78 mm2 (approximately 7 DA) 
and must reside completely within the 
FAF imaging field (Field 230 degree 
image centered on the fovea)
o
If GA is multifocal, at least 1 focal 
lesion must be 0.5 mm2
(approximately 1 DA)
was changed to
Well demarcated area(s) of GA secondary to AMD 
with no evidence of prior or active CNV in the 
study eye
o
The total GA lesion size 1.2 mm2

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(approximately 0.5 disc area [DA]) 
and 17.78 mm2 (approximately 7 
DA) and must reside completely within 
the FAF imaging field (Field 230 
degree image centered on the fovea)
o
If GA is multifocal, at least 1 focal 
lesion must be 1.2 mm2
(approximately 0.5 DA)
Rationale for change
A typographical error was erased and GA lesion 
size for inclusion was changed in order to resemble 
the later phase study population
Section to be changed
3.3.3. Exclusion criteria #2, 8
Description of change
Criteria were clarified to be applicable to the study 
eye only 
Rationale for change
Clarification
Section to be changed
7.4
Description of change
The process for the use of study data for internal 
decision making was clarified
Rationale for change
Clarification
11.2
GLOBAL AMENDMENT 2
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Product(s)
Title of protocol
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Description of change
Rationale for change

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
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Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
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c20065772
2.0
clinical-trial-protocol-version-02
A biomarker evaluation study in patients with geographic atrophy secondary to
age-related macular degeneration (AMD) evaluating the use of microperimetry
(fundus-controlled perimetry) and Swept Source-OCT in assessing changes in retinal
sensitivity and anatomy over time.
Author-Clinical Trial Leader
21 Aug 2019 14:06 CEST
Author-Trial Statistician
21 Aug 2019 16:37 CEST
Approval-Team Member Medicine
21 Aug 2019 19:35 CEST
Verification-Paper Signature
Completion
22 Aug 2019 14:36 CEST

Boehringer Ingelheim 
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(Continued) Signatures (obtained electronically) 
 
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c20065772
2.0