Conditions: Neovascular (Wet) Age-related Macular Degeneration
Keywords: Aflibercept Anti-vascular endothelial growth factor Treatment interval extension
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
Researchers are looking for a better way to treat people who have neovascular (wet) age-related macular degeneration (nAMD or wet AMD). In people with wet AMD, the body makes too much of a protein called vascular endothelial growth factor (VEGF). This causes too many blood vessels to grow in the area of sharpest vision in the eye, called macula. Fluid buildup due to leakage from these vessels can damage the macula, leading to vision problems such as blurring or a blind spot in the central (straight ahead) vision needed for reading or face recognition or car driving. Wet AMD is common in people aged 50 and older.

The study treatment intravitreal aflibercept (also called BAY865321) is injected into the eye. It works by blocking the VEGF protein and thus reduces blood vessel growth. It has already been approved for patients with wet AMD to be given as intravitreal injection monthly at start and then every 8 weeks or longer. Repeated injections of aflibercept prevent worsening of vision but place a burden on the patient.

Doctors try to increase the time between injections (treatment interval) in routine clinical practice based on individual patient needs. This is called treat and extend (T\&E). Treatment intervals are stepwise extended or shortened depending on how the treatment works. This is checked with optical coherence tomography (OCT), an imaging technique used to observe relevant changes in the eye.

The main purpose of this study is to learn how well aflibercept works if treatment intervals are extended faster (timepoint of extension is the same for both treatments arms), compared to standard T\&E regimen in people with wet AMD in a preselected patient population with no fluid after treatment initiation.

To answer this, researchers will assess changes in vision called best corrected visual acuity (BCVA) between study start and after 36 weeks. Changes will then be compared between participants whose treatment intervals were extended early and those on standard T\&E regimen.

All participants will receive 2 mg aflibercept as intravitreal injection for up to 52 weeks in intervals of every 4 to 16 weeks.

Each participant will be in the study for up to 56 weeks. During this time 4 visits to the study site are set for all participants. The other visits are set individually. A final phone call is planned 3 days after treatment at the end of study.

During the study, the doctors and their study team will:

* check patients' eye health using various eye examination techniques (slit lamp microscopy, OCT, and ophthalmoscopy) that may necessitate eye drops to widen the pupil)
* measure patients' eye vision (BCVA)
* do physical examinations
* check vital signs
* ask the participants questions about how they are feeling and what adverse events they are having.

An adverse event is any medical problem that a participant has during a study. Doctors keep track of all adverse events that happen in studies, even if they do not think the adverse events might be related to the study treatments.

In addition, participants in the fast extension arm will be provided with a home monitoring OCT device.

Detailed description:

Arms:
arm 1: After the initial study injection at baseline, participants will receive their next study injection at Week 16. Participants in this study arm will also be issued a home monitoring device, which will allow for regular OCT monitoring (at least 5 times a week) at home. arm 2: Participants will receive treatment in intervals maintained (8 weeks) or adjusted in 2 weeks increments each time (up to a maximum of 16 weeks and minimum of 4 weeks), as long as all extension/shortening criteria are met.

Interventions: intervention 1: Aflibercept(BAY86-5321, Eylea)
Intervention descriptions: intervention 1: 2mg, intravitreal (IVT) injection

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Clinical Study Protocol 
Official Title: 
A Parallel-group Phase 4, Open-label, Two-arm Study to Assess the 
Safety and Efficacy of Intravitreal (IVT) Aflibercept with Proactive 
Customized Treatment Intervals in Patients ≥50 Years of Age with 
No Fluid Due to Choroidal Neovascularization (CNV) Lesions 
Secondary to Neovascular (wet) Age-related Macular Degeneration 
(nAMD) Following Treatment Initiation with Aflibercept 
NCT Number: 
NCT05473715 
Document Date: 
25 MAY 2022 
 


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Title Page 
Protocol Title:  
A Parallel-group Phase 4, Open-label, Two-arm Study to Assess the Safety and Efficacy of 
Intravitreal (IVT) Aflibercept with Proactive Customized Treatment Intervals in Patients ≥50 
Years of Age with No Fluid Due to Choroidal Neovascularization (CNV) Lesions Secondary 
to Neovascular (wet) Age-related Macular Degeneration (nAMD) Following Treatment 
Initiation with Aflibercept 
Protocol Number: 
21912 
Protocol Version:  
Final, Version 1.0 
Compound Number: 
BAY 86-5321/IVT aflibercept/Eylea® 
Short Title:  
An Interventional Study to Investigate the Safety and Efficacy of IVT Aflibercept with 
Proactive Customized Treatment Intervals in Patients ≥50 Years of Age with No Fluid Due to 
CNV Lesions Secondary to nAMD Following Treatment Initiation with Aflibercept 
Study Phase: 
4 
Acronym: 
XPAND 
Sponsor Name:  
Bayer AG 
Legal Registered Address: 
Bayer AG, 51368 Leverkusen, Germany  
Regulatory Agency Identifier Number(s): 
European Clinical Trials Database (EudraCT): 2022-000690-73 
Protocol Date:  
25 May 2022 


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Role: 
 
(
 
This is an electronically generated document that does not bear any Sponsor signatures. The 
signature of the Sponsor’s medically responsible person is filed in the trial master file and 
available on request. 
 
 
Medical Monitor name and contact information will be provided separately. 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
Sponsor is not permitted.  
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
 
PPD
PPD
PPD


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Table of Contents 
Title Page ............................................................................................................................... 1 
Table of Contents ................................................................................................................. 3 
Table of Tables ..................................................................................................................... 5 
Table of Figures .................................................................................................................... 5 
1. 
Protocol Summary ........................................................................................................ 6 
1.1 
Synopsis ....................................................................................................................... 6 
1.2 
Schema ....................................................................................................................... 11 
1.3 
Schedule of Activities ................................................................................................ 12 
2. 
Introduction ................................................................................................................. 15 
2.1 
Study Rationale .......................................................................................................... 15 
2.2 
Background ................................................................................................................ 15 
2.3 
Benefit/Risk Assessment ........................................................................................... 16 
2.3.1 
Risk Assessment ..................................................................................................... 16 
2.3.2 
Benefit Assessment ................................................................................................ 18 
2.3.3 
Overall Benefit: Risk Conclusion ........................................................................... 19 
3. 
Objectives and Endpoints/Estimands ........................................................................ 19 
4. 
Study Design ................................................................................................................ 20 
4.1 
Overall Design ........................................................................................................... 20 
4.2 
Scientific Rationale for Study Design ....................................................................... 23 
4.3 
Justification for Dose ................................................................................................. 23 
4.4 
End of Study Definition ............................................................................................. 24 
5. 
Study Population ......................................................................................................... 24 
5.1 
Inclusion Criteria ....................................................................................................... 24 
5.2 
Exclusion Criteria ...................................................................................................... 25 
5.3 
Lifestyle Considerations ............................................................................................ 25 
5.4 
Screen Failures ........................................................................................................... 26 
6. 
Study Intervention(s) and Concomitant Therapy .................................................... 26 
6.1 
Study Intervention Administered ............................................................................... 26 
6.1.1 
Medical Devices ..................................................................................................... 27 
6.2 
Preparation, Handling, Storage, and Accountability ................................................. 27 
6.3 
Measures to Minimize Bias: Randomization ............................................................. 28 
6.4 
Study Intervention Compliance ................................................................................. 28 
6.5 
Continued Access to Study Intervention after the End of the Study ......................... 28 
6.6 
Treatment of Overdose .............................................................................................. 28 
6.7 
Concomitant Therapy ................................................................................................ 29 
6.7.1 
Allowed and Prohibited Medications ..................................................................... 29 
6.7.2 
Fellow Eye Treatment ............................................................................................ 29 
7. 
Discontinuation of Study Intervention and Patient Discontinuation/Withdrawal30 
7.1 
Discontinuation of Study Intervention ....................................................................... 30 
7.2 
Patient Discontinuation/Withdrawal from the Study ................................................. 30 
7.3 
Lost to Follow-Up ...................................................................................................... 31 
8. 
Study Assessments and Procedures ........................................................................... 31 


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8.1 
Efficacy Assessments ................................................................................................ 32 
8.1.1 
Ophthalmic and General Examinations .................................................................. 32 
8.1.1.1 
Best Corrected Visual Acuity .............................................................................. 32 
8.1.1.2 
Spectral Domain Optical Coherence Tomography ............................................. 32 
8.1.1.3 
Optical Coherence Tomography Angiography ................................................... 32 
8.1.1.4 
Indirect Ophthalmoscopy .................................................................................... 33 
8.1.1.5 
Slit Lamp Biomicroscopy .................................................................................... 33 
8.1.1.6 
Intraocular Pressure ............................................................................................. 33 
8.1.2 
Home OCT User Questionnaire ............................................................................. 33 
8.2 
Safety Assessments .................................................................................................... 33 
8.2.1 
Physical Examinations ............................................................................................ 33 
8.2.2 
Vital Signs .............................................................................................................. 33 
8.2.3 
Pregnancy Testing .................................................................................................. 34 
8.3 
Adverse Events, Serious Adverse Events and Other Safety Reporting ..................... 34 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information ................................................................................................... 34 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ....................... 34 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events ................................... 34 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events ......................... 35 
8.3.5 
Pregnancy ............................................................................................................... 35 
8.3.6 
Adverse Events of Special Interest ......................................................................... 35 
8.3.7 
Medical Device Deficiencies .................................................................................. 36 
8.3.7.1 
Time Period for Detecting Medical Device Deficiencies ................................... 36 
8.3.7.2 
Follow-up of Medical Device Deficiencies ........................................................ 36 
8.3.7.3 
Prompt Reporting of Device Deficiencies to the Sponsor .................................. 36 
8.3.7.4 
Regulatory Reporting Requirements for Device Deficiencies ............................ 36 
8.4 
Pharmacokinetics ....................................................................................................... 37 
8.5 
Genetics and/or Pharmacogenomics .......................................................................... 37 
8.6 
Biomarkers ................................................................................................................. 37 
8.7 
Immunogenicity Assessments .................................................................................... 37 
8.8 
Health Economics OR Medical Resource Utilization and Health Economics .......... 37 
9. 
Statistical Considerations ........................................................................................... 37 
9.1 
Statistical Hypotheses ................................................................................................ 37 
9.1.1 
Multiplicity Adjustment ......................................................................................... 38 
9.2 
Analysis Sets .............................................................................................................. 38 
9.3 
Statistical Analyses .................................................................................................... 38 
9.3.1 
General Considerations........................................................................................... 38 
9.3.2 
Primary Endpoint/Estimand Analysis .................................................................... 39 
9.3.3 
Secondary Endpoints/Estimands Analysis ............................................................. 40 
9.3.4 
Exploratory Endpoint(s) Analysis .......................................................................... 42 
9.3.5 
Safety Analysis ....................................................................................................... 42 
9.3.6 
Other Analysis ........................................................................................................ 43 
9.4 
Interim Analysis ......................................................................................................... 43 
9.5 
Sample Size Determination ....................................................................................... 43 
10. Supporting Documentation and Operational Considerations ................................ 45 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .................... 45 
10.1.1 Regulatory and Ethical Considerations .................................................................. 45 
10.1.2 Financial Disclosure ............................................................................................... 45 


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10.1.3 Informed Consent Process ...................................................................................... 45 
10.1.4 Data Protection ....................................................................................................... 46 
10.1.5 Committees Structure ............................................................................................. 46 
10.1.6 Dissemination of Clinical Study Data .................................................................... 46 
10.1.7 Data Quality Assurance .......................................................................................... 47 
10.1.8 Source Documents .................................................................................................. 47 
10.1.9 Study and Site Start and Closure ............................................................................ 48 
10.1.10 Publication Policy ................................................................................................... 48 
10.2 Appendix 2: Adverse Events and Serious Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting ............................ 49 
10.2.1 Definition of AE ..................................................................................................... 49 
10.2.2 Definition of SAE ................................................................................................... 50 
10.2.3 Recording and Follow-Up of AE and/or SAE ........................................................ 51 
10.2.4 Reporting of SAEs .................................................................................................. 53 
10.3 Appendix 3: Contraceptive Guidance and Collection of Pregnancy Information ..... 54 
10.3.1 Definitions .............................................................................................................. 54 
10.3.2 Collection of Pregnancy Information ..................................................................... 54 
10.4 Appendix 4: Adverse Events, Serious Adverse Events, and Device Deficiencies: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting in 
Medical Device Studies ............................................................................................. 56 
10.4.1 Definition of Medical Device AE ........................................................................... 56 
10.4.2 Definition of SAE ................................................................................................... 56 
10.4.3 Definition of Device Deficiency............................................................................. 57 
10.4.4 Recording and Follow-Up of AE and/or SAE and Device Deficiencies ................ 57 
10.4.5 Reporting of SAEs .................................................................................................. 59 
10.5 Appendix 5: Customized Treatment Interval Arm Monitoring Flow ........................ 61 
10.6 Appendix 6: Patient Training for Use of Home OCT and Monitoring of Home OCT 
Images ........................................................................................................................ 62 
10.7 Appendix 7: Abbreviations ........................................................................................ 63 
11. References .................................................................................................................... 65 
Table of Tables 
Table 1–1: Schedule of Activities ............................................................................................ 12 
Table 2–1: All Treatment-emergent Adverse Drug Reactions Reported in Patients in Phase 3 
Studies ................................................................................................................... 17 
Table 6–1: Study Intervention .................................................................................................. 26 
Table 6–2: Study Arms ............................................................................................................ 26 
Table of Figures 
Figure 1-1: Study Design ......................................................................................................... 11 
Figure 10-1: Home-OCT monitoring flow of customized Treatment Interval Arm ................ 61 


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1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title: A Parallel-group Phase 4, Open-label, Two-arm Study to Assess the Safety 
and Efficacy of Intravitreal (IVT) Aflibercept with Proactive Customized 
Treatment Intervals in Patients ≥50 Years of Age with No Fluid Due to 
Choroidal Neovascularization (CNV) Lesions Secondary to Neovascular 
(wet) Age-related-Macular Degeneration (nAMD) Following Treatment 
Initiation with Aflibercept 
Short Title: 
An interventional Study to Investigate the Safety and Efficacy of IVT 
Aflibercept with Proactive Customized Treatment Intervals in Patient ≥50 
Years of Age with No Fluid Due to CNV Lesions Secondary to nAMD 
Following Treatment Initiation with Aflibercept 
Rationale: 
The use of anti-vascular endothelial growth factor (anti-VEGF) agents for the treatment of 
neovascular “wet” age-related macular degeneration (nAMD) has become the standard of 
care. The frequency of dosing monthly anti-VEGFs has introduced a burden of illness on 
patients and caregivers as well as capability constraints on physicians in practice. Physicians 
have developed a practicing trend towards individualizing treatment to reduce the burden of 
patients and minimize reimbursement issues and healthcare costs. The current individualized 
treatment gaining momentum with practicing physicians is referred to as treat and extend 
(T&E), where the patient is injected at every visit and the follow-up examination intervals are 
incrementally extended or shortened according to the response to treatment. 
After 3 monthly initial doses, the treatment interval may be maintained at 2 months or further 
extended using a T&E dosing regimen, where injection intervals are adjusted in 2- or 
4-weekly increments to maintain stable visual and/or anatomic outcomes according to the 
approved European Union (EU) label for Eylea® (also known as aflibercept 2 mg). Optical 
coherence tomography (OCT) has been used in clinical practice to guide the detection of 
macular fluid in order to direct T&E increase, maintenance, or decrease of follow-up intervals 
and injections. This imaging modality readily permits visualization of anatomic changes 
consistent with choroidal neovascularization (CNV) in nAMD and allows assessment of the 
treatment response. However, until recently, OCT imaging was only possible in-office and 
was rarely conducted more frequently than every 4 weeks.  
In spite of the encouraging results of Phase 4 T&E study (ALTAIR) and the supporting 
Phase 3b/4 study (ARIES) results, and the resulting label update for Eylea®, allowing for 
rapid, 4-week extension of treatment intervals up to 16 weeks, both are rarely done in 
everyday clinical practice, due to fear of catastrophic disease recurrence.  
Artificial intelligence (AI) and new digital technologies are expected to transform medicine 
and especially ophthalmology fundamentally in the near future. Home monitoring is one 
potential mass application for such approaches and as of yet, there is no data on how home 
monitoring that can support treatment with Eylea®. In this study we investigate the rapid 
extension of a preselected patient population to a 16 week treatment interval. A digital drug 
development tool (home OCT) will provide an additional layer of assessments between 2 
injection visits and therefore may have the potential to increase confidence of physicians and 
patients in applying long treatment intervals. The coronavirus disease 2019 (COVID-19) 


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pandemic has strongly impacted on ophthalmology. Reignited interest in home monitoring for 
exudative retinal disease is expected to persist as we transition to the “new normal”. 
Objectives and Endpoints/Estimands: 
Objectives 
Endpoints/Estimands 
Primary 
• 
To assess whether 2 mg intravitreal 
(IVT) aflibercept administered at a 
customized treatment interval 
(determined after the first extended 
treatment interval) is non-inferior to 
2 mg IVT aflibercept administered 
according to a standard treat and 
extend (T&E) regimen (initiated after 
the first extended treatment interval) in 
patients with no fluid following 
treatment initiation for neovascular 
(wet) age-related macular 
degeneration (nAMD) 
Primary Endpoint:  
• 
Change in best-corrected visual acuity (BCVA) 
(early treatment diabetic retinopathy study 
[ETDRS] letters) from baseline to Week 36 
Secondary 
• 
To assess treatment burden of 2 mg 
IVT aflibercept administered at a 
customized treatment interval 
compared with 2 mg IVT aflibercept 
administered according to a standard 
T&E regimen (initiated after the first 
extended treatment interval) in patients 
with no fluid following treatment 
initiation for nAMD 
Key Secondary Endpoint: 
• 
Number of IVT aflibercept injections per patient 
up to Week 52 (descriptively) 
Secondary Endpoints: 
• 
Number of IVT aflibercept injections per patient 
until Week 36 
• 
Number of patients achieving pre-defined 
treatment intervals (≥4, ≥8, ≥10, ≥12¸ ≥14, and 
16 weeks) at Weeks 36 and 52  
• 
Change in BCVA (ETDRS letters) from baseline 
to Week 52 
• 
To evaluate the safety of aflibercept 
with proactive treatment intervals 
• 
Treatment-emergent adverse events (TEAEs) 
and treatment-emergent serious adverse events 
(TESAEs) through Weeks 36 and 52 
Other pre-specified exploratory 
• 
To assess morphologic outcomes of 
2 mg IVT aflibercept administered at a 
customized treatment interval 
compared with 2 mg IVT aflibercept 
administered according to a standard 
T&E regimen (initiated after the first 
extended treatment interval) in patients 
with no fluid following treatment 
initiation for nAMD 
Other Pre-specified Exploratory Endpoints: 
• 
Change in central subfield retinal thickness 
(CST) [µm] from baseline to Weeks 36 and 52 
• 
Change in CST compared to treatment initiation 
(16 weeks before baseline) at Weeks 36 and 52 
• 
Number of patients without any fluid at treatment 
initiation (16 weeks before baseline), baseline, 
Weeks 36, and 52 
➢ 
without intraretinal fluid (IRF) 
➢ 
without subretinal fluid (SRF)  
➢ 
without sub-retinal pigment epithelium (sub-
RPE) fluid 
Customized treatment interval arm only: 
• 
Change in retinal fluid volume and in volume by 
compartment (IRF and SRF) 
• 
Area under the curve (AUC) of fluid volumes  
• 
Agreement of home monitoring findings with 
spectral domain optical coherence tomography 
(SD-OCT) in-office monitoring performed at the 
same day 


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Objectives 
Endpoints/Estimands 
• 
Assess the change in choroidal 
neovascularization (CNV) size in both 
study arms with optical coherence 
tomography angiography (OCT-A) at 
study visits (optional for center) 
• 
To monitor the conversion rate from 
dry to wet form of AMD in fellow eye 
with OCT-A at study visits (optional for 
center) 
• 
To assess handling satisfaction with 
patient Home OCT user experience 
questionnaire 
• 
Assess change in CNV size using OCT-A 
(optional for center) in both study arms at study 
visits 
 
 
• 
Number of patients with newly developed CNV 
in fellow eye in OCT-A at Weeks 36 and 52 in 
eyes with dry AMD signs at baseline for patients 
in both arms 
• 
Number of patients for agreement levels 1 to 5 
assessed at Week 36 
 
Overall Design: 
This is a multicenter, active-controlled, open-label, parallel-group treatment, 1:1 randomized 
Phase 4 study of male and/or female patients ≥50 years of age after treatment initiation with 
intravitreal (IVT) aflibercept for active CNV lesions secondary to nAMD. Control arm is 
widely adopted and approved T&E regimen. 
In total, approximately 108 patients in Europe and Canada will be randomized. The study 
treatment phase will be 52 weeks plus the maximal length of the screening phase (up to 
4 weeks) and the 30 days (phone) follow-up phase after the last injection which may be after 
the last patient last visit (LPLV). 
Patients must give written informed consent before any data documentation and any study 
procedure. The study comprises a screening phase of up to 4 weeks (Visit 1; Week -4 until 
Day -1), a baseline visit (Visit 2; Week 0/Day 1), and a treatment phase (which starts at 
baseline) of 52 weeks.  
Only patients with treatment naïve eyes which have received the 3 initial injections according 
to the label qualify for a screening visit of the study (between Weeks 12 and 16 when 
counting from the treatment start of nAMD).  
The 3 initial injections will be administered as routine treatment outside of the study. 
In the unlikely event that 2 eyes of a patient started treatment at the same time the eye with 
worse BCVA will be designated as the study eye. If a patient has similar BCVA in both eyes, 
the eye with the clearest media will be selected as the study eye. If the ocular media of both 
eyes are similar in clarity, the patient’s non-dominant eye (if identifiable) will be selected as 
the study eye. Starting at baseline (Week 0/Day 1), aflibercept 2 mg IVT treatment will be 
administered to the study eye as detailed below in intervals maximum of 16 weeks and 
minimum of 4 weeks. 
Patients will be stratified based on BCVA gains from treatment initiation to study start 
(captured during screening) and randomized 1:1 into 1 of the following 2 arms: 
• Customized Treatment interval arm 
• T&E, 2-week adjustment arm 
After randomization, the treatment intervals will not be less than 4 weeks nor more than 
16 weeks for both arms. 


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During the treatment phase, the next IVT aflibercept injection will be determined by 
Investigators at each treatment visit according to the following criteria: 
• Shortening of subsequent treatment interval from the last interval 
When any of the following criteria are met for the study eye, subsequent treatment 
interval will be shortened by 1 week in the customized treatment interval arm and by 
2 weeks in the standard T&E, 2-week adjustment arm. 
➢ Presence of intraretinal fluid  
Or 
➢ Subretinal fluid increasing to exceed 50 µm 
Or any of the following: 
➢ Loss of ≥5 early treatment diabetic retinopathy study (ETDRS) letters due to 
disease activity 
➢ New neovascularization 
➢ New macular hemorrhage 
Minimum interval must not be less than 4 weeks during entire period of the study. 
• Maintenance of last treatment interval 
➢ No intraretinal fluid 
And 
➢ Subretinal fluid 
Increasing but 
Not exceeding 50 µm in thickness 
➢ No loss of ≥5 ETDRS letters 
➢ No new neovascularization 
➢ No new hemorrhage 
• Extension of subsequent treatment interval from the last interval 
➢ No intraretinal fluid 
And 
➢ Subretinal fluid 
Unchanged or decreased compared to previous visit 
➢ No loss of ≥5 ETDRS letters 
➢ No new neovascularization 
➢ No new hemorrhage 
If all of the above criteria are met for the study eye, subsequent treatment interval will 
be extended by 2 weeks in the standard T&E, 2-week adjustment arm and by 4 weeks 
in the customized treatment interval arm until a maximum treatment interval of 
16 weeks is reached (e.g., if prior T&E interval was 13 weeks then there will only be 
an extension of 3 weeks to reach the maximum of 16 weeks). 
The study patients will have study visits in accordance with the treatment interval determined 
by the application of the treatment algorithm (as described above). 


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In addition, there are 2 mandatory study visits at Weeks 36 and 52 which may or may not 
coincide with a treatment visit but which have to be attended by every patient as examinations 
are performed from which the primary and secondary outcomes are determined. 
After day of final visit (Week 52 ± 7 days or early termination), administration of study drug 
is not allowed. Any subsequent treatment of the underlying disease of a patient is not part of 
the study and is at the discretion of the patient’s physician. Such treatment should only occur 
after all study relevant assessments have been performed. 
The treating Investigator must follow-up by phone on any adverse events (AEs) that are 
ongoing or may occur within 30 days of the last administration of study drug. Information 
regarding such events is to be reported under this protocol (i.e., not as spontaneous reports). 
All ocular assessments are to be conducted in both eyes, unless indicated otherwise. 
Assessments of ocular efficacy and safety will include BCVA, spectral domain optical 
coherence tomography (SD-OCT), optical coherence tomography angiography (OCT-A), 
patient Home OCT user experience questionnaire (only applicable for patients in the 
customized treatment interval arm), intraocular pressure (IOP), indirect ophthalmoscopy, slit 
lamp biomicroscopy, and AEs; these will be assessed at all study visits (“study visits” are all 
mandatory visits and injection visits and “other visits” are unscheduled visits).  
Short Summary: 
The purpose of this study is to investigate the safety and efficacy of IVT aflibercept with 
proactive customized treatment intervals in patients ≥50 years of age with no fluid due to 
CNV lesions secondary to nAMD following treatment initiation with aflibercept. 
Study details include the following: 
• Study duration per patient:  
➢ Screening phase: Up to 4 weeks 
➢ Treatment phase: Up to 52 weeks 
➢ Telephone follow-up phase: Up to 30 days 
• Visit frequency: Screening visit, Weeks 0 (baseline), 36, and 52. Following 
discontinuation of study treatment, patients will be followed unless they withdraw 
their informed consent for study participation or are lost to follow-up. 
Number of Patients: 
Approximately 108 patients will be randomized in 1:1 ratio to achieve 54 patients in each 
arm. 
Intervention Groups and Duration: 
• Customized treatment interval arm: 
In this treatment arm treatment interval will be extended in a single step from an 
extended treatment interval of 8 weeks to an 16 weeks interval (test arm, rapid 
treatment individualization). After the initial study injection at baseline, patients will 
receive their next study injection at Week 16. Patients in this study arm will also be 
issued a home monitoring device, which will allow for regular OCT monitoring (at 
least 5 times a week) at home. If no fluid exceeding patient threshold emerges between 
the treatment intervals, the patient will stay at a 16 weeks treatment interval until the 
end of the study. 


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If, before completing the planned treatment interval, recurrent fluid is detected by the 
home monitoring device the patient will be asked by the Investigator to return to the 
study site within 3 days at the latest to confirm the findings by SD-OCT. If fluid is 
verified, the patient will be treated immediately, and the next treatment interval will be 
equal to the time between the last study injection and the SD-OCT confirmed 
emergence of new fluid minus 7 days, unless fluid is verified 30 days after treatment. 
After reduction of the treatment interval the following intervals will be extended in 
4 weeks increments up to a maximum of 16 weeks, if all extension criteria are met. 
The monitoring flow of the customized treatment interval arm is depicted in Appendix 
10.5. 
• T&E, 2-week adjustment arm: 
In this treatment arm, starting at baseline, patients will receive treatment in intervals 
maintained (8 weeks) or adjusted in 2 weeks increments each time (up to a maximum 
of 16 weeks and minimum of 4 weeks), depending on extension/shortening criteria. 
Data Monitoring/Other Committee: 
No 
Steering Committee: 
Yes 
1.2 
Schema 
Figure 1-1: Study Design 
 
The end of the study will be achieved as soon as the last patient has undergone their last study visit (plus AE 
follow-up for recently injected patients) in all centers in all participating countries. 
IRF=intraretinal fluid, OCT=optical coherence tomography, SD-OCT=spectral domain optical coherence 
tomography, SRF=subretinal fluid, T&E=treat and extend, wk = week. 
 


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1.3 
Schedule of Activities 
Table 1–1: Schedule of Activities 
Study Phase 
Screeninga 
Baseline 
Treatment 
Treatment Arms 
All Patients 
T&E, 2-Week 
Adjustment Arm 
Customized Treatment 
Interval Arm 
All Patients 
Visit/Wk 
V1 
Wk -4 (Day -28) until 
Day -1 
V2 
Wk 0 (Day 1) 
Visits determined 
by extension 
criteria 
Wk 16 unless earlier visit 
required. Additional visits 
determined by extension 
criteria 
End of 
study/ 
Wk 52 or 
early 
termination 
Study Visits 
Wk -4 until Day -1 
Wk 0 
Injection visits  
+ Wk 36b 
Injection visits  
+ Wk 36b 
Wk 52b 
Administrative 
Informed consent  
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
Demographic datac 
X 
 
 
 
 
Medical/ophthalmic history 
X 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
Study Intervention 
Administration of study treatment 
 
X 
Xd 
Xd 
(X)e 
Determination of next treatment interval 
 
X 
X 
X 
 
Ocular Evaluationf 
BCVA using ETDRS chart 
X 
X 
X 
X 
X 
SD-OCT 
X 
X 
X 
X 
X 
OCT-A (optional)  
 
(X) 
(X) 
(X) 
(X) 
Patient Home OCT user experience 
questionnaire 
 
 
 
X 
 
Indirect ophthalmoscopy  
X 
X 
X 
X 
X 
Slit lamp biomicroscopy 
X 
X 
X 
X 
X 
IOPg 
X 
X 
X 
X 
X 
Safety 
Physical examinationh 
X 
 
 
 
 


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Study Phase 
Screeninga 
Baseline 
Treatment 
Treatment Arms 
All Patients 
T&E, 2-Week 
Adjustment Arm 
Customized Treatment 
Interval Arm 
All Patients 
Visit/Wk 
V1 
Wk -4 (Day -28) until 
Day -1 
V2 
Wk 0 (Day 1) 
Visits determined 
by extension 
criteria 
Wk 16 unless earlier visit 
required. Additional visits 
determined by extension 
criteria 
End of 
study/ 
Wk 52 or 
early 
termination 
Study Visits 
Wk -4 until Day -1 
Wk 0 
Injection visits  
+ Wk 36b 
Injection visits  
+ Wk 36b 
Wk 52b 
Vital signsi 
X 
X 
X 
X 
X 
Ocular and non-ocular AEsj 
X 
X 
X 
X 
Xk 
Telephone safety checkl 
 
(X) 
(X) 
(X) 
X 
Laboratory Testing 
Pregnancy testm 
X 
(X)m 
(X)m 
(X)m 
(X)m 
AE=adverse event, BCVA=best-corrected visual acuity, BMI=body mass index, eCRF=electronic case report form, ETDRS=early treatment diabetic retinopathy study, 
IOP=intraocular pressure, IVT=intravitreal, OCT=optical coherence tomography, OCT-A=optical coherence tomography angiography, PRO=patient-reported outcome, SD-
OCT=spectral domain optical coherence tomography, T&E=treat and extend, Wk=week, WOCBP=women of childbearing potential. 
The end of the study will be achieved as soon as the last patient has undergone their last study visit (plus AE follow-up for recently injected patients) in all centers in all 
participating countries. 
a) The screening visit and baseline visit can be combined in case screening is planned within 1 week before the scheduled baseline visit. 
b) Visit window for injection visits and mandatory visits is +/-7 days. 
c) Patient demographic data including the following, should be documented in the eCRF: year of birth, age, sex, race, and smoking status. 
d) Administration of study treatment only if required per treatment schedule. 
e) Treatment of underlying disease (intravitreal injection) on the day of the final if it coincides with a regular injection visit. Such treatment should only occur after all study 
relevant assessments have been performed. 
f) 
All ocular assessments are to be conducted in both eyes, unless indicated otherwise. Assessments of ocular efficacy and safety will include BCVA, SD-OCT, OCT-A, 
PRO questionnaire, indirect ophthalmoscopy, slit lamp biomicroscopy, IOP, and AEs; these will be assessed at all study visits.  
g) Pre- and post-dose, as applicable. If a patient receives a study injection, indirect ophthalmoscopy should be conducted post-dose per local practice and IOP should be 
assessed in the study eye 30 to 60 minutes post-dosing. 
h) Weight, height, and BMI. 
i) 
Temperature, heart rate, and blood pressure. 
j) 
Any AE occurring up to 30 days after the last IVT aflibercept injection has to be documented, regardless of the relationship to the study drug or the seriousness of the 
event and reported in accordance with this protocol (i.e. not as a spontaneous report). For any drug-related AE occurring after 30 days after the last IVT application of 
aflibercept, the standard procedures that are in place for spontaneous reporting will be followed. If a patient prematurely withdraws from the study, AEs should be 
recorded until withdrawal or 30 days after the last dose of study drug, whichever is later. 


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k) The treating Investigator must follow-up by phone on any AEs that are ongoing or may occur within 30 days of the last administration of study drug. Information 
regarding such events is to be reported under this protocol (i.e., not as spontaneous reports). 
l) 
If a patient has received an injection of study medication 30 days or less before the end of study visit a mandatory safety telephone needs to be made approximately 
30 days after that last treatment to ensure no signs or symptoms of retinal detachment, endophthalmitis, or other AEs have occurred. This telephone call will occur after 
the end of study visit. An optional safety telephone call will be made approximately 3 days after treatment at all other visits as per local standard. 
m) For WOCBP only. Urine pregnancy test for WOCBP. 


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2. 
Introduction 
2.1 
Study Rationale 
The use of anti-vascular endothelial growth factor (anti-VEGF) agents for the treatment of 
neovascular “wet” age-related macular degeneration (nAMD) has become the standard of 
care. The frequency of dosing for monthly anti-VEGFs has introduced a burden of illness on 
patients and caregivers as well as capability constraints on physicians in practice. Physicians 
have developed a practicing trend towards individualizing treatment to reduce the burden of 
patients and minimize reimbursement issues and healthcare costs. The current individualized 
treatment gaining momentum with practicing physicians is referred to as treat and extend 
(T&E), where the patient is injected at every visit and the follow-up examination intervals are 
incrementally extended or shortened according to the response to treatment. 
After 3 monthly initial doses, the treatment interval may be maintained at 2 months or further 
extended using a T&E dosing regimen, where injection intervals are adjusted in 2- or 
4-weekly increments to maintain stable visual and/or anatomic outcomes, according to the 
approved European Union (EU) label for Eylea® (also known as aflibercept 2 mg). Optical 
coherence tomography (OCT) has been used in clinical practice to guide the detection of 
macular fluid in order to direct T&E increase, maintenance, or decrease of follow-up intervals 
and injections. This imaging modality readily permits visualization of anatomic changes 
consistent with choroidal neovascularization (CNV) in nAMD, and allows assessment of the 
treatment response. However, until recently, OCT imaging was only possible in-office and 
was rarely conducted more frequently than every 4 weeks.  
In spite of the encouraging results of Phase 4 T&E study (ALTAIR) and the supporting 
Phase 3b/4 study (ARIES) results, and the resulting label update for Eylea®, allowing for 
rapid, 4-week extension of treatment intervals up to 16 weeks, both are rarely done in 
everyday clinical practice, due to fear of catastrophic disease recurrence.  
Artificial intelligence (AI) and new digital technologies are expected to transform medicine 
and especially ophthalmology fundamentally in the near future. Home monitoring is one 
potential mass application for such approaches and as of yet, there is no data on how home 
monitoring that can support treatment with Eylea®. In this study we try to understand whether 
an additional layer of assessments during the whole treatment interval by a digital drug 
development tool can increase the confidence of physicians and patients to increase treatment 
to longer intervals (maximum 16 weeks). The coronavirus disease 2019 (COVID-19) 
pandemic has strongly impacted on ophthalmology. Reignited interest in home monitoring for 
exudative retinal disease is expected to persist as we transition to the “new normal”. 
2.2 
Background 
Age-related macular degeneration (AMD) is a leading cause of adult blindness in the 
developed world (Rahmani et al,1996). There are 2 forms of AMD, the dry and the wet 
(neovascular) form. Neovascular AMD is a major health issue in aging populations globally 
(Ladas et al. 2004, Scassellati-Sforzolini et al. 2001, Lafaut et al. 2000). Vision loss in nAMD 
results from the abnormal growth and leakage of blood vessels in the macula.  
The inhibition of VEGF activity by pharmacological intervention has proven to be a viable 
approach for the treatment of neovascular AMD (Maruko et al. 2007). Intravitreal (IVT)-
administered anti-VEGF therapies like aflibercept inhibit neovascular vessel growth and 
leakage in the retina, and they are currently the standard of care for patients with nAMD. 


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They not only maintain visual function but also provide clinically meaningful visual gains. 
Treatment of nAMD is chronic and long-term in most patients to suppress retinal edema and 
recurrences of CNV. Although the globally approved IVT anti-VEGF therapies are 
efficacious and well tolerated, the need for IVT aflibercept injections every 4 to 8 weeks, 
specifically in the initial phase and during maintenance of treatment, represents a significant 
burden to physicians, patients and caregivers. While the IVT procedure is straightforward and 
relatively easy to perform, capacity issues for ensuring an appropriate injection frequency in 
order to achieve patient outcomes similar to those seen in the pivotal studies represent an 
increasing challenge to individual practices and the healthcare system overall. 
The use of anti-VEGF agents in an individualized, proactive T&E for nAMD has become the 
standard of care. Utilization of proactive IVT aflibercept T&E regimens allows for a 
pragmatic approach to treatment and offers benefits to physicians and patients. With 
proactive, individualized T&E dosing regimens, the need for interim monitoring is 
minimized, as is the risk of disease recurrence. Reducing the number of appointments per 
patient and minimizing the need for monitoring visits could ease clinic flow and patient 
burden. Furthermore, planning the next injection helps minimize the possibility of treatment 
delays and facilitates clinic management (Mitchell et al. 2021). 
This study will investigate the safety and efficacy of IVT aflibercept with proactive 
customized treatment intervals in patients ≥50 years of age with no fluid due to CNV lesions 
secondary to nAMD following treatment initiation with aflibercept. 
Refer to Section 4.2 for a discussion on the rationale for study design and Section 4.3 for dose 
justification.  
2.3 
Benefit/Risk Assessment 
Aflibercept is marketed for the treatment of adult patients with several retinal diseases that are 
characterized by up-regulation of VEGF, are related to pathological neo-vascularization 
and/or vascular leakage, and can result in retinal thickening and edema, which is thought to 
contribute to vision loss. The efficacy and safety of aflibercept 2 mg used in adult patients 
with retinal diseases are well established; and its benefit-risk profile is considered favorable. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of aflibercept may be found in the Investigator’s Brochure 
(IB). 
2.3.1 
Risk Assessment 
Based on current available data, it is anticipated that the safety profile of aflibercept in a 
customized treatment interval arm applied to preselected nAMD patients with a dry retina 
before study start, will be similar to that of the approved T&E regimen, and includes 
identified risks of aflibercept, such as hypersensitivity, and identified risks of the injection 
procedure, such as intraocular inflammation/infection, retinal tear, retinal detachment, 
transient increase in intraocular pressure (IOP), and traumatic cataract. Therefore, the same 
contraindications, precautions and warnings for Eylea® will also apply to this study. 
The adverse reactions associated with Eylea® are shown in Table 2–1 (Company Core Data 
Sheet [CCDS]). The adverse reactions are listed by system organ class and frequency using 
the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon 
(≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000). Within each frequency grouping, adverse 
drug reactions are presented in order of decreasing seriousness. 


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Table 2–1: All Treatment-emergent Adverse Drug Reactions Reported in Patients in 
Phase 3 Studies 
System 
Organ 
Class 
Very 
Common 
Common 
Uncommon 
Rare 
Immune 
system 
disorders 
  
  
Hypersensitivity***  
  
Eye 
disorders 
Conjunctival 
hemorrhage, 
Eye pain 
Retinal pigment epithelial tear*, 
Detachment of the retinal 
pigment epithelium, 
Cataract, 
Cataract cortical, 
Cataract nuclear, 
Cataract subcapsular,  
Corneal erosion,  
Corneal abrasion, 
Intraocular pressure increased, 
Vision blurred, 
Vitreous floaters, 
Vitreous detachment, 
Injection site pain, 
Foreign body sensation in eyes,  
Lacrimation increased, 
Eyelid edema, 
Injection site hemorrhage,  
Punctate keratitis, 
Conjunctival hyperemia, 
Ocular hyperemia 
Endophthalmitis**, 
Retinal detachment, 
Retinal tear, 
Uveitis, 
Iritis, 
Iridocyclitis, 
Lenticular opacities, 
Corneal epithelium 
defect,  
Anterior chamber 
flare, 
Corneal edema 
Cataract 
traumatic, 
Vitritis, 
Hypopyon 
AMD=age-related macular degeneration. 
*Conditions known to be associated with wet AMD. Observed in the wet AMD studies only. 
**Culture positive and culture negative endophthalmitis. 
***During the post-marketing period, reports of hypersensitivity included rash, pruritus, urticaria, and isolated 
cases of severe anaphylactic/anaphylactoid reactions. 
A detailed description of adverse reactions is provided in the CCDS of Eylea®. 
The protocol has been designed to minimize the risk to the study patients. Special warnings 
and precautions for the use of aflibercept are reflected in strict inclusion and exclusion criteria 
for this study. 
Patients will be monitored to detect AEs during the study and followed appropriately to 
ensure the resolution of AEs. Safety assessments will consist of the regular measurements of 
vital signs and physical examinations as well as monitoring and recording of AEs and serious 
adverse events (SAEs). 
Risk Assessment for COVID-19 Pandemic: 
There is currently an outbreak of respiratory disease (COVID-19) caused by a novel severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Appropriate medical measures have 
been implemented into this protocol to detect COVID-19 disease to confirm eligibility of 
patients and to safely conduct the study. 
Aflibercept is a soluble decoy receptor fusion protein that has been shown to bind to VEGF-
A, placental growth factor (PlGF) and VEGF-B, with subsequent blockade of activity 
demonstrated for VEGF-A and PlGF and is believed not to cause immune suppression. 
Measures to mitigate the additional risks caused by COVID-19 are: 


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This study is going to start enrolling only when the Sponsor and contract research 
organization (CRO) in collaboration deem it is safe to start the study.  
Current national laws and local recommendations for prevention of pandemic will be strictly 
adhered to. 
Once clinical signs of infection are reported by patients, the Investigator needs to determine 
whether samples can be collected, and safety data can be recorded on site. If not, AEs and 
concomitant medications will be obtained via phone calls. Daily body temperature 
measurement is recommended. 
The study drug will not be administered to patients upon identification of any signs of 
COVID-19 infection. 
Confirmation of COVID-19 infection by optional laboratory assessment will be conducted 
based on availability (test capacity and turnaround time) of approved tests and on the 
Investigator’s discretion. This would include serology testing at screening and virus testing 
prior to any admission. 
The probability of virus transmission will be controlled as much as possible by: 
• Advice for patient to adhere to local requirements for reduction of the public exposure 
while ambulatory. 
• Patients are asked for any contact with a person who has tested positive for SARS-
CoV-2. If applicable, patients will be referred to the local health care system for 
further -follow-up- and treatment. 
• Physical distancing and person to person contact restrictions will be applied during 
site visits and in-house confinement. 
• Where physical distancing is not possible, personal protective equipment will be used 
by study patient (face mask, gloves) and staff (for example but not limited to masks, 
gloves, protectors, medical suits) if deemed appropriate by the Investigators and site 
staff and guided by local requirements. 
• Logistical improvements of the site and structural measures of the study site building 
will be implemented to further improve physical distancing. 
2.3.2 
Benefit Assessment 
Marketing authorizations have been granted for aflibercept (Eylea®, [aflibercept] IVT 
injection) for a 2 mg dose (delivered as a 50 µL [0.05 mL] injection of 40 mg/mL) in more 
than 110 countries for the treatment of patients with nAMD including the United States (US), 
countries in the EU (European Commission), Japan, Australia, and Canada.  
The T&E treatment schedule allows a controlled prolongation of treatment intervals without 
interim visits needed between injections. 
Going beyond the currently approved treatment intervals in a preselected population may 
further reduce treatment intensity burden for patients and their care givers. 
The additional use of a a digital drug development tool which provides an additional layer of 
assessments during the treatment period will allow ongoing surveillance of patient disease 
status and increase confidence in fast prolongation to maximal treatment intervals. 


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2.3.3 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to patients in this study, the potential 
risks identified in association with aflibercept are justified by the anticipated benefits that may 
be afforded to patients with nAMD. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of aflibercept may be found in the IB. 
With proactive, individualized T&E dosing regimens, the need for interim monitoring is 
minimized, as is the risk of disease recurrence. In preselected patients who respond fast to the 
treatment with anti-VEGFs and experience complete dryness of the retina for 8 weeks 
preceding the start of the study, an even faster prolongation of treatment intervals is 
appropriate , which would further reduce the number of appointments per patient. By 
minimizing the need for monitoring visits patient flow within the clinic can be optimized and 
patient burden could be decreased. Furthermore, this study will use Home monitoring in one 
study arm which allows the patient to provide OCT scans in short time intervals (several 
times per week up to daily) to the treating physician who can surveille at an ongoing basis 
treatment success and patient safety and as such decrease risk of disease recurrence. Home 
OCT assessments may further minimize the risk of treatment delays and improve use of clinic 
resources. 
3. 
Objectives and Endpoints/Estimands 
Objectives 
Endpoints/Estimands 
Primary 
• 
To assess whether 2 mg intravitreal 
(IVT) aflibercept administered at a 
customized treatment interval 
(determined after the first extended 
treatment interval) is non-inferior to 
2 mg IVT aflibercept administered 
according to a standard treat and 
extend (T&E) regimen (initiated after 
the first extended treatment interval) in 
patients with no fluid following 
treatment initiation for neovascular 
(wet) age-related macular 
degeneration (nAMD) 
Primary Endpoint:  
• 
Change in best-corrected visual acuity (BCVA) 
(early treatment diabetic retinopathy study 
[ETDRS] letters) from baseline to Week 36  
Secondary 
• 
To assess treatment burden of 2 mg 
IVT aflibercept administered at a 
customized treatment interval 
compared with 2 mg IVT aflibercept 
administered according to a standard 
T&E regimen (initiated after the first 
extended treatment interval) in patients 
with no fluid following treatment 
initiation for nAMD 
Key Secondary Endpoint: 
• 
Number of IVT aflibercept injections per patient 
up to Week 52 (descriptively) 
Secondary Endpoints: 
• 
Number of IVT aflibercept injections per patient 
until Week 36 
• 
Number of patients achieving pre-defined 
treatment intervals (≥4, ≥8, ≥10, ≥12¸ ≥14, and 
16 weeks) at Weeks 36 and 52  
• 
Change in BCVA (ETDRS letters) from baseline 
to Week 52 
• 
To evaluate the safety of aflibercept 
with proactive treatment intervals 
• 
Treatment-emergent adverse events (TEAEs) 
and treatment-emergent serious adverse events 
(TESAEs) through Weeks 36 and 52 


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Objectives 
Endpoints/Estimands 
Other pre-specified exploratory 
• 
To assess morphologic outcomes of 
2 mg IVT aflibercept administered at a 
customized treatment interval 
compared with 2 mg IVT aflibercept 
administered according to a standard 
T&E regimen (initiated after the first 
extended treatment interval) in patients 
with no fluid following treatment 
initiation for nAMD 
Other Pre-specified Exploratory Endpoints: 
• 
Change in central subfield retinal thickness 
(CST) [µm] from baseline to Weeks 36 and 52 
• 
Change in CST compared to treatment initiation 
(16 weeks before baseline) at Weeks 36 and 52 
• 
Number of patients without any fluid at treatment 
initiation (16 weeks before baseline), baseline, 
Weeks 36, and 52 
➢ 
without intraretinal fluid (IRF) 
➢ 
without subretinal fluid (SRF) 
➢ 
without sub-retinal pigment epithelium (sub-
RPE) fluid 
Customized treatment interval arm only: 
• 
Change in retinal fluid volume and in volume by 
compartment (IRF and SRF) 
• 
Area under the curve (AUC) of fluid volumes  
• 
Agreement of home monitoring findings with 
spectral domain optical coherence tomography 
(SD-OCT) in-office monitoring performed at the 
same day 
• 
Assess the change in choroidal 
neovascularization (CNV) size in both 
study arms with optical coherence 
tomography angiography (OCT-A) at 
study visits (optional for center) 
• 
To monitor the conversion rate from 
dry to wet form of AMD in fellow eye 
with OCT-A at study visits (optional for 
center) 
• 
To assess handling satisfaction with 
patient Home OCT user experience 
questionnaire 
• 
Assess change in CNV size using OCT-A 
(optional for center) in both study arms at study 
visits 
 
 
• 
Number of patients with newly developed CNV 
in fellow eye in OCT-A at Weeks 36 and 52 in 
eyes with dry AMD signs at baseline for patients 
in both arms 
 
• 
Number of patients for agreement levels 1 to 5 
assessed at Week 36 
 
4. 
Study Design 
4.1 
Overall Design 
This is a multicenter, active-controlled, open-label, parallel-group treatment, 1:1 randomized 
Phase 4 study of male and/or female patients ≥50 years of age after treatment initiation with 
IVT aflibercept for active CNV lesions secondary to nAMD. Control arm is widely adopted 
and approved T&E regimen. 
In total, approximately 108 patients in Europe and Canada will be randomized. The study 
treatment phase will be 52 weeks plus the maximal length of the screening phase (up to 
4 weeks) and the 30 days (phone) follow-up phase after the last injection which may be after 
the last patient last visit (LPLV). 
Patients must give written informed consent before any data documentation and any study 
procedure. The study comprises a screening phase of up to 4 weeks (Visit 1; Week -4 until 
Day -1), a baseline visit (Visit 2; Week 0/Day 1), and a treatment phase (which starts at 
baseline) of 52 weeks. 


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Only patients with treatment naïve eyes which have received the 3 initial injections according 
to the label qualify for a screening visit of the study (between Weeks 12 and 16 when 
counting from the treatment start of nAMD).  
The 3 initial injections will be administered as routine treatment outside of the study. 
In the unlikely event that 2 eyes of a patient started treatment at the same time the eye with 
worse BCVA will be designated as the study eye. If a patient has similar BCVA in both eyes, 
the eye with the clearest media will be selected as the study eye. If the ocular media of both 
eyes are similar in clarity, the patient’s non-dominant eye (if identifiable) will be selected as 
the study eye. Starting at baseline (Week 0/Day 1), aflibercept 2 mg IVT treatment will be 
administered to the study eye as detailed below in intervals maximum of 16 weeks and 
minimum of 4 weeks. 
Patients will be stratified based on BCVA gains from treatment initiation to study start 
(captured during screening) and randomized 1:1 into 1 of the following 2 arms: 
• Customized treatment interval arm: 
• In this treatment arm treatment interval will be extended in a single step from an 
extended treatment interval of 8 weeks to an 16 weeks interval (test arm, rapid 
treatment individualization). After the initial study injections at baseline, patients will 
receive their next study injection at Week 16.  
Patients in this study arm will also be issued a digital drug development tool which 
allows an additional layer of assessments in an ongoing way (at least 5 times a week) 
at home. If no abnormal assessments between preplanned visits are seen, the patient 
will be evaluated at these study visits and the new treatment interval be determined. 
If abnormal assessments during the treatment interval are reported by the digital drug 
development tool, the patient will be asked by the Investigator to return to the study 
site within 3 days at the latest to confirm the findings by spectral domain optical 
coherence tomography (SD-OCT). If fluid is verified and the treatment algorithm 
requires a change of treatment interval, the patient will be treated immediately, and the 
next treatment interval will be equal to the time between the last study injection and 
the SD-OCT-confirmed emergence of new fluid minus 7 days, unless fluid is verified 
30 days after treatment. After reduction of the treatment interval the following 
intervals will be extended in 4 weeks increments up to a maximum of 16 weeks, if all 
extension criteria are met. If the findings are not confirmed by SD-OCT or no change 
is required as per treatment algorithm the patient will go on with the current treatment 
interval.  
The monitoring flow of the customized treatment interval arm is depicted in Appendix 
10.5. 
• T&E, 2 week-adjustment arm: 
In this treatment arm, starting at baseline, patients will receive treatment in intervals 
maintained (8 weeks) or adjusted in 2 weeks increments each time (up to a maximum 
of 16 weeks and minimum of 4 weeks), depending on extension/shortening criteria. 
After randomization, the treatment intervals will not be less than 4 weeks nor more than 
16 weeks for both arms. 


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During the treatment phase, the next IVT aflibercept injection will be determined by 
Investigators at each treatment visit according to the following criteria: 
• Shortening of subsequent treatment interval from the last interval 
When any of the following criteria are met for the study eye, subsequent treatment 
interval will be shortened by 1 week in the customized treatment interval arm and by 
2 weeks in the standard T&E, 2-week adjustment arm. 
➢ Presence of intraretinal fluid  
Or 
➢ Subretinal fluid increasing to exceed 50 µm 
Or any of the following: 
➢ Loss of ≥5 early treatment diabetic retinopathy study (ETDRS) letters due to 
disease activity 
➢ New neovascularization 
➢ New macular hemorrhage 
Minimum interval must not be less than 4 weeks during entire period of the study. 
• Maintenance of last treatment interval 
➢ No intraretinal fluid 
And 
➢ Subretinal fluid 
Increasing but 
Not exceeding 50 µm in thickness 
➢ No loss of ≥5 ETDRS letters 
➢ No new neovascularization 
➢ No new hemorrhage 
• Extension of subsequent treatment interval from the last interval 
➢ No intraretinal fluid 
And 
➢ Subretinal fluid 
Unchanged or decreased compared to previous visit 
➢ No loss of ≥5 ETDRS letters 
➢ No new neovascularization 
➢ No new hemorrhage 
If all of the above criteria are met for the study eye, subsequent treatment interval will 
be extended by 2 weeks in the standard T&E, 2-week adjustment arm and by 4 weeks 
in the customized treatment interval arm until a maximum treatment interval of 
16 weeks is reached (e.g., if prior T&E interval was 13 weeks then there will only be 
an extension of 3 weeks to reach the maximum of 16 weeks). 
The study patients will have study visits in accordance with the treatment interval determined 
by the application of the treatment algorithm (as described above). 


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In addition, there are 2 mandatory study visits at Weeks 36 and 52 which may or may not 
coincide with a treatment visit but which have to be attended by every patient as examinations 
are performed from which the primary and secondary outcomes are determined. 
After day of final visit (Week 52 ± 7 days or early termination), administration of study drug 
is not allowed. Any subsequent treatment of the underlying disease of a patient is not part of 
the study and is at the discretion of the patient’s physician. Such treatment should only occur 
after all study relevant assessments have been performed. 
The treating Investigator must follow-up by phone on any AEs that are ongoing or may occur 
within 30 days of the last administration of study drug. Information regarding such events is 
to be reported under this protocol (i.e., not as spontaneous reports). 
All ocular assessments are to be conducted in both eyes, unless indicated otherwise. 
Assessments of ocular efficacy and safety will include BCVA, SD-OCT, optical coherence 
tomography angiography (OCT-A), patient Home OCT user experience questionnaire (only 
applicable for patients in Home OCT arm), IOP, indirect ophthalmoscopy, slit lamp 
biomicroscopy, and AEs; these will be assessed at all study visits (“study visits” are all 
mandatory visits and injection visits and “other visits” are unscheduled visits).  
A Steering Committee will be established to guide all aspects of the study. 
4.2 
Scientific Rationale for Study Design 
The use of anti-VEGF agents in an individualized, proactive T&E for nAMD has become the 
standard of care. The SARS-CoV-2 pandemic has shown that there still is a major unmet need 
in predicting the treatment interval to optimize clinic capacity. 
This study in patients with nAMD aims to assess non-inferiority of IVT aflibercept proactive 
customized treatment intervals compared with IVT aflibercept proactive T&E in maintaining 
BCVA gains following treatment initiation with aflibercept. 
The non-inferiority design is adequate to assess the study objectives. 
Open-label setting: Since there is no adequate way to mask home monitoring without 
jeopardizing its effect on treatment guidance, masking the study would disrupt the primary 
objective and, thus, was not considered to be a viable option. 
The primary study endpoint at Week 36 corresponds to an overall treatment time of 52 weeks 
of the patients with nAMD. It also coincides with the completion of treatment circles of the 
2 study groups. The end of study 52 weeks after study start would allow both study groups to 
reach the maximum treatment interval of 16 weeks. 
4.3 
Justification for Dose 
The recommended dose for aflibercept is 2 mg (equivalent to 50 µL). Aflibercept treatment is 
initiated with 1 injection per month for 3 consecutive doses, followed by 1 injection 
after2 months. Based on the physician’s judgment of visual and/or anatomic outcomes, the 
treatment interval may be maintained at 2 months or further extended using a T&E dosing 
regimen, where injection intervals are adjusted in 2- or 4-weekly increments to maintain 
stable visual and/or anatomic outcomes. If visual and/or anatomic outcomes deteriorate, the 
treatment interval should be shortened accordingly. There is no requirement for monitoring 
between injections. Based on the physician’s judgment the schedule of monitoring visits may 
be more frequent than the injection visits.  


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4.4 
End of Study Definition 
The end of the study will be achieved as soon as the last patient has undergone their last study 
visit (plus AE follow-up for recently injected patients) in all centers in all participating 
countries.  
5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
Eligibility for participation in this study will be based on the inclusion/exclusion criteria. An 
individual patient may only be randomized once. 
Patients eligible for this study must have had active CNV lesions secondary to nAMD at 
treatment initiation and 3 initial IVT aflibercept injections as per label. The patients’ ability to 
properly handle a Home OCT device to participate in the study will be determined by the 
Investigator.  
Only one eye will be designated as the study eye. In the rare event that a patient meets 
eligibility criteria in both eyes, the eye with worse BCVA will be selected. If there is no 
objective basis for selecting the study eye, factors such as ocular dominance, other ocular 
pathology and patient preference should be considered in making the selection.  
Ophthalmic eligibility criteria apply to the study eye only unless otherwise specified. 
Inclusion and exclusion criteria will be assessed during the screening phase and the patient 
must sign the informed consent form (ICF) before any of the inclusion/exclusion criteria are 
assessed. 
5.1 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
1. Written informed consent and able to read (or if unable to read due to visual impairment, 
be read to verbatim by the person administering the informed consent or a family 
member), understand, and willing to sign the ICF. 
2. Men and women ≥50 years of age. 
3. At treatment initiation, active macular neovascular lesions secondary to nAMD (Patients 
with polypoidal choroidal vasculopathy or retinal angiomatous proliferation are eligible 
to participate in the study, and their condition should be captured in the electronic case 
report form [eCRF]). 
4. Treatment initiation with 3 × monthly IVT aflibercept injections (Weeks -16, -12, and -8 
to planned study baseline visit) resulting in absence of any fluid at week -8. 
5. ETDRS BCVA of at least 25 letters (20/320 Snellen equivalent) in the study eye at 
screening visit. 
6. Willing, committed, and able to return for all clinic visits and complete all study-related 
procedures. 
7. Able to use the provided monitoring device and willing to perform 5 × weekly self-
assessments in the Investigator’s opinion. 


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8. Women and men of reproductive potential must agree to use adequate contraception 
when sexually active. This applies for the time period between signing of the ICF and 
3 months after the last administration of study drug. 
The definition of adequate contraception will be based on the judgment of the 
Investigator and on local requirements. 
Acceptable methods of contraception include, but are not limited to, (i) condoms (male or 
female) with or without a spermicidal agent; (ii) diaphragm or cervical cap with 
spermicide; (iii) intra-uterine device; (iv) hormone-based contraception. Patients must 
agree to utilize 2 reliable and acceptable methods of contraception simultaneously. 
5.2 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
1. Any contraindication to IVT anti-VEGF treatment or treatment with Eylea® as detailed in 
the Summary of Product Characteristics (SmPC). 
2. Any prior ocular (in the study eye) or systemic treatment (including investigational 
agents) or surgery for nAMD, except the 3 × monthly IVT aflibercept injections required 
for treatment initiation and dietary supplements or vitamins. 
3. Any presence of intraretinal and subretinal fluid at screening and baseline visit. 
4. Any ocular or systemic condition expected to interfere with study outcomes and 
procedures, including but not limited to: 
• Scar, fibrosis or other lesions (e.g., retinal pigment epithelium [RPE] tears, macular 
hole stage 2 or above and others) involving the center of the macula in the study eye. 
• Clinically relevant opacities or conditions involving the optic media including 
cataract, corneal dystrophies or s.p. corneal transplant in the study eye. 
• Uncontrolled glaucoma (defined as IOP ≥25 mm Hg despite treatment with 
antiglaucoma medication) in the study eye or prior trabeculectomy or other filtration 
surgery in the study eye. 
• Intraocular surgery, periocular surgery, or cataract surgery within 90 days before 
Day 1 in the study eye, except the IVT aflibercept injections required for treatment 
initiation and any history of vitrectomy, retinal radiation therapy, retinal detachment or 
treatment or surgery for retinal detachment in the study eye. 
• Aphakia or pseudophakia with absence of posterior capsule (unless as a result of an 
yttrium aluminum garnet posterior capsulotomy) in the study eye. 
5. Participation as a patient in any clinical study within 12 weeks before screening. 
6. Close affiliation with the investigational site; e.g., a close relative of the Investigator, 
dependent person (e.g., employee or student of the investigational site). 
7. Previously screen failed patients for this study. 
5.3 
Lifestyle Considerations 
No lifestyle restrictions are required during the study. 


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5.4 
Screen Failures 
A screen failure occurs when a patient consents to participate in the clinical study but is not 
subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
and eligibility criteria. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be rescreened. 
6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study patient according to the 
study protocol. 
6.1 
Study Intervention Administered 
Table 6–1: Study Intervention 
Intervention Label 
Investigational Drug 
Intervention Name 
Aflibercept 2 mg 
Type  
Drug 
Dose Formulation 
Solution in Vial 
Unit Dose Strength(s) 
40 mg/mL 
Dosage Level(s) 
2 mg (50 µL) 
Route of Administration 
IVT injection 
Use 
Experimental regimen based on Customized regimen vs. standard 
T&E regimen 
Packaging and Labeling 
Study Intervention will be provided in sterile 2 mL glass vials. Each 
vial will be labeled as required per country requirement 
IVT=intravitreal, OCT=optical coherence tomography, T&E=treat and extend. 
Each vial is for single use only. 
Table 6–2: Study Arms 
OCT=optical coherence tomography, T&E=treat and extend. 
Arm Title 
Customized treatment interval 
arm 
T&E, 2-week adjustment arm 
Arm Type 
Experimental 
Active comparator 
Arm Description 
After the initial study injection at 
baseline, patients will receive their 
next study injection at Week 16. 
Patients in this study arm will also 
be issued a home monitoring 
device, which will allow for regular 
OCT monitoring (at least 5 times a 
week) at home. 
Patients will receive treatment 
in intervals maintained 
(8 weeks) or adjusted in 
2 weeks increments each time 
(up to a maximum of 16 weeks 
and minimum of 4 weeks), as 
long as all extension/shortening 
criteria are met. 
Associated Intervention 
Labels 
Investigational drug 


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6.1.1 
Medical Devices 
Medical devices and diagnostic devices (Home OCT devices) used in this study include both 
devices that help prepare the study intervention (study drug), as well as devices that are used 
to gather additional clinical data and Home OCT device that is an observational tool for the 
patients only. The Home OCT system is a diagnostic device and Sponsor will need to report 
device incidents and deficiencies to the legal manufacturer according to the agreement. These 
devices are not Conformité Européene (CE) marked (or Food and Drug Administration [FDA] 
cleared) according to the regulatory requirements specific for the country where the study site 
is located. 
The Sponsor will provide 2 devices to be used in the study: 
• 18-gauge filter needle to be used in the preparation of the study medication. 
• The Home OCT device that is an observational tool for the patients only. The Home 
OCT system is a diagnostic device. 
The Home OCT device (digital drug development tool) used in the study is a patient self-
operated tele-connected retinal OCT imaging device for automated data transmission and 
remote review of images and analytics results provided by the cloud-based artificial 
intelligence enabled OCT Analyzer (OA). The Home OCT uses a fixed, predefined grid of 
88 B-scans to cover an area of 3 × 3mm (10 × 10 image field). The specifications of the 
spectral domain OCT contain a central wavelength of 830 nm, a scanning speed of 10,000 A-
scans per second and 500 A-scans per B-scan. 
Instructions for use of these devices are provided by the legal manufacturer of these devices. 
Deficiencies (including malfunctions, use error, and inadequate labeling) related to the filter 
needles and Home OCT device shall be documented and reported to the Sponsor by the 
Investigator throughout the clinical investigation (see Section 8.3.7) so they can be 
appropriately managed by the Sponsor. 
6.2 
Preparation, Handling, Storage, and Accountability 
The Investigator or designee must maintain a log to confirm appropriate temperature 
conditions have been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
Only patients randomized in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized site 
staff. 
The Investigator or the head of the institution (where applicable) is responsible for study 
intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Investigator site file, if applicable. 
The study intervention will be supplied in kits that include the following: 
• Sterile study intervention in sealed glass vials (see Table 6–1) 
• Filter needle (18-gauge) 


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Study intervention is to be stored in the refrigerator (2°C to 8°C) and must not be frozen. The 
vials must be kept in the outer carton to protect them from light. When study intervention is 
removed from the refrigerator, the solution should be inspected visually and it should have no 
evidence of turbidity. If particulates, cloudiness, or discoloration are visible, the vial must not 
be used. Study drug can withstand brief exposures to temperatures up to 25°C, such as those 
that may occur during finishing, shipping, and handling, without compromising either the 
physical or chemical stability or the potency of the protein. 
6.3 
Measures to Minimize Bias: Randomization 
Patients will be randomly assigned in a 1:1 ratio to 1 of 2 parallel treatment arms as described 
in Section 4.1. Randomization will be stratified based on BCVA gains from treatment 
initiation to study start (captured during screening), to ensure balanced distribution of the 
treatment arms within each stratum (i.e., <8 or ≥8 letters gain in BCVA). 
Patients will be centrally assigned to randomized study intervention using an Interactive 
Response System (IXRS). The treatment allocation will be done according to a generated 
randomization list specified by the Sponsor or delegate. Before the study is initiated, the 
directions for the IXRS will be provided to each site. 
Study intervention will be dispensed at the study visits summarized in the Schedule of 
Activities (SoA) (Section 1.3). 
Returned study intervention should not be re-dispensed to the patients. 
6.4 
Study Intervention Compliance 
Study intervention will be administered by a qualified ophthalmologist. Details of IVT 
aflibercept injection will be recorded in the eCRF (e.g., time of injection, type of anesthesia, 
treatment site). 
6.5 
Continued Access to Study Intervention after the End of the Study 
Intervention will not be supplied after the end of the study. Patients will not be restricted with 
regard to pursuing available approved treatments for nAMD.  
6.6 
Treatment of Overdose 
For this study, any dose of study intervention greater than 2 mg per injected eye will be 
considered an overdose. 
Overdosing with increased injection volume may increase IOP. In these cases, evaluation of 
IOP and central retinal artery perfusion should be performed immediately after the injection 
and monitored until normalized. If there is severe elevation of IOP causing disruption of 
central retinal artery perfusion, immediate performance of an anterior segment paracentesis 
should be considered. 
In the event of an overdose, the Investigator should: 
• Contact the Medical Monitor immediately. 
• Evaluate the patient to determine, in consultation with the Medical Monitor, whether 
study intervention should be interrupted or whether the dose should be reduced. 
• Closely monitor the patient for any AE/SAE and laboratory abnormalities. 


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• Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient. 
6.7 
Concomitant Therapy 
6.7.1 
Allowed and Prohibited Medications 
For prohibited drugs and procedures prior to the study, including treatments in either the 
study eye or the fellow eye, see Section 5.2. 
Patients may not receive any standard or investigational agents for treatment of their nAMD 
in the study eye other than IVT aflibercept as specified in this protocol until they have 
completed the end of study/early termination visit assessments. This includes medications 
administered locally (e.g., IVT, by juxtascleral or periorbital routes), as well as those 
administered systemically with the intent of treating the fellow eye.  
Any medication considered necessary for the patient’s welfare, and that is not expected to 
interfere with the evaluation of the study intervention, may be given at the discretion of the 
Investigator. 
Any medication or vaccine (including any sedation, anesthesia, eye drops used for the study 
procedures, blood-derived products, prescription or over-the-counter medicines, probiotics, 
vitamins, and herbal supplements) that the patient receives during the study must be recorded 
along with:  
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.7.2 
Fellow Eye Treatment 
Only 1 eye per patient may be enrolled in the study. If a patient’s fellow (non-study) eye 
requires anti-VEGF treatment during the patient’s participation in the study, the fellow eye 
should be treated with aflibercept 2 mg according to the approved treatment regimen in the 
respective country, irrespective of the randomization assignment of the patient. The costs of 
aflibercept 2 mg used for treatment of the fellow eye will be supported by the Sponsor in 
compliance with local regulations. Although the fellow eye can receive treatment, it will not 
be considered an additional study eye. Patients who receive treatment for the fellow eye 
should remain in the study. Treatment of the fellow eye will be documented in the eCRF 
Concomitant Medication page. Safety for the fellow eye will be monitored; AEs/SAEs will be 
reported in the eCRF. Once the fellow eye receives aflibercept 2 mg therapy during the study, 
AEs will be assessed as related/not related to “aflibercept 2 mg (fellow eye)” in addition to 
being assessed as related/not related to the study drug delivered to the study eye (aflibercept 
2 mg), IVT aflibercept injection-procedure, and other protocol-specified procedures. 


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7. 
Discontinuation of Study Intervention and Patient 
Discontinuation/Withdrawal  
7.1 
Discontinuation of Study Intervention  
Study intervention discontinuation can be triggered by the patient (or legally authorized 
representative) or by the treating Investigator. 
Patients for whom study intervention is planned at any time during the study but not 
administrated will be considered to have temporarily discontinued study intervention. If study 
intervention is temporarily discontinued, it can be restarted at any time during the study but 
not later than 16 weeks. 
In rare instances, it may be necessary for a patient to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the patient will remain in the 
study to be evaluated for safety evaluation up to 30 days after the last study intervention. See 
the SoA (Section 1.3) for data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed. 
7.2 
Patient Discontinuation/Withdrawal from the Study 
A patient may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
Patients must be withdrawn from the study if any of the following occurs: 
• Relevant laboratory abnormality or SAEs, if the Sponsor or Investigator sees this as 
medical reason to warrant withdrawal.  
• AE (ocular or non-ocular) that, from the patient’s or the Investigator’s view, is potent 
enough to require withdrawal from the study. The Investigator must notify the 
Sponsor immediately if a patient is withdrawn because of an AE/SAE.  
• At the discretion of the treating Investigator. The development of conditions, which 
would have prevented a patient’s entry into the study according to the selection 
criteria, is no reason per se for withdrawal. However, the withdrawal in such cases 
remains at the discretion of the treating Investigator. 
• Decision by the Investigator or the Sponsor that termination is in the patient’s best 
medical interest or administrative decision for a reason other than an AE/SAE. 
• A female patient becomes pregnant. Refer to Section 8.3.5.  
• Lost to follow-up. Refer to Section 7.3.  
• Decision by the Sponsor to halt the entire study. 
Patients may be withdrawn from the study if any of the following occurs: 
• Any treatment for nAMD other than study interventions in the study eye is considered 
a prohibited treatment, and patient must be withdrawn from the study.  
• Systemic anti-angiogenic agents were taken by the patient during the study.  
• If, in the Investigator's opinion, continuation of the study would be harmful to the 
patient's well-being.  


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• At the specific request of the Sponsor and in liaison with the Investigator (e.g., 
obvious noncompliance or safety concerns). 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted, as shown in the SoA (Section 1.3). See SoA for data to be collected at the time 
of study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
The patient will be permanently discontinued from the study intervention and the study at that 
time. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
Patients who withdraw from the study will not be replaced. 
7.3 
Lost to Follow-Up 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible, counsel the patient on the importance of maintaining the assigned visit 
schedule, and ascertain whether the patient wishes to and/or should continue in the 
study. 
• Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls, and if 
necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the patient’s 
medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers 
or exemptions are not allowed. Patients should be seen for all visits on the designated day, 
with an allowed “visit window” as indicated in the SoA. Any unscheduled visits (e.g., for 
safety follow-up) must be documented in the eCRF. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  


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Procedures conducted as part of the patient’s routine clinical management and obtained before 
signing of the ICF may be utilized for screening or baseline purposes provided the procedures 
met the protocol-specified criteria and were performed within the timeframe defined in the 
SoA. 
8.1 
Efficacy Assessments  
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3). 
8.1.1 
Ophthalmic and General Examinations 
Note: In this section, all ophthalmic examinations are described, irrespective of whether they 
are used for efficacy or safety assessments.  
Ophthalmic evaluations will be conducted according to the SoA (Section 1.3).  
All ophthalmic examinations are to be conducted pre-injection in both eyes and post-injection 
in the study eye only, unless indicated otherwise.  
At any visit, ophthalmic examinations not stipulated by this protocol may take place outside 
of this protocol at the discretion of the Investigator. 
8.1.1.1 
Best Corrected Visual Acuity 
Visual function will be assessed using the ETDRS protocol (Early Treatment Diabetic 
Retinopathy Study Research Group. 1985) starting at 4 meters. Refraction is to be done at 
each visit.  
Visual acuity examiners must be certified to ensure consistent measurement of BCVA. Any 
certified and trained study personnel may perform this assessment (including but not limited 
to ophthalmologist, optometrist, or technician). For each patient, the same examiner should 
perform all assessments whenever possible. BCVA should be done before any other ocular 
procedures are performed. 
8.1.1.2 
Spectral Domain Optical Coherence Tomography  
Retinal and lesion characteristics will be evaluated using SD-OCT. For all visits where the 
SD-OCT procedure is scheduled, images will be captured and read by the technician and 
Investigator for individual treatment decisions and sent to an independent reading center 
where images will be read by readers. The patients’ eligibility to take part in the study in 
terms of SD-OCT will be reconfirmed by the central reading center. The same SD-OCT 
imaging system used at screening and Day 1 must be used at all follow-up visits in each 
patient. Images will be taken in both eyes before dosing (active injection). All SD-OCTs will 
be archived electronically by the study sites as part of the source documentation. The study 
manual will further specify the acquisition and assessment for OCT during the study. 
8.1.1.3 
Optical Coherence Tomography Angiography 
OCT-A will be performed at sites with the relevant equipment. 
The same imaging modality used at screening must be used at all follow-up visits in each 
patient. Images will be taken in both eyes before dosing (active injection) if applicable.  
All OCT-As will be archived electronically by the study sites as part of the source 
documentation. The study manual will further specify the acquisition and assessment for 
OCT-A during the study. 


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8.1.1.4 
Indirect Ophthalmoscopy 
Indirect ophthalmoscopy will be performed according to local medical practice and applicable 
medical standards at the site.  
Patient’ posterior pole and peripheral retina will be examined by indirect ophthalmoscopy or 
equivalent investigation at each study visit pre-dose (bilateral) by the Investigator and post-
dose (study eye) by the Investigator. Post-dose evaluation must be performed immediately 
after injection. 
8.1.1.5 
Slit Lamp Biomicroscopy 
The slit lamp biomicroscopy will be performed according to local medical practice and 
applicable medical standards at the site.  
Patients’ anterior eye structure and ocular adnexa will be examined bilaterally (pre-dose on 
visits with active injection) at each study visit using a slit lamp by the Investigator. 
8.1.1.6 
Intraocular Pressure 
IOP will be measured using a calibrated Goldman applanation tonometry, rebound tonometry 
Icare, or Tonopen and the same method of measurement must be used in each patient 
throughout the study.  
At all visits, IOP should be measured bilaterally by the Investigator (or designee). On days 
when study intervention is administered, IOP should also be measured approximately 
30 minutes after administration of study intervention (study eye only) by the Investigator (or 
designee).  
If multiple post-injection measurements are performed, the final measurement before the 
patient leaves should be documented in the eCRF. Any injection-related clinically significant 
increase in IOP should be reported as AE and documented in electronic data capture (EDC) 
system. 
8.1.2 
Home OCT User Questionnaire  
Patient user experience with Home OCT device will be assessed with the device vendor 
questionnaire (only applicable for patients in customized treatment interval arm). 
8.2 
Safety Assessments  
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 
Physical Examinations 
A routine physical examination will assess cardiovascular, respiratory, gastrointestinal, and 
neurological systems and will follow the standard practice of the site. Body weight, height, 
and body mass index (BMI) should be measured at Visit 1 (screening). The assessment will 
be based on the clinical judgment of the Investigator and aim to evaluate the overall health of 
the patient. 
8.2.2 
Vital Signs 
Temperature, heart rate, and blood pressure will be measured according to the local medical 
practice and regulations.  
Vital signs should be measured pre-injection, if applicable, per the procedure outlined in the 
study manual.  


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Clinically significant abnormal findings will be reported as AEs in the eCRF. 
8.2.3 
Pregnancy Testing 
For women of childbearing potential (WOCBP), a negative urine pregnancy test at screening 
is required for eligibility. A negative urine pregnancy test is required before any treatment 
(including rescue regimen) is administered at subsequent visits in either the study eye or the 
fellow eye (see the SoA in Section 1.3). Pregnancy testing is not required for women not 
considered WOCBP. Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria. 
Pregnancy test results will be recorded in the eCRF. 
8.3 
Adverse Events, Serious Adverse Events and Other Safety Reporting 
The definitions of AEs and SAEs can be found in Section 10.2. 
The definitions of device-related safety events can be found in Section 10.4. Device 
deficiencies are covered in Section 8.3.7. 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the patient to discontinue the study intervention or the study (see 
Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.2. 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information 
(S)AEs will be collected from signing of the ICF until the last follow-up visit at the 
timepoints specified in the SoA (Section 1.3). 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of learning of the event, as indicated in 
Section 10.2. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation. However, if the Investigator learns of any SAE, including a death, 
at any time after a patient has been discharged from the study, and he/she considers the event 
to be reasonably related to the study intervention or study participation, the Investigator must 
promptly notify the Sponsor. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the 


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event is otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is provided in Section 10.2.  
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
intervention under clinical investigation are met.  
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRBs)/independent ethics 
committees (IECs), and Investigators. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then 
file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements. 
For all studies except those using medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
8.3.5 
Pregnancy 
Details of all pregnancies in female patients and, if indicated, female partners of male patient 
will be collected after the start of study intervention and until 90 days after the last dose of 
study intervention. 
If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the pregnancy. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs, and will be reported as such. 
The patient/pregnant female patient will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the patient/pregnant female 
patient and the neonate and the information will be forwarded to the Sponsor. 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in Section 8.3.4. 
While the Investigator is not obligated to actively seek this information in former study 
patient/pregnant female patient, he or she may learn of an SAE through spontaneous 
reporting. 
Any female patient who becomes pregnant while participating in the study may be requested 
to discontinue the study intervention. 
8.3.6 
Adverse Events of Special Interest  
No AEs of special interest are defined. 


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8.3.7 
Medical Device Deficiencies 
Medical devices are being provided for use in this study as the study intervention. To fulfill 
regulatory reporting obligations worldwide, the Investigator is responsible for the detection 
and documentation of events meeting the definitions of device deficiency that occur during 
the study with such devices. 
The definition of a medical device deficiency can be found in Section 10.4. 
Device deficiencies only should be reported to the Sponsor, by completing the product 
technical complaints (PTC) form and submitting it to the Sponsor via the email address (ptc-
imp@bayer.com) given to the site. 
NOTE: Deficiencies fulfilling the definition of an AE/SAE will follow the processes outlined 
in Section 10.2 of the protocol.  
8.3.7.1 
Time Period for Detecting Medical Device Deficiencies 
Medical device deficiencies that result in an incident will be detected, documented, and 
reported to the Sponsor during all periods of the study in which the medical device is used.  
If the Investigator learns of any device deficiency at any time after a patient has been 
discharged from the study, and such deficiency is considered reasonably related to a medical 
device provided for the study, the Investigator will promptly notify the Sponsor. 
The method of documenting medical device deficiencies is provided in Section 10.4. 
8.3.7.2 
Follow-up of Medical Device Deficiencies 
Follow-up applies to all patients, including those who discontinue study intervention. 
The Investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the Investigator.  
8.3.7.3 
Prompt Reporting of Device Deficiencies to the Sponsor 
Device deficiencies will be reported to the Sponsor within 24 hours after the Investigator 
determines that the event meets the protocol definition of a medical device deficiency. 
The Medical Device Deficiency Report Form will be sent to the Sponsor by emailing the 
completed product technical complaint form (see Section 8.3.7). If email is unavailable, then 
fax should be utilized. 
The Sponsor will be the contact for the receipt of device deficiency reports. 
8.3.7.4 
Regulatory Reporting Requirements for Device Deficiencies 
The Investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study in order for the Sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies. 
The Investigator, or responsible person according to local requirements (e.g., the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of device deficiencies to the IRB/IEC. 


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8.4 
Pharmacokinetics 
Pharmacokinetic(s) (PK) parameters are not evaluated in this study. 
8.5 
Genetics and/or Pharmacogenomics 
Genetics are not evaluated in this study. 
8.6 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.7 
Immunogenicity Assessments 
Not applicable. 
8.8 
Health Economics OR Medical Resource Utilization and Health 
Economics  
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 
9. 
Statistical Considerations  
The statistical analysis plan (SAP) will be finalized prior to first patient first visit and it will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoint. 
9.1 
Statistical Hypotheses 
The test problem in relation to the primary objective and/or estimand, see Section 3, is 
described below. The hypothesis testing for the primary estimand will be conducted at one-
sided significance level of 2.5%. 
One-sided test problem (related to primary estimand): 
Null hypothesis H0: μ1≤ μ2 - D vs. alternative hypothesis H1: μ1 >μ2 - D, where 
• D = non-inferiority margin. 
• μi = absolute mean change in BCVA as measured by the ETDRS letter score for the 
study eye from baseline to Week 36 in treatment arm i. 
• i = 1: customized treatment interval arm; 2: standard T&E 2-week adjustment arm. 
Note that a higher ETDRS letter score represents better vision. The aim is to show that the 
customized treatment interval arm is no less effective than the standard T&E 2-week 
adjustment arm, using a non-inferiority margin of 5 letters for the difference of the means of 
change from baseline in BCVA as measured by the ETDRS letter score for the study eye at 
Week 36. 
The non-inferiority margin D is set to 5 letters and the rationale is that previous studies with 
anti-VEGF therapies in other indications regarded a difference of 5 letters as clinically 
relevant. The threshold of 5 letters has a clinical relevance and a direct meaning for the 
patients in terms of ETDRS chart, given that 5 letters are equal to 1 line in the chart. This 
choice of the non-inferiority margin is consistent with the margin used in the ARIES study. 


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Analyses on the key secondary and other secondary objectives/estimands will be conducted in 
an exploratory way and therefore no formal statistical hypothesis testing is planned. 
9.1.1 
Multiplicity Adjustment 
The multiplicity control is not relevant for the study, given that: 
• There is only one test problem in relation to the primary objective to compare the 
2 study arms (i.e., customized treatment interval arm vs. standard T&E 2-week 
adjustment arm) 
• The analyses on the key secondary and other secondary objectives will be conducted 
in an exploratory way. 
9.2 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
• The full analysis set (FAS) includes all randomized patients who receive any study 
treatment injection, excluding treatment initiation prior to screening, and have a 
baseline and at least one post-baseline BCVA assessment. The FAS will be analyzed 
“as randomized”. 
• The safety analysis set (SAF) includes all patients who receive any study treatment 
injection, excluding treatment initiation prior to screening. The SAF will be analyzed 
“as treated”. 
The FAS is used to analyze endpoints related to the efficacy objectives and the SAF is used to 
analyze the endpoints and assessments related to safety. 
9.3 
Statistical Analyses 
9.3.1 
General Considerations 
Descriptive Statistics 
All variables will be analyzed descriptively with appropriate statistical methods; continuous 
variables will be summarized by descriptive statistics (number of patients, mean, standard 
deviation [STD], minimum, median and maximum) and categorical variables will be 
summarized by frequency tables (absolute and relative frequencies). 
Baseline Definition 
For efficacy endpoints, the last observed assessment prior to randomization will be considered 
the baseline assessment, unless otherwise specified. 
For safety endpoints, the last observed assessment prior to the first injection of study 
treatment will be considered the baseline assessment, unless otherwise specified. 
Stratification Factors 
A stratification by visual outcomes at screening is planned, to ensure equal allocation of 
subgroups, thereby making it easier to interpret the results. Visual outcomes will be 
determined at the screening visit, depending on whether the patients reached <8 or ≥8 letters 
gain in BCVA relative to aflibercept initiation prior to study enrollment (i.e., treatment 
initiation at 16 weeks before baseline). 


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Missing Data Handling 
In general, data will not be imputed for the safety analysis. 
See the Sections 9.3.2 and 9.3.3 for the data imputations for the efficacy analyses. 
Unscheduled Assessments 
Extra assessments (e.g., vital signs associated with non-protocol clinical visits or obtained in 
the course of investigating or managing AEs) will be included in data listings, but not in data 
summaries. If more than one measurement is available for a given visit, the first observation 
will be used in the data summaries and all observations will be presented in the data listings. 
Statistical Software 
Statistical analysis will be performed using statistical analysis software; the version used will 
be specified in the SAP. 
9.3.2 
Primary Endpoint/Estimand Analysis 
The estimand of primary interest will be based on a hypothetical strategy. 
It describes the change in BCVA from baseline for all patients that started treatment assuming 
all patients have stayed on treatment until Week 36. 
The estimand is specified through the following definitions of population, variable, treatment 
condition, intercurrent events, and population-level summary: 
Population: 
Target population defined by the inclusion/exclusion criteria 
(see Section 5). 
Variable: 
Absolute change from baseline to Week 36 in BCVA as 
measured by the ETDRS letter score for the study eye. 
Treatment condition: 
Aflibercept customized treatment interval arm vs. aflibercept 
standard T&E 2-week adjustment arm. 
Intercurrent events: 
Premature discontinuation from treatment/study. 
Start of alternative anti-VEGF treatment, prior to treatment 
and/or study discontinuation. 
Shortening/extension of the dosing interval will not be 
considered an intercurrent event, but as part of the randomized 
treatment regimen. 
Further intercurrent events might be specified in the SAP. 
Population-level summary: 
Difference in mean change from baseline to Week 36 in 
BCVA between the customized treatment interval arm and 
standard T&E 2-week adjustment arm. 
The primary statistical analysis will be performed on the FAS by randomized treatment arm. 
The methodological approach will be the calculation of two-sided 95% confidence interval 
(CI) for the difference in the least squares means (customized treatment interval arm - 
standard T&E 2-week adjustment arm) of the change in ETDRS letter score from baseline to 
Week 36 based on a mixed-effect model repeated measure (MMRM) analysis making use of 
all observed BCVA data from baseline up to Week 36 (including censoring for alternative 
anti-VEGF). The MMRM will include the fixed categorical effects of treatment, visit, 


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treatment-by-visit interaction and stratification variable; the fixed continuous covariate of 
baseline BCVA score; and visit as a repeated measure. Restricted maximum likelihood 
estimation will be used. An unstructured covariance matrix will be used to model the within-
patient error and the Kenward-Roger approximation will be used to estimate the degrees of 
freedom. Further details (e.g., non-convergence of the model, handling of missing data) will 
be provided in the SAP. 
The customized treatment interval arm will be considered to be non-inferior to the standard 
T&E 2-week adjustment arm if this analysis is statistically significant, i.e., if the CI of the 
difference lies entirely above -5 letters, where a positive difference favors the customized 
treatment interval arm. 
The sensitivity analysis of the primary efficacy endpoint will be based on a “while on 
treatment” strategy. 
It describes the change from baseline for all patients that started treatment until the timepoint 
when they discontinued treatment or had an intercurrent event with a major impact on the 
applied treatment regimen. 
The following sensitivity analyses will be performed: 
• Analysis of covariance (ANCOVA) with last observation carried forward (LOCF) 
Analysis of covariance with the BCVA measure at baseline as a covariate, and the 
treatment arm and the stratification variable as fixed factors. 
Missing data will be imputed using LOCF method. Observed values from both 
scheduled and unscheduled post-baseline visits will be used for the LOCF imputation. 
For patients who discontinue treatment but continue in the study and start an 
alternative anti-VEGF treatment, the efficacy data will be censored at the time the 
patient started alternative anti-VEGF treatment in the study eye. Missing data will be 
imputed by the last observation prior to receiving alternative anti-VEGF treatment. 
• Complete case analysis 
The same main methodology will be applied but with no imputation of missing data. 
Patients with missing BCVA assessment at Week 36 will be excluded from the 
analysis. 
9.3.3 
Secondary Endpoints/Estimands Analysis 
The estimand of key secondary interest will be based on a “while on treatment” strategy. 
It describes the number of injections per patient up to study Week 52, for all patients that 
started treatment until the timepoint when they discontinued treatment or had an intercurrent 
event with a major impact on the applied treatment regimen. 
The estimand is specified through the following definitions of population, variable, treatment 
condition, intercurrent events, and population-level summary: 
Population: 
Target population defined by the inclusion/exclusion criteria 
(see Section 5). 
Variable: 
Number of IVT aflibercept injections in the study eye per 
patient in the time frame from baseline to Week 52. 
Treatment condition: 
Aflibercept customized treatment interval arm vs. aflibercept 
standard T&E 2-week adjustment arm. 


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Intercurrent events: 
Premature discontinuation from treatment/study. 
Start of alternative anti-VEGF treatment, prior to treatment 
and/or study discontinuation. 
Shortening/extension of the dosing interval will not be 
considered an intercurrent event, but as part of the randomized 
treatment regimen. 
Further intercurrent events might be specified in the SAP. 
Population-level summary: 
Difference in mean number of injections per patient in the time 
frame from baseline to Week 52 between the customized 
treatment interval arm and T&E 2-week adjustment arm. 
The secondary statistical analysis will be performed on the FAS by randomized treatment 
arm, in a descriptive manner, by means of an analysis of covariance with the treatment arm 
and the stratification variable as fixed factors. 
The treatment difference in the mean number of injections per patient (customized treatment 
interval arm vs. standard T&E 2-week adjustment arm) and its two-sided 95% CI will be 
estimated, as a reference. 
No imputation of missing data will be performed, therefore the actual/observed number of 
injections per patients from baseline to Week 52 will be analyzed. 
The following sensitivity analysis will be performed: 
• Complete case analysis 
The same methodology will be applied but considering only data of patients who stay 
on treatment until Week 52. Patients who prematurely discontinue from 
treatment/study or who start an alternative anti-VEGF treatment, prior to treatment 
and/or study discontinuation or completion will be excluded from the analysis. 
Analyses on the other secondary efficacy endpoints will be conducted on the FAS, by 
randomized treatment arm, as defined in Sections 9.2 and 9.3.1 in a descriptive manner 
adjusting for the stratification factors. This may include 95% CIs for treatment differences in 
an exploratory way. 
The other secondary efficacy endpoints are: 
• Mean number of IVT aflibercept injections in the study eye per patient until study 
Week 36. 
• Proportion of patients achieving pre-defined treatment intervals (≥4, ≥8, ≥10, ≥12, 
≥14, and 16 weeks) at Weeks 36 and 52. 
• Mean change in BCVA [ETDRS letters score in the study eye] from baseline to 
Week 52. 
For the mean number of IVT aflibercept injections, the same analysis as per the secondary 
estimand (i.e., ANCOVA analysis) will be conducted. 
For the proportion of patients achieving pre-defined treatment intervals, the difference 
between the proportions (customized treatment interval arm - standard T&E 2-week 
adjustment arm) will be analyzed by means of a logistic regression with the treatment arm and 
the stratification variables as fixed factors. 
For the mean change in BCVA, the same analysis as per the primary estimand will be 
conducted.  


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Further details will be provided in the SAP. 
9.3.4 
Exploratory Endpoint(s) Analysis 
Analyses on exploratory variables will be conducted on the FAS, by randomized treatment 
arm, as defined in Sections 9.2 and 9.3.1 in a descriptive manner. This includes 95% CIs for 
treatment differences in an exploratory way. 
The exploratory endpoints are: 
For both treatment arms: 
• Change in central subfield retinal thickness (CST) [µm] from baseline to Weeks 36 
and 52 in the study eye. 
• Change in CST compared to treatment initiation (i.e., 16 weeks before baseline) at 
Weeks 36 and 52 in the study eye. 
• Proportion of patients without any fluid/ without intraretinal fluid (IRF)/subretinal 
fluid (SRF) nor sub-retinal pigment epithelium (sub-RPE) fluid at treatment-initiation 
(i.e., 16 weeks before baseline), baseline, Weeks 36 and 52 in the study eye. 
For the customized treatment interval arm only: 
• Change in retinal fluid volume and in volume by compartment (IRF and SRF) in the 
study eye. 
• Area under the curve (AUC) of fluid volumes in the study eye. 
• Agreement of home monitoring findings with SD-OCT in-office monitoring 
performed at the closest time prior to the office visit. 
For both treatment arms: 
• Change in CNV size using OCT-A (optional for center) in the study eye at study 
visits. 
• Number of patients with newly developed CNV in fellow eye in OCT-A at Weeks 36 
and 52 in eyes with dry AMD signs at baseline. 
For the customized treatment interval arm only: 
• Number of patients for agreement levels 1 to 5 assessed at Week 36. 
Further details will be provided in the SAP. 
9.3.5 
Safety Analysis 
The safety variables are defined in Sections 9.2 and 9.3. 
The safety analysis will be conducted in the SAF by actual treatment arm. 
AEs that occurred or worsened after the first injection of study drug and no later than 30 days 
after the last injection of study drug will be considered as treatment-emergent adverse events 
(TEAEs). 
Treatment-emergent ocular AEs will be presented by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term within the primary system organ class and summarized 
by actual treatment arm for the study eye and the fellow eye separately. Treatment-emergent 
nonocular AEs will be also summarized. Intensity and causal relationship to the study 
drug/IVT injection will be analyzed descriptively. SAEs including narratives will be 
documented separately. 


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Other safety variables (e.g., slit lamp assessments, indirect ophthalmoscopy assessments, IOP 
measurements and vital signs) will be analyzed descriptively including changes from baseline. 
9.3.6 
Other Analysis 
Analysis of other variables and/or parameters and subgroup analyses will be further detailed 
in the SAP. 
9.4 
Interim Analysis 
No formal statistical interim analysis is planned. The primary endpoint/estimand will be 
analyzed and the summaries up to Week 36 will be provided when all patients have completed 
Week 36 (or withdrew). The analysis will only use data collected up to Week 36 or premature 
discontinuation, whichever occurs first. No decisions on the outcome and/or study will be 
made (e.g., terminating the study or changing the design). Therefore, no α-adjustment seems 
to be necessary. 
All the secondary and exploratory endpoints/estimands will be analyzed and the summaries 
up to Week 52 will be provided when all patients have completed the study (i.e., completed 
Week 52 or prematurely withdrew, whichever occurs first). The analysis will use all data 
collected. 
9.5 
Sample Size Determination 
In ARIES study, patients which were dry (as no IRF and no SRF) at Weeks 8 and 16 in the 
early T&E arm (N=59) had a mean BCVA change of -0.5 letters from Week 16 to Week 52 
with a STD of 6.6  
In ALTAIR study, patients which were dry (as no IRF and no SRF) at Weeks 8 and 16 in the 
2-week adjustment arm (N=55) had a mean BCVA change of -0.7 letters from Week 16 to 
Week 52 with a STD of 7.2 and the 4-week adjustment arm (N=61) had a mean BCVA 
change of -0.5 letters from Week 16 to Week 52 with a STD of 6.1. 
Under the assumptions that: 
• The customized treatment interval arm is similar to the 4-week adjustment arm from 
ALTAIR study (i.e., N=61 with a mean BCVA change of -0.5 letters from Week 16 to 
Week 52 with a STD of 6.1). 
• The standard T&E 2-week adjustment arm is similar to the 2-week adjustment arm 
from ALTAIR study (i.e. N=55 with a mean BCVA change of -0.7 letters from 
Week 16 to Week 52 with a STD of 7.2). 
• There is no true difference in mean BCVA change from baseline to Week 36 between 
both arms (which would be equal to the change from Week 16 to Week 52 in ALTAIR 
and ARIES studies). 
• Both arms will have standard deviation of 7 for the mean change in BCVA from 
baseline to Week 36. 
A sample size of N=86 patients in total would be needed to show a non-inferiority of 
customized treatment interval arm compared to the standard T&E 2-week adjustment arm, 
using a non-inferiority margin of 5 letters, for the difference of the means change from 
baseline in BCVA at Week 36, achieving a power of 90% using a one-sided test with a 
significance level α of 2.5%. Assuming an expected dropout rate of 20%, a sample size of 
approximately N=108 patients in total (54 patients per arm) will be randomized. 


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The sample size was calculated using NCSS PASS 13 “Non-Inferiority Tests for Two Means 
using Differences”. 


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10. 
Supporting Documentation and Operational Considerations 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines 
• Applicable local laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. Any substantial modification of the protocol will be submitted to the 
competent authorities as substantial amendments for approval, in accordance with ICH GCP 
and national and international regulations. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study patients. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
10.1.3 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the patients or their legally authorized representative and answer all 
questions regarding the study.  


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Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 Code of Federal Regulations (CFR) 50, local regulations, ICH 
guidelines, privacy and data protection requirements, where applicable, and the IRB/IEC or 
study center.  
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
A copy of the ICF(s) must be provided to the patients or their legally authorized 
representative.  
10.1.4 
Data Protection 
Patients will be assigned a unique identifier by the Sponsor. Any patient records, datasets or 
biological samples that are transferred to the Sponsor will contain the identifier only; patient 
names or any information which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient who will be required to give consent for their data to be used as 
described in the informed consent  
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5 
Committees Structure 
Steering Committee 
A Steering Committee will be established to guide the study in all aspects of safety and 
efficacy and must ensure that all relevant information is provided by Investigators. The 
composition of the committee, the functional roles, and responsibilities will be specified in its 
charter. 
10.1.6 
Dissemination of Clinical Study Data 
Result Summaries of Bayer's Sponsored clinical studies in drug development Phases 2, 3, and 
4 and Phase 1 studies in patients are provided in the Bayer Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases". In addition results of clinical drug 
studies will be provided on the publicly funded website ClinicalTrials.gov and EU Clinical 
Trials Register in line with the applicable regulations. 
Bayer commits to sharing upon request from qualified scientific and medical researchers 
patient-level clinical study data, study-level clinical study data, and protocols from clinical 
studies in patients for medicines and indications approved in the US and EU on or after 
January 01, 2014 as necessary for conducting legitimate research. 


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All Bayer-sponsored clinical studies are considered for publication in the scientific literature 
irrespective of whether the results of the clinical studies are positive or negative. 
10.1.7 
Data Quality Assurance 
All patient data relating to the study will be recorded on printed or eCRFs unless transmitted 
to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.  
Guidance on completion of case report forms (CRFs) will be provided in eCRF Completion 
Instructions. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
The Sponsor assumes accountability for actions delegated to other individuals (e.g., contract 
research organizations). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 25 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.  
10.1.8 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site and in 
computer systems used by the remote monitoring service provider in case of Home OCT data. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
Definition of what constitutes source data and its origin can be found in the Source Data 
Location List (SDLL) or equivalent. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The Sponsor will perform monitoring to confirm that data entered into the CRF by authorized 
site personnel are accurate, complete, and verifiable from source documents; that the safety 
and rights of patients are being protected; and that the study is being conducted in accordance 
with the currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  


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10.1.9 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 
The first act of recruitment is the first patient screened and will be the study start date. 
Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of patients 
by the Investigator 
• Total number of patients included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the patient and 
should assure appropriate patient therapy and/or follow-up. 
10.1.10 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments.  
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 


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10.2 
Appendix 2: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and Reporting 
10.2.1 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study patient, associated 
with the use of study intervention, whether or not considered related to the study 
intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated 
with the use of study intervention. 
 
Events Meeting the AE Definition  
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (i.e., not 
related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfill the definition of 
an AE or SAE. 
 
Events NOT Meeting the AE Definition  
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the patient’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
patient’s condition. 


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• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
10.2.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose, meets the 
one or more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
• The term life-threatening in the definition of serious 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, 
which hypothetically might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the patient has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 


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f. 
Other situations: 
• Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that may jeopardize the patient or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. 
These events should usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment 
for allergic bronchospasm, blood dyscrasias, convulsions, or development of 
intervention dependency or intervention abuse. 
 
10.2.3 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The Investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the Investigator to send photocopies of the patient’s medical 
records to the Sponsor in lieu of completion of the AE/SAE eCRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all patient identifiers, with the exception of 
the patient number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
• The Investigator will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to one of the following categories:  
o Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
o Moderate: Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL). Instrumental ADL 
refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
o Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self-care ADL. Self-care ADL refers to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden. 
 


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Assessment of Causality 
• The Investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. The Investigator will use clinical judgment 
to determine the relationship. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to the Sponsor. However, it is 
very important that the Investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
• If a patient dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem 
findings including histopathology. 
• New or updated information will be recorded in the originally submitted 
documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours 
of receipt of the information. 
 


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10.2.4 
Reporting of SAEs 
 
SAE Reporting via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to the Sponsor will be the electronic 
data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
transmission (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study patient or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the Medical Monitor by telephone. 
• Contacts for SAE reporting can be found in the safety reporting gateway. 
 
SAE Reporting to via Paper Data Collection Tool 
• Email transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Medical Monitor. 
• In rare circumstances and if email transmission is not feasible, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE data collection tool within the designated reporting 
timeframes. 
• Contacts for SAE reporting can be found in the Investigator site file. 
 


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10.3 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.3.1 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are considered WOCBP (fertile) 
1. Following menarche 
2. From the time of menarche until becoming premenopausal unless permanently sterile (see 
below): 
• A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
➢ A high follicle stimulating hormone (FSH) level in the post-menopausal range 
may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required.  
➢ Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of post-menopausal status before study enrollment. 
• Permanent sterilization methods (for the purpose of this study) include: 
➢ Documented hysterectomy 
➢ Documented bilateral salpingectomy 
➢ Documented bilateral oophorectomy 
➢ For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), Investigator discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the patient’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
10.3.2 
Collection of Pregnancy Information: 
Male Patients With Partners Who Become Pregnant 
• The Investigator will attempt to collect pregnancy information on any male patient’s 
female partner who becomes pregnant while the male patient is in this study. This 
applies only to male patients who receive study intervention. 


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• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow-up will be at least 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for the procedure. 
Female Patients Who Become Pregnant 
• Any female patient who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study.  
• The Investigator will collect pregnancy information on any female patient who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of 
learning of a patient’s pregnancy. 
• The patient will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the patient and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will be required 
for at least 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
➢ While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
➢ A spontaneous abortion (occurring at 22 weeks gestational age) is always 
considered to be an SAE and will be reported as such. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.5. While the Investigator is not obligated to actively seek this information 
in former study patients, he or she may learn of an SAE through spontaneous 
reporting. 


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10.4 
Appendix 4: Adverse Events, Serious Adverse Events, and Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting in Medical Device Studies 
The definitions and procedures detailed in this appendix are in accordance with ISO 14155 
and the European Medical Device Regulation (MDR) 2017/745 for clinical device research (if 
applicable).  
Both the Investigator and the Sponsor will comply with all local reporting requirements for 
medical devices. 
The detection and documentation procedures described in this protocol apply to all Sponsor 
medical devices provided for use in the study. See Section 6.1.1 for the list of Sponsor 
medical devices. 
10.4.1 
Definition of Medical Device AE 
 
Medical Device AE Definition  
• A medical device AE is any untoward medical occurrence in a clinical study 
patient, users, or other persons, temporally associated with the use of study 
intervention, whether or not considered related to the medical device (digital drug 
development tool). An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of an medical device. This 
definition includes events related to the medical device or comparator and events 
related to the procedures involved except for events in users or other persons, 
which only include events related to devices. 
10.4.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 


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A Medical Device SAE is any SAE that: 
a. Led to death  
b. Led to serious deterioration in the health of the patient, that either resulted in: 
• A life-threatening illness or injury. The term ‘life-threatening' in the definition of 
serious' 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, which hypothetically might have caused death, 
if it were more severe. 
• A permanent impairment of a body structure or a body function. 
• Inpatient or prolonged hospitalization, planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE. 
• Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
• Chronic disease (MDR 2017/745). 
c. Led to fetal distress, fetal death or a congenital abnormality or birth defect  
d. Is a suspected transmission of any infectious agent via a medicinal product 
 
10.4.3 
Definition of Device Deficiency 
 
Device Deficiency Definition 
• A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and inadequacy of the information supplied by 
the manufacturer. 
 
10.4.4 
Recording and Follow-Up of AE and/or SAE and Device Deficiencies 
 
AE, SAE, and Device Deficiency Recording 
• When an AE/SAE/device deficiency occurs, it is the responsibility of the 
Investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event. 
• The Investigator will then record all relevant AE/SAE/device deficiency 
information in the patient’s medical records, in accordance with the Investigator’s 
normal clinical practice and on the appropriate form. 


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• It is not acceptable for the Investigator to send photocopies of the patient’s 
medical records to the Sponsor in lieu of completion of the AE/SAE/medical 
device incident page. 
• There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all patient identifiers, with the exception of 
the patient number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
• For device deficiencies, it is very important that the Investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency. 
A remedial action is any action other than routine maintenance or servicing of a medical 
device where such action is necessary to prevent recurrence of a device deficiency. This 
includes any amendment to the device design to prevent recurrence. 
For PTC that are not related to an AE or SAE, a PTC form should be completed and 
reported to the Sponsor electronically or via the email address (ptc-imp@bayer.com). 
For device deficiencies that caused an AE or SAE, complete the AE CRF and MDI CRF. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE/SAE/device deficiency 
reported during the study and assign it to one of the following categories:  
• Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Moderate: Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc. 
• Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self-care ADL. Self-care ADL refers to bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden.  
 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency. The Investigator will use 
clinical judgment to determine the relationship. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship 
cannot be ruled out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the IB in his/her assessment. 


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• For each AE/SAE/device deficiency, the Investigator must document in the 
medical notes that he/she has reviewed the AE/SAE/device deficiency and has 
provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to the Sponsor. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE/SAE/device Deficiency 
• The Investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by the Sponsor to elucidate the nature and/or causality of the 
AE/SAE/device deficiency as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. 
• If a patient dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any postmortem 
findings including histopathology. 
• New or updated information will be recorded in the originally completed form. 
• The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of receipt of the information. 
 
10.4.5 
Reporting of SAEs 
 
SAE Reporting via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to the Sponsor will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next table) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study patient or receives updated 
data on a previously reported SAE after the electronic data collection tool has 


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been taken off-line, then the site can report this information on a paper SAE form 
(see next table) or to the Medical Monitor by telephone. 
• Contacts for SAE reporting can be found in safety reporting gateway. 
 
SAE Reporting to via Paper Data Collection Tool 
• Email transmission of the SAE paper data collection tool is the preferred method 
to transmit this information to the Sponsor. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE paper collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE data collection tool within the designated reporting 
time frames. 
• Contacts for SAE reporting can be found in the Investigator site file. 


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10.5 
Appendix 5: Customized Treatment Interval Arm Monitoring Flow 
Figure 10-1: Home-OCT monitoring flow of customized Treatment Interval Arm 
 
IRF=intraretinal fluid, OCT=optical coherence tomography, SL=self-limiting, SRF= subretinal fluid 


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10.6 
Appendix 6: Patient Training for Use of Home OCT and Monitoring of 
Home OCT Images 
Patient Training for Use of Home OCT 
• The study site will introduce the Home OCT to the patient through the Informed 
Consent Form and patient brochure. 
• The device vendor will schedule a call prior to Home OCT device delivery to review 
self-imaging instructions and self-imaging frequency requirements. 
• The patient will use the Home OCT’s setup material to install the device in their 
home. 
• The device vendor will provide confirmation to the patient of first Home OCT image 
transmission to the device vendor Health Cloud success. 
• The device vendor will call patient if no transmission is received within one business 
day from Home OCT device delivery. 
• The device vendor will perform scheduled patient engagement calls following start of 
home self-imaging following two (2) weeks followed by monthly for the duration of 
the home monitoring period. 
• The device vendor will perform compliance calls to patient following a gap of 2 days 
in self-imaging, with a call on the next business day. 
Monitoring of Home OCT images 
Bayer, the device vendor, and the Principal Investigators have access to patient scan data 
through the cloud-based Home OCT Web Viewer. Bayer will not have access to the patient’s 
name or other identifiable information in the viewer. After logging in, physicians can select a 
patient’s data to review by querying patient identifiers or by scrolling through a patient or 
notification list. 
After selecting a patient or notification, the physician will see data similar to other OCT 
device outputs such as: patient specific Home OCTID, eye selected, and chronological 
volume scans. 
In the viewer tabs utilizing the OCT analyzer platform, the fluid volume information from 
self-imaging is presented to the physician in trajectories of IRF, SRF, and total retinal fluid 
(TRF) volume over the monitoring period. Also available are visualization of the original B-
scans, B-scans with fluid segmentation and fluid thickness maps. In addition to the broad 
view of the trajectories, the fluid thickness maps guide the physician to review B-scans where 
fluid is present and to visualize morphology in a time efficient manner. This information 
allows the user to identify the fluid status and trends of increase, stability and decrease in 
volume (IRF/SRF) between office visits. 
The physician can choose to set a periodic review of the fluid trajectory as it evolves over 
time. The physician should use a simple interface available on-line to request a notification 
upon SRF/IRF/TRF reaching a certain fluid volume threshold specific to that eye. The 
notification criteria are defined by the physician based on their clinical judgement on when a 
review of the trajectory and related B-scan data to support their decision-making process is 
warranted. 


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10.7 
Appendix 7: Abbreviations 
Abbreviation 
Description 
ADL 
activities of daily living 
AE 
adverse event 
AI 
artificial intelligence 
AMD 
age-related macular degeneration 
ANCOVA 
analysis of covariance 
BCVA 
best-corrected visual acuity 
BMI 
body mass index 
CCDS 
Company Core Data Sheet 
CNV 
choroidal neovascularization 
CI 
confidence interval 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CST 
central subfield retinal thickness 
eCRF 
electronic case report form 
ETDRS 
early treatment diabetic retinopathy study 
EU 
European Union 
FAS 
full analysis set 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IRF 
intraretinal fluid 
IVT 
intravitreal 
IXRS 
Interactive Response System 
LOCF 
last observation carried forward 
LPLV 
last patient last visit 
MDR 
Medical Device Regulation 
MMRM 
mixed-effect model repeated measure 
nAMD 
neovascular (wet) age-related macular degeneration 
OA 
OCT Analyzer 
OCT 
optical coherence tomography 
OCT-A 
optical coherence tomography angiography 
PIGF 
placental growth factor 
PRO 
patient-reported outcome 
PTC 
product technical complaints 
RPE 
retinal pigment epithelium 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD-OCT 
spectral domain optical coherence tomography 
SoA 
schedule of activities 
SRF 
subretinal fluid 
STD 
Standard deviation 
Sub-RPE 
Sub-retinal pigment epithelium 
T&E 
treat and extend 
TEAE 
treatment-emergent adverse events 
TRF 
total retinal fluid 


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Abbreviation 
Description 
US 
United States 
VEGF 
vascular endothelial growth factor 
WOCBP 
woman (women) of childbearing potential 


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11. 
References 
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic 
macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early 
Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985;103:1796-
806. 
Eylea Company Core Data Sheet. https://medsafe.govt.nz/profs/Datasheet/e/eyleainj.pdf. 
Accessed 24 Dec 2021. 
Eylea Summary of Product Characteristics. 
https://www.ema.europa.eu/en/documents/product-information/eylea-epar-product-
information_en.pdf. Accessed 30 Nov 2021. 
Investigator's Brochure of BAY 86-5321. Edition No. 15, dated 31 Jan 2020. 
Ladas ID, Rouvas AA, Moschos MM., Synodinos EE, Karagiannis DA, and Koutsandrea CN. 
Polypoidal choroidal vasculopathy and exudative age-related macular degeneration in Greek 
population. Eye (Lond). 2004;18(5):455-9. 
Lafaut BA, Leys AM, Snyers B, Rasquin F, and De Laey JJ. Polypoidal choroidal 
vasculopathy in Caucasians. Graefes Arch Clin Exp Ophthalmol. 2000;238(9):752-9. 
Maruko I, Iida T, Saito M, Nagayama D, and Saito K. Clinical characteristics of exudative 
age-related macular degeneration in Japanese patients. Am J Ophthalmol. 2007;144(1):15-22. 
Mitchell P, Holz FG, Hykin P, Midena E, Souied E, Allmeier H, et al. Efficacy and safety of 
intravitreal aflibercept using a treat-and extend regimen for neovascular age-related macular 
degeneration: The ARIES Study: A Randomized Clinical Trial. Retina. 2021;41(9):1911-20. 
Rahmani B, Tielsch JM, Katz J, Gottsch J, Quigley H, Javitt J, et al. The cause-specific 
prevalence of visual impairment in an urban population. The Baltimore Eye Survey. 
Ophthalmology. 1996;103(11):1721-6. 
Scassellati-Sforzolini B, Mariotti C, Bryan R, Yannuzzi, LA, Giuliani M, and Giovannini A. 
Polypoidal choroidal vasculopathy in Italy. Retina. 2001;21(2):121-5. 
 

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A Parallel-group Phase 4, Open-label, Two-arm Study to Assess the 
Safety and Efficacy of Intravitreal (IVT) Aflibercept with Proactive 
Customized Treatment Intervals in Patients ≥50 Years of Age with 
No Fluid Due to Choroidal Neovascularization (CNV) Lesions 
Secondary to Neovascular (wet) Age-related Macular Degeneration 
(nAMD) Following Treatment Initiation with Aflibercept 
NCT Number: 
NCT05473715 
Document Date: 
10 MAR 2023 
 


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Title page 
Protocol Title: 
A Parallel-group Phase 4, Open-label, Two-arm Study to Assess the Safety and Efficacy of 
Intravitreal (IVT) Aflibercept with Proactive Customized Treatment Intervals in Patients ≥50 
Years of Age with No Fluid Due to Choroidal Neovascularization (CNV) Lesions Secondary 
to Neovascular (wet) Age-related Macular Degeneration (nAMD) Following Treatment 
Initiation with Aflibercept 
Protocol Number: 
 
 
 
21912 
Compound Number: 
 
 
BAY 86-5321/IVT aflibercept/Eylea® 
Short Title: 
An Interventional Study to Investigate the Safety and Efficacy of IVT Aflibercept with 
Proactive Customized Treatment Intervals in Patients ≥50 Years of Age with No Fluid Due to 
CNV Lesions Secondary to nAMD Following Treatment Initiation with Aflibercept 
Acronym: 
 
 
 
 
XPAND 
Sponsor Name: 
 
 
 
Bayer AG 
Legal Registered Address: 
Bayer AG, 51368 Leverkusen, Germany 
Regulatory Agency Identifier Number(s): 
European Clinical Trials Database (EudraCT): 2022-000690-73 
 
Date:  
 
 
 
 
10 MAR 2023 
Version: 
 
 
 
 
1.0 
Statistical Analysis Plan template version: 4.0 
 
 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.  
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures. 
The approval of the Statistical Analysis Plan is documented in a separate signature document. 
 
 


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Table of Contents 
 
Title page ............................................................................................................................... 1 
Table of Contents ................................................................................................................. 2 
Table of Tables ..................................................................................................................... 3 
Version History ..................................................................................................................... 4 
List of Abbreviations ............................................................................................................ 5 
1. 
Introduction ................................................................................................................... 7 
1.1 
Objectives, Endpoints and Estimands .......................................................................... 8 
1.2 
Study Design ................................................................................................................ 9 
2. 
Statistical Hypothesis .................................................................................................. 13 
2.1 
Multiplicity Adjustment ............................................................................................. 13 
3. 
Analysis Sets ................................................................................................................ 14 
4. 
Statistical Analyses ...................................................................................................... 15 
4.1 
General Considerations .............................................................................................. 15 
4.1.1 
General Principles................................................................................................... 15 
4.1.2 
Descriptive Statistics .............................................................................................. 15 
4.1.3 
Baseline Definition ................................................................................................. 16 
4.1.4 
Stratification Factors .............................................................................................. 16 
4.1.5 
Handling of Dropouts ............................................................................................. 17 
4.1.6 
Missing Data Handling ........................................................................................... 17 
4.1.7 
Unscheduled Assessments ...................................................................................... 18 
4.1.8 
Early Discontinuation Visit and Visit Windowing ................................................. 19 
4.1.9 
Statistical Software ................................................................................................. 20 
4.1.10 Imaging data assessed by the reading center .......................................................... 20 
4.1.11 Definition of Fellow Eye Treatment ....................................................................... 20 
4.1.12 Definition of Prohibited Medications ..................................................................... 21 
4.1.13 Pooling of Data ....................................................................................................... 21 
4.1.14 Data Review ........................................................................................................... 21 
4.1.15 Coronavirus Disease 2019 Related Outputs/Procedures ........................................ 22 
4.2 
Primary Endpoint/Estimand Analysis ........................................................................ 23 
4.2.1 
Definition of Endpoint ............................................................................................ 23 
4.2.2 
Main Analytical Approach ..................................................................................... 24 
4.2.3 
Sensitivity Analyses ............................................................................................... 25 
4.3 
Secondary Endpoints/Estimands Analysis ................................................................. 26 
4.3.1 
Key Secondary Endpoint/Estimand ........................................................................ 26 
4.3.2 
Supportive Secondary Endpoints ........................................................................... 28 
4.4 
Exploratory Endpoints Analysis ................................................................................ 31 
4.5 
Safety Analyses .......................................................................................................... 32 
4.5.1 
Extent of Exposure ................................................................................................. 32 
4.5.2 
Adverse Events ....................................................................................................... 33 
4.5.3 
Additional Safety Assessments .............................................................................. 35 
4.6 
Other Analyses ........................................................................................................... 36 
4.6.1 
Subgroup Analyses ................................................................................................. 36 


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4.7 
Interim Analyses ........................................................................................................ 37 
4.8 
Changes to Protocol-planned Analyses ..................................................................... 38 
5. 
Sample Size Determination ........................................................................................ 39 
6. 
Supporting Documentation ........................................................................................ 40 
6.1 
Population characteristic ............................................................................................ 40 
6.1.1 
Participant disposition ............................................................................................ 40 
6.1.2 
Demography and disease characteristics ................................................................ 40 
6.1.3 
Medical history ....................................................................................................... 41 
6.1.4 
Prior and concomitant medication .......................................................................... 41 
6.2 
Data Cut-Off Specifications ....................................................................................... 42 
6.2.1 
Definitions .............................................................................................................. 42 
6.2.2 
Data cut-off rules .................................................................................................... 43 
7. 
References .................................................................................................................... 47 
8. 
Appendix ...................................................................................................................... 48 
8.1 
Handling of Questionnaires ....................................................................................... 48 
8.1.1 
Patient Home OCT User Experience Questionnaire .............................................. 48 
8.2 
Strategies for Occurrence of Intercurrent Events....................................................... 50 
8.3 
Participating Regions and Countries .......................................................................... 52 
 
Table of Tables 
Table 1-1: Objectives and Endpoints/Estimands ....................................................................... 8 
Table 4-1: Re-mapping Rule for Early Discontinuation Visit and All Other Visits ................ 20 
Table 6-1 Comments for trial design domains ......................................................................... 44 
Table 6-2 Comments for datasets without dates ...................................................................... 45 
Table 6-3 Comments for single date variables and single start dates ...................................... 45 
Table 6-4 Comments for single end dates and variables with corresponding start and end date
 ............................................................................................................................... 46 
Table 8-1 Notal Vision Patient Home OCT User Experience Questionnaire .......................... 49 
Table 8-2: Strategies for Occurrence of ICEs for Primary Endpoint (i.e., Mean Change in 
BCVA from Baseline to Week 36) ........................................................................ 50 
Table 8-3: Strategies for Occurrence of ICEs for Key Secondary Endpoint (i.e., Number of 
Injections up to Week 52) ..................................................................................... 51 
Table 8-4: Participating Regions and Countries ...................................................................... 52 
 
 
 


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Version History 
This Statistical Analysis Plan (SAP) for Study BAY 86-5321/21912 is based on the protocol 
Version 1.0 dated 25MAY2022.  
 
SAP 
Version Date 
Change 
Rationale 
1.0 
10MAR2023 Not applicable 
Original version 
 
 
 
 
 
 


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List of Abbreviations 
 
AE 
Adverse Event 
AMD 
Age-Related Macular Degeneration 
ANCOVA 
Analysis of Covariance 
anti-VEGF 
Anti-Vascular Endothelial Growth Factor 
ATC 
Anatomical Therapeutic Chemical  
AUC 
Area Under the Curve 
BCVA 
Best-Corrected Visual Acuity 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CNV 
Choroidal Neovascularization 
COVID-19 
Coronavirus Disease 2019 
CSR 
Clinical Study Report 
CST 
Central subfield retinal thickness 
DB 
Database 
eCRF 
Electronic Case Report Form 
ED 
Early Discontinuation 
EOS 
End of Study 
ES 
Enrolled Set 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
ICE 
Intercurrent Event 
IOP 
Intraocular Pressure 
IRF 
Intraretinal Fluid 
ISO 
International Organization for Standardization 
IVT 
Intravitreal 
IXRS 
Interactive Response System 
LOCF 
Last Observation Carried Forward 
LPLV 
Last Patient Last Visit 
LSmean 
Least-square mean 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measurements 
MSSO 
Maintenance and Support Service Organization 
nAMD 
Neovascular (wet) Age-Related Macular Degeneration 
OCT 
Optical Coherence Tomography 
OCT-A 
Optical Coherence Tomography Angiography 
PCV 
Polypoidal Choroidal Vascularization 
PD 
Protocol Deviation 
PPS 
Per Protocol Set 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 


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SD-OCT 
Spectral Domain Optical Coherence Tomography 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
SRF 
Subretinal Fluid 
sub-RPE 
Subretinal Pigment Epithelium 
T&E 
Treat and Extend 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TFLs 
Tables, Figures and Listings 
VA 
Visual Acuity 
WHO 
World Health Organization 
 
 


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1. 
Introduction 
Age-related macular degeneration (AMD) is a leading cause of adult blindness in the 
developed world. There are 2 forms of AMD, the dry and the wet (neovascular) form. 
Neovascular AMD (nAMD) is a major health issue in aging populations globally. Vision loss 
in nAMD results from the abnormal growth and leakage of blood vessels in the macula. 
Intravitreal (IVT)-administered anti-vascular endothelial growth factor (anti-VEGF) therapies 
like aflibercept inhibit neovascular vessel growth and leakage in the retina, and they are 
currently the standard of care for patients with nAMD. Although the globally approved IVT 
anti-VEGF therapies are efficacious and well tolerated, the need for IVT aflibercept injections 
every 4 to 8 weeks, specifically in the initial phase and during maintenance of treatment, 
represents a significant burden to physicians, patients and caregivers. While the IVT 
procedure is straightforward and relatively easy to perform, capacity issues for ensuring an 
appropriate injection frequency in order to achieve patient outcomes similar to those seen in 
the pivotal studies represent an increasing challenge to individual practices and the healthcare 
system overall. 
The use of anti-VEGF agents in an individualized, proactive treat and extend (T&E) for 
nAMD has become the standard of care. Utilization of proactive IVT aflibercept T&E 
regimens allows for a pragmatic approach to treatment and offers benefits to physicians and 
patients. With proactive, individualized T&E dosing regimens, the need for interim 
monitoring is minimized, as is the risk of disease recurrence. Reducing the number of 
appointments per patient and minimizing the need for monitoring visits could ease clinic flow 
and patient burden. Furthermore, planning the next injection helps minimize the possibility of 
treatment delays and facilitates clinic management. 
This study will investigate the safety and efficacy of IVT aflibercept with proactive 
customized treatment intervals in patients ≥50 years of age with no fluid due to choroidal 
neovascularization (CNV) lesions secondary to nAMD following treatment initiation with 
aflibercept. 
This statistical analysis plan (SAP) describes all details of the required statistical analyses to 
be conducted at Weeks 36 and 52 (end of study [EOS]). The summary tables, figures and 
listings (TFLs) to be included in the Clinical Study Report (CSR) will be defined in a separate 
document. This SAP is based on the integrated clinical study protocol version 1.0 (dated 
25 MAY 2022). All references to study protocol hereafter refer to this version of the protocol. 
Changes to the protocol-planned analyses are described in Section 4.8. 


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1.1 
Objectives, Endpoints and Estimands 
Table 1-1: Objectives and Endpoints/Estimands 
Objectives 
Endpoints/Estimands 
Primary 
 
To assess whether 2 mg intravitreal 
(IVT) aflibercept administered at a 
customized treatment interval 
(determined after the first extended 
treatment interval) is non-inferior to 2 mg 
IVT aflibercept administered according to 
a standard treat and extend (T&E) 
regimen (initiated after the first extended 
treatment interval) in patients with no 
fluid following treatment initiation for 
neovascular (wet) age-related macular 
degeneration (nAMD) 
Primary Efficacy Endpoint 
• 
Change in best-corrected visual acuity (BCVA) 
(early treatment diabetic retinopathy study 
[ETDRS] letters) from baseline to Week 36 
Secondary - Efficacy 
 
To assess treatment burden of 2 mg IVT 
aflibercept administered at a customized 
treatment interval compared with 2 mg 
IVT aflibercept administered according to 
a standard T&E regimen (initiated after 
the first extended treatment interval) in 
patients with no fluid following treatment 
initiation for nAMD 
Key Secondary Efficacy Endpoint 
• 
Number of IVT aflibercept injections per 
patient up to Week 52 (descriptively) 
 
Additional Secondary Efficacy Endpoints 
• 
Number of IVT aflibercept injections per 
patient until Week 36 
• 
Number of patients achieving pre-defined 
treatment intervals (≥4, ≥8, ≥10, ≥12¸ ≥14, and 
16 weeks) at Weeks 36 and 52 
• 
Change in BCVA (ETDRS letters) from 
baseline to Week 52 
Secondary - Safety 
 
To evaluate the safety of aflibercept with 
proactive treatment intervals 
Secondary Safety Endpoint 
• 
Treatment-emergent adverse events (TEAEs) 
and treatment-emergent serious AEs 
(TESAEs) through Weeks 36 and 52 
Other Pre-Specified Exploratory 
 
To assess morphologic outcomes of 
2 mg IVT aflibercept administered at a 
customized treatment interval compared 
with 2 mg IVT aflibercept administered 
according to a standard T&E regimen 
(initiated after the first extended 
treatment interval) in patients with no 
fluid following treatment initiation for 
nAMD 
Other Pre-specified Exploratory Endpoints 
• 
Change in central subfield retinal thickness 
(CST) [μm] from baseline to Weeks 36 and 52 
• 
Change in CST compared to treatment 
initiation (16 weeks before baseline) at 
Weeks 36 and 52  
• 
Number of patients without any fluid at 
treatment initiation (16 weeks before baseline), 
baseline, Weeks 36, and 52 
o 
without intraretinal fluid (IRF) 
o 
without subretinal fluid (SRF) 
o 
without sub-retinal pigment epithelium 
(sub-RPE) fluid 
Customized treatment interval arm only: 
• 
Change in retinal fluid volume and in volume 
by compartment (IRF and SRF) 
• 
Area under the curve (AUC) of fluid volumes 
• 
Agreement of home monitoring findings with 
spectral domain optical coherence tomography 
(SD-OCT) in-office monitoring performed at 
the same day 


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Table 1-1: Objectives and Endpoints/Estimands 
Objectives 
Endpoints/Estimands 
Assess the change in choroidal 
neovascularization (CNV) size in both 
study arms with optical coherence 
tomography angiography (OCT-A) at 
study visits (optional for center) 
• 
Assess change in CNV size using OCT-A 
(optional for center) in both study arms at 
study visits 
To monitor the conversion rate from dry 
to wet form of AMD in fellow eye with 
OCT-A at study visits (optional for 
center) 
• 
Number of patients with newly developed CNV 
in fellow eye in OCT-A at Weeks 36 and 52 in 
eyes with dry AMD signs at baseline for 
patients in both arms 
To assess handling satisfaction with 
patient Home OCT user experience 
questionnaire 
• 
Number of patients for agreement levels 1 to 5 
assessed at Week 36 
(Home OCT-customized treatment interval arm 
only) 
1.2 
Study Design 
This is a multicenter, active-controlled, open-label, parallel-group treatment, 1:1 randomized 
Phase 4 study of male and/or female patients ≥50 years of age after treatment initiation with 
IVT aflibercept for active CNV lesions secondary to nAMD. The control arm is the widely 
adopted and approved T&E regimen. 
In total, approximately 108 patients in Europe and Canada will be randomized. The study 
treatment phase will be 52 weeks plus the maximal length of the screening phase (up to 
4 weeks) and the 30 days (phone) follow-up phase after the last injection which may be after 
the last patient last visit (LPLV). 
Patients must give written informed consent before any data documentation and any study 
procedure. The study comprises a screening phase of up to 4 weeks (Visit 1; Week -4 until 
Day -1), a baseline visit (Visit 2; Week 0/Day 1), and a treatment phase (which starts at 
baseline) of 52 weeks. 
Only patients with treatment naïve eyes which have received the 3 initial injections according 
to the label qualify for a screening visit of the study (between Weeks 12 and 16 when 
counting from the treatment start of nAMD). 
The 3 initial injections will be administered as routine treatment outside of the study. 
In the unlikely event that 2 eyes of a patient started treatment at the same time the eye with 
worse best-corrected visual acuity (BCVA) will be designated as the study eye. If a patient 
has similar BCVA in both eyes, the eye with the clearest media will be selected as the study 
eye. If the ocular media of both eyes are similar in clarity, the patient’s non-dominant eye (if 
identifiable) will be selected as the study eye. Starting at baseline (Week 0/Day 1), aflibercept 
2 mg IVT treatment will be administered to the study eye as detailed below in intervals 
maximum of 16 weeks and minimum of 4 weeks. 
Patients will be stratified based on BCVA gains in the study eye from treatment initiation to 
study start (captured during screening - <8 or ≥8 letters gain in BCVA) and randomized 1:1 
into one of the following parallel arms: 
• Customized treatment interval arm 
In this treatment arm treatment interval will be extended in a single step from an 
extended treatment interval of 8 weeks to a 16 week interval (test arm, rapid treatment 


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individualization). After the initial study injection at baseline, patients will receive 
their next study injection at Week 16. 
Patients in this study arm will also be issued a digital drug development tool, which 
allows an additional layer of assessments in an ongoing way (at least 5 times a week) 
at home. If no abnormal assessments between preplanned visits are seen, the patient 
will be evaluated at these study visits and the new treatment interval be determined. 
If abnormal assessments during the treatment interval are reported by the digital drug 
development tool, the patient will be asked by the Investigator to return to the study 
site within 3 days at the latest to confirm the findings by spectral domain optical 
coherence tomography (SD-OCT). If fluid is verified and the treatment algorithm 
requires a change of treatment interval, the patient will be treated immediately, and the 
next treatment interval will be equal to the time between the last study injection and 
the SD-OCT-confirmed emergence of new fluid minus 7 days, unless fluid is verified 
30 days after treatment (minimum treatment interval is once per month). After 
reduction of the treatment interval the following intervals will be extended in 4 weeks 
increments up to a maximum of 16 weeks, if all extension criteria are met. If the 
findings are not confirmed by SD-OCT or no change is required as per treatment 
algorithm, the patient will go on with the current treatment interval. 
• T&E, 2 week-adjustment arm 
In this treatment arm, starting at baseline, patients will receive treatment in intervals 
maintained (8 weeks) or adjusted in 2 weeks increments each time (up to a maximum 
of 16 weeks and minimum of 4 weeks), depending on extension/shortening criteria. 
After randomization, the treatment intervals will not be less than 4 weeks nor more than 
16 weeks for both arms. 
During the treatment phase, the next IVT aflibercept injection will be determined by 
Investigators at each treatment visit according to the following criteria: 
• Shortening of subsequent treatment interval from the last interval 
When any of the following criteria are met for the study eye, subsequent treatment 
interval will be shortened by 1 week in the customized treatment arm and by 2 weeks 
in the standard T&E, 2-week adjustment arm. 
o Presence of intraretinal fluid 
Or 
o Subretinal fluid increasing to exceed 50 μm 
Or any of the following: 
o Loss of ≥5 early treatment diabetic retinopathy study (ETDRS) letters due to 
disease activity 
o New neovascularization 
o New macular hemorrhage 
Minimum interval must not be less than 4 weeks during entire period of the study. 
• Maintenance of last treatment interval 
o No intraretinal fluid 


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And 
o Subretinal fluid 
Increasing but not exceeding 50 μm in thickness 
o No loss of ≥5 ETDRS letters 
o No new neovascularization 
o No new hemorrhage 
• Extension of subsequent treatment interval from the last interval 
o No intraretinal fluid 
And 
o Subretinal fluid 
Unchanged or decreased compared to previous visit 
o No loss of ≥5 ETDRS letters 
o No new neovascularization 
o No new hemorrhage 
If all of the above criteria are met for the study eye, subsequent treatment interval 
will be extended by 2 weeks in the standard T&E, 2-week adjustment arm and by 
4 weeks in the customized treatment interval arm until a maximum treatment 
interval of 16 weeks is reached (e.g., if prior T&E interval was 13 weeks then 
there will only be an extension of 3 weeks to reach the maximum of 16 weeks). 
The study patients will have study visits in accordance with the treatment interval determined 
by the application of the treatment algorithm (as described above). 
In addition, there are 2 mandatory study visits at Weeks 36 and 52 which may or may not 
coincide with a treatment visit but which have to be attended by every patient as examinations 
are performed from which the primary and secondary outcomes are determined. 
After day of final visit (Week 52 ± 7 days or early termination), administration of study drug 
is not allowed. Any subsequent treatment of the underlying disease of a patient is not part of 
the study and is at the discretion of the patient’s physician. Such treatment should only occur 
after all study relevant assessments have been performed. 
The treating Investigator must follow-up by phone on any adverse events (AEs) that are 
ongoing or may occur within 30 days of the last administration of study drug. Information 
regarding such events is to be reported under the study protocol (i.e., not as spontaneous 
reports). 
All ocular assessments are to be conducted in both eyes, unless indicated otherwise. 
Assessments of ocular efficacy and safety will include BCVA, SD-OCT, optical coherence 
tomography angiography (OCT-A), patient Home OCT user experience questionnaire (only 
applicable for patients in Home OCT arm), intraocular pressure (IOP), indirect 
ophthalmoscopy, slit lamp biomicroscopy, and AEs; these will be assessed at all study visits 
(“study visits” are all mandatory visits and injection visits, and “other visits” are unscheduled 
visits). 


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Patients will be centrally assigned to randomized study intervention using an Interactive 
Response System (IXRS). The treatment allocation will be done according to a generated 
randomization list specified by the Sponsor or delegate. Before the study is initiated, the 
directions for the IXRS will be provided to each site 
The primary endpoint/estimand will be analyzed and the summaries up to Week 36 will be 
provided when all patients have completed Week 36 (or withdrew). The analysis will only use 
data collected up to Week 36 or premature discontinuation, whichever occurs first. All the 
secondary and exploratory endpoints/estimands will be analyzed and the summaries up to 
Week 52 will be provided when all patients have completed the study (i.e., completed 
Week 52 or prematurely withdrew, whichever occurs first). The analysis will use all data 
collected. This SAP covers all the planned analyses. 
The databases (DBs) and analyses at Week 36 will only include study intervention 
information up to the visit prior to Week 36. For this visit (Week 36) only data assessed prior 
to the study intervention will be part of the DB/analyses. Further details are provided in 
Section 6.2. 
 
 


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2. 
Statistical Hypothesis 
The test problem in relation to the primary objective and/or estimand will be conducted at a 
one-sided significance level of 2.5% after all patients completed Week 36 (or discontinued 
prematurely) using the following method: 
Null hypothesis H0: μ1≤ μ2 - D vs. alternative hypothesis H1: μ1 >μ2 - D, where 
• D = non-inferiority margin. 
• μi = absolute mean change in BCVA as measured by the ETDRS letter score for the 
study eye from baseline to Week 36 in treatment arm i. 
• i = 1: customized treatment interval arm; 2: standard T&E 2-week adjustment arm. 
Note that a higher ETDRS letter score represents better vision. The aim is to show that the 
customized treatment interval arm is no less effective than the standard T&E 2-week 
adjustment arm, using a non-inferiority margin of 5 letters for the difference of the means of 
change from baseline in BCVA as measured by the ETDRS letter score for the study eye at 
Week 36. 
The non-inferiority margin D is set to 5 letters and the rationale is that previous studies with 
anti-VEGF therapies in other indications regarded a difference of 5 letters as clinically 
relevant. The threshold of 5 letters has a clinical relevance and a direct meaning for the 
patients in terms of ETDRS chart, given that 5 letters are equal to 1 line in the chart. This 
choice of the non-inferiority margin is consistent with the margin used in the ARIES study. 
Analyses on the key secondary, other secondary, and exploratory objectives/estimands will be 
conducted in an exploratory way and therefore no formal statistical hypothesis testing is 
planned. 
2.1 
Multiplicity Adjustment 
The multiplicity control for the significance level is not relevant for the study, given that: 
• There is only one test problem in relation to the primary objective to compare the 
2 study arms (i.e., customized treatment interval arm vs. standard T&E 2-week 
adjustment arm) 
• The analyses on the key secondary, other secondary and exploratory objectives will be 
conducted in an exploratory way, without any formal statistical hypothesis testing. 
 
 


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3. 
Analysis Sets 
Primary, key secondary, other secondary, and exploratory efficacy variables will be evaluated 
on the Full Analysis Set (FAS). The primary and key secondary efficacy variables will be 
evaluated on the Per Protocol Set (PPS). Safety variables will be analyzed using the Safety 
Analysis Set (SAF). 
Final decisions regarding the assignment of patients to analysis sets will be made during the 
Data Review Meetings prior to Weeks 36 and 52 and the list of important deviations and 
validity findings will be documented in the Data Review Meeting minutes (see 
Section 4.1.14). 
Throughout this section the phrase “as randomized” is equivalent to the analysis being 
performed using the planned treatment arm. 
All enrolled subjects (ES) 
All ES will include all patients who signed the informed consent form. 
All randomized subjects 
This analysis set will include all randomized patients. 
Full analysis set (FAS) 
The FAS will include all randomized patients. The FAS will be analyzed “as randomized”, 
with subjects categorized into the customized treatment interval arm or the T&E 2 week-
adjustment arm. 
Safety analysis set (SAF) 
The SAF will include all patients who receive any study treatment injection, excluding 
treatment initiation prior to screening. The SAF will be analyzed “as randomized”. 
Per protocol set (PPS) 
The PPS will include all participants in the FAS who did not have an important deviation 
from the protocol affecting the primary efficacy variable or a validity finding as listed below. 
More concretely this means, the PPS will include all participants in the FAS that: 
• did not have any violation of relevant inclusion / exclusion criteria  
• had a baseline BCVA value available 
• had at least one post-baseline BCVA value available 
• received any study treatment 
• were randomized and had study drug administered at the baseline visit. 
Other relevant deviations from the protocol affecting efficacy will be considered as 
intercurrent events in the context of the Estimands strategy described in Appendix 8.2. 
The final determination on the exclusion of participants from the PPS will be made during the 
Data Review Meetings held in accordance with ICH E9 prior to database freeze/lock on 
Week 36/52 data. 
The PPS will be analyzed “as randomized”. 
 
 


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4. 
Statistical Analyses 
4.1 
General Considerations 
4.1.1 
General Principles 
The below mentioned general principles will be followed throughout the study: 
• Study day will be calculated as: 
o For event, assessment or visit prior to the first injection date: 
event/assessment/visit date – first injection date 
o For event, assessment or visit on the same day or after the first injection date: 
event/assessment/visit date – first injection date + 1 day. 
• All p-values should have 4 decimal digits; in case of p-values less than 0.0001, they 
will be displayed as <.0001. 
• Summary tables, in general, will be presented by treatment arm as follows: 
Customized treatment 
interval 
N=xx 
Standard 
T&E 
N=xx 
Total 
N=xx 
“Total” column will be optional. 
• All variables shown in summaries will also be included in patient data listings. 
• Patient data listings will be presented and sorted by treatment arm, unique patient 
identifier, and relevant dates, if applicable. 
• Dates will be formatted as <day> <month (first 3 letters in capitals)> <year> (e.g., 
05JUL2008) or according to the International Organization for Standardization (ISO) 
8601 standard (e.g., 2012-02-29). 
• Rounding for all variables will occur only as the last step, immediately prior to 
presentation in listings and tables. No intermediate rounding will be performed on 
derived variables. 
• Every table, listing and figure will be produced with an electronic date stamp to 
document when it was produced. 
4.1.2 
Descriptive Statistics 
Continuous data will be summarized in terms of the number of observations, mean, standard 
deviation (SD), median, lower and upper quartiles, confidence intervals (CIs), minimum, and 
maximum. 
The minimum and maximum will be reported to the same number of decimal places as the 
raw data recorded in the DB. All other statistics (mean, SD, median, quartiles, and CIs) will 
have one additional decimal place more than the raw data recorded in the DB. 
Categorical data will be summarized in terms of the number of patients providing data at the 
relevant time point (n), frequency counts, and percentages. 
Percentages will be presented to one decimal place. 
Percentages will not be presented for zero counts. 
Unless otherwise stated, percentages will be calculated using n (the number of observations 


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with non-missing values) as the denominator. 
If applicable, the category ‘missing’ will be added as needed as a separate category. 
4.1.3 
Baseline Definition 
For efficacy endpoints, the last valid non-missing assessment prior to or on the randomization 
date will be considered the baseline assessment. However, if an evaluable assessment is only 
available after randomization but before the date of first injection, then this assessment will be 
used as baseline. 
For safety endpoints, the last valid-non missing assessment prior to the first injection of study 
treatment in the study eye (Visit 2; Week 0/Day 1) will be considered the baseline assessment. 
For assessments on the day of first injection: 
• Where time is not captured but a nominal pre-injection indicator is available, the 
nominal pre-injection indicator will serve as sufficient evidence that the assessment 
occurred prior to first injection. For example, if the “Time taken” field is not 
completed at Visit 2 (Week 0/Day 1) on the “Intraocular pressure (Pre-Injection)” 
eCRF, then the information from this eCRF can still be considered the baseline 
assessment because the eCRF title indicates it must be completed pre-injection rather 
than the “Intraocular pressure (Post-Injection)” eCRF. 
• Where neither time nor a nominal pre-injection indicator are captured, the assessment 
will be considered to be prior to the first injection if such procedures are required by 
the study protocol to be conducted before the first injection. For example, the “Vital 
Signs” eCRF does not have a time field and the name of the eCRF does not indicate 
when the assessment was performed. The protocol indicates that vital signs should be 
measured pre-injection so the information from the “Vital Signs” eCRF at Visit 2 
(Week 0/Day 1) can be considered the baseline assessment. 
Change from baseline will be calculated as the visit value of interest minus the baseline value. 
4.1.4 
Stratification Factors 
A stratification by visual outcomes at screening is planned, to ensure equal allocation of 
subgroups, thereby making it easier to interpret the results. Visual outcomes will be 
determined at the screening visit, depending on whether the patients reached <8 or ≥8 letters 
gain in BCVA relative to aflibercept initiation prior to study enrollment (i.e., treatment 
initiation at 16 weeks before baseline). 
4.1.4.1 
Handling of Mis-stratifications 
Patients will be randomly assigned in a 1:1 ratio to the two treatment arms by means of a 
stratified randomization based on visual outcomes at screening. The stratification variable 
aims to ensure equal allocation of subgroups, thereby making it easier to interpret the results. 
Visual outcomes will be determined at the screening visit, depending on whether the patients 
reached <8 or ≥8 letters gain in BCVA relative to aflibercept initiation prior to study 
enrollment (i.e., treatment initiation at 16 weeks before baseline). Randomization will be 
managed by means of an IXRS system and stratification will be based on the information 
entered into the IXRS system. 
Possible mis-stratifications (i.e., stratification errors) will not exclude the respective patients 
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In general, whenever referring to the stratification variable for statistical models and subgroup 
analysis, the value entered in the IXRS system will be used instead of the potentially 
different, correct one recorded on the electronic Case Report Form (eCRF). 
4.1.5 
Handling of Dropouts 
Dropouts will be defined as patients who prematurely discontinue from the study and study 
intervention at the same time for any reason. This also includes patients who are lost to 
follow-up. Possible reasons for premature discontinuation from the study can be found in the 
study protocol, Section 7.2. It may be also necessary for a patient to discontinue study 
intervention permanently, while remaining in the study to be evaluated for safety evaluation 
as described in the study protocol, Section 7.1. 
In the case of such premature discontinuation of the study intervention, all assessments, as 
described in the study protocol for the EOS/early discontinuation (ED) visit, should be 
completed (ED assessments). Early discontinuation visit will be re-mapped to an injection 
visit window/week or relevant regular visit window, as described in Section 4.1.8. 
Data assessed after the time period as described in Appendix 8.2, but prior to study 
completion or discontinuation will not be used in the efficacy analyses. 
Handling of missing data due to dropouts is described in Section 4.2 for efficacy variables. 
No action for missing data due to dropouts is taken for other variables. Patients who dropped 
out will not be excluded from any summaries, except where clearly stated. 
4.1.6 
Missing Data Handling 
All missing or partial data will be presented in the patient data listings as they are recorded on 
the eCRF. 
4.1.6.1 
Additional Descriptive Analyses in the Presence of Missing Data 
The number of patients who prematurely discontinued from the study and/or study 
intervention for any reason, as well as the reasons for premature discontinuation from the 
study and/or study intervention, will be reported. Kaplan-Meier plots for “Time to end of 
study” and “Time to end of study intervention” will be provided. 
4.1.6.2 
General Rules 
Where appropriate, the following rules will be implemented so as not to exclude patients from 
statistical analyses due to missing or incomplete data: 
• Efficacy variables 
Statistical methods for missing data in efficacy variables are described in Section 4.2. 
• Safety variables 
Missing data in safety variables will generally not be imputed. 
However, safety assessment values of the form of “<x” (i.e., below the lower limit of 
quantification) or “>x” (i.e., above the upper limit of quantification) will be imputed 
as “x” in the calculation of summary statistics but displayed as “<x” or “>x” in the 
listings. 
Additionally, AEs that have missing causality will be assumed to be related to study 
drug. 
• Dates for concomitant medications and adverse events 
For AEs and medications the complete start and stop date must be available to 


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determine if the AE or the medication is occurring during the study intervention 
period. 
When only partial dates are available, the following rules will be used. 
Incomplete or missing start date: 
o Missing day: Impute the 1st day of the month, unless the month/year is the 
same month/year of the first injection date. In this case, impute the first 
injection date. 
o Missing day and month: Impute 1st January, unless the year is the same as the 
first injection date. In this case, impute the first injection date. 
o Completely missing: Impute the first injection date, unless the end date 
suggests the missing date could have started prior to the first injection date. In 
this case, impute 1st January of the same year as the end date. 
o Note: When imputing a start date, ensure that the new imputed date is sensible 
(i.e., prior to the end date of the AE or medication). 
Incomplete or missing stop date: 
o Missing day: Impute the last day of the month, unless the month/year is the 
same month/year of the last injection date. In this case, impute the last 
injection date. 
o Missing day and month: Impute 31st December, unless the year is the same as 
the last injection date. In this case, impute the last injection date. 
o Completely missing: 
➢ AE: Since there is no ongoing flag recorded in eCRF, then assume that 
the AE is still ongoing (i.e., do not impute a date). 
➢ Medication: If the ongoing flag is entered, then do not impute an end 
date and assume the medication is ongoing. If the ongoing flag is not 
entered, then impute a date that is after the last injection date (i.e., last 
injection date + 1 day). 
o Note: When imputing a stop date, ensure that the new imputed date is sensible 
(i.e., after the start date of the AE or medication). 
Imputed dates will only be used to determine whether the AE is treatment emergent or 
not and whether the medication is prior/concomitant/post-treatment. 
Imputed dates will not be used for the derivation of the duration of AEs/medications. 
Imputed dates will be used for summary tables only, while listings will contain the 
original (partial) entries. 
4.1.7 
Unscheduled Assessments 
Handling of repeated measurements at the same visit 
If measurements were repeated at the same scheduled visit or the same study injection visit, 
the value actually flagged as scheduled and potentially used in the data summaries and 
analysis, depending on the visit windowing described in Section 4.1.8, will be the: 
• Last non-missing repeated measurement, if visit is before start of treatment 
• First non-missing repeated measurement, if visit is after start of treatment. 
All observations will be presented in the data listings. 


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Handling of measurements at unscheduled visits 
Any measurements taken at unscheduled visits will be shown in patient data listings but will 
not be included in any summary tables, in general. If more than one measurement of a 
variable is taken at an unscheduled visit, all measurements will be shown in listings. 
In case any injection data will be captured as an unscheduled assessment, information from 
that visit will still be included in all analyses after following the visit windowing described in 
Section 4.1.8. 
4.1.8 
Early Discontinuation Visit and Visit Windowing 
If patients prematurely discontinue from the study intervention and/or from the study, they 
will be asked to come for an ED visit. At the ED visit all study procedures, including ocular 
efficacy and safety measurements as well as non-ocular safety measurements, will be 
performed. Visit-based information of the ED visit will be either re-mapped to an injection 
visit window/week or relevant regular visit window, where no other corresponding injection 
or regular study visit was recorded. This data will be reported as observed value for the 
respective visit. 
All other visits will be mapped for analysis as shown in Table 4-1Error! Reference source 
not found.. 
Mapping of Early Discontinuation visit to injection or regular study visits 
Early discontinuation visit will be re-mapped to either an injection visit window/week or a 
relevant regular visit window as shown in Table 4-1, where no other corresponding injection 
or regular study visit was recorded, in order to ensure meaningful presentation of information 
on a visit level, e.g., in summary tables by visit. 
Where more than one visit is mapped to one of the visits presented in Table 4-1, the non-
missing measurement closest to the target day within the window will be used in data 
summaries and analysis. If two measurements are equally distant from the target day, then the 
first occurrence of the two will be selected. 
If the visit windowing shown in Table 4-1 causes issues with any analysis, then wider visit 
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Table 4-1: Re-mapping Rule for Early Discontinuation Visit and All Other Visits 
Study day of Early Discontinuation 
visit or any other visits 
Corresponding timing of 
injection or regular visit 
Re-mapped visit 
[1 - 43] 
Week 4 ± 7 days 
Week 4 
57 ± 14 = (43 - 71] 
Week 8 ± 7 days 
Week 8 
85 ± 14 = (71 - 99] 
Week 12 ± 7 days 
Week 12 
113 ± 14 = (99 - 127] 
Week 16 ± 7 days 
Week 16 
141 ± 14 = (127 - 155] 
Week 20 ± 7 days 
Week 20 
169 ± 14 = (155 - 183] 
Week 24 ± 7 days 
Week 24 
197 ± 14 = (183 - 211] 
Week 28 ± 7 days 
Week 28 
225 ± 14 = (211 - 239] 
Week 32 ± 7 days 
Week 32 
253 ± 14 = (239 - 267] 
Week 36 ± 7 days 
Week 36 
281 ± 14 = (267 - 295] 
Week 40 ± 7 days 
Week 40 
309 ± 14 = (295 - 323] 
Week 44 ± 7 days 
Week 44 
337 ± 14 = (323 - 351] 
Week 48 ± 7 days 
Week 48 
365 - 14/+ 7 = (351 - 372]* 
Week 52 ± 7 days 
Week 52 
“[“ and “]” mean lower and upper limits included, while “(“ means lower limit not included. 
Study day = assessment date – first injection date + 1 day. 
* For the Early Discontinuation visit, the re-mapping to Week 52 would be for (351 – 357]. Any visit 
after that would already be classified as the Week 52 visit. 
4.1.9 
Statistical Software 
The statistical evaluation will be performed by using the software package SAS release 9.4 or 
higher (SAS Institute Inc., Cary, NC, USA). 
4.1.10 
Imaging data assessed by the reading center 
In summary tables the following parameters from the reading center will be evaluated and 
classified as follows: 
From SD-OCT assessment:  
• Intraretinal fluid 3 mm 
• Intraretinal fluid 6 mm 
• Subretinal fluid 3 mm 
• Subretinal fluid 6 mm 
• Central subfield retinal thickness (CST) (note: it is recorded in µm) 
From OCT-A assessment: 
• CNV area (note: it is recorded in mm2) 
4.1.11 
Definition of Fellow Eye Treatment 
Fellow eye treatment will be identified from the concomitant medication page by 
• Selecting for any of the following medications and corresponding biosimilars 
(available in the Biosimilars, Medical Histories and Definition of Grouped Adverse 
Event Terms document):  
o Aflibercept (trade name: Eylea) 
o Bevacizumab (trade name: Avastin) 
o Brolucizumab (trade name: Beovu) 


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o Ranibizumab (trade name: Lucentis) 
o Faricimab (trade name: Vabysmo) 
o Conbercept (trade name Lumitin) 
o Pegaptanib sodium (trade name: Macugen) 
• Selecting for the laterality of the fellow eye. 
Medication that was administered prior to the first injection of study treatment will be 
considered prior fellow eye treatment, whereas medication that was administered at the first 
injection of study treatment or later will be considered concomitant fellow eye treatment (i.e. 
bilateral treatment). 
4.1.12 
Definition of Prohibited Medications 
Prohibited medications as identified from the prior and concomitant medication page are 
• Any of the following anti-VEGF medications and corresponding biosimilars (available 
in the Biosimilars, Medical Histories and Definition of Grouped Adverse Event Terms 
document) administered in the study eye:  
o Aflibercept (trade name: Eylea), unless administered as study intervention 
o Bevacizumab (trade name: Avastin) 
o Brolucizumab (trade name: Beovu) 
o Ranibizumab (trade name: Lucentis) 
o Faricimab (trade name: Vabysmo) 
o Conbercept (trade name Lumitin) 
o Pegaptanib sodium (trade name: Macugen) 
• Medications and corresponding biosimilars (available in the Biosimilars, Medical 
Histories and Definition of Grouped Adverse Event Terms document) administered 
systemically with the intent of treating AMD in the study or fellow eye: 
o Verteporfin (trade name Visudyne) 
Any medication considered necessary for the participant’s welfare, and that is not expected to 
interfere with the evaluation of the study intervention, may be given at the discretion of the 
investigator. 
4.1.13 
Pooling of Data 
All sites will be combined together for the purposes of the analysis. 
4.1.14 
Data Review 
Upon each DB release (Weeks 36 and 52), listings of protocol deviations (PDs) and validity 
findings, as well as the analysis datasets will be produced after release of the final pre-
freeze/pre-lock clinical eCRF DB and discussed in Data Review Meetings. At this time, a 
review of concomitant medications will take place in order to identify any prohibited 
medications as important protocol deviations. The results of these meetings may comprise 
decisions and details relevant for statistical evaluation. Any changes to the statistical analysis 
prompted by the results of the Data Review Meetings will be documented in an amendment to 
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After the clinical eCRF DB is frozen/locked, the analysis datasets will be created again and 
will be compared with the pre-freeze/pre-lock analysis datasets to verify if there were changes 
to the clinical eCRF DB and/or to the relevant PDs. 
4.1.15 
Coronavirus Disease 2019 Related Outputs/Procedures 
This study started after the onset of the coronavirus disease 2019 (COVID-19) pandemic. A 
listing will be provided that displays all patients affected by the COVID-19 related study 
disruption by unique patient identifier and by investigational site, and a description of how the 
patient’s study participation was altered. Other listings will display all patients with PDs 
associated with the COVID-19 pandemic and with COVID-19 AEs. Furthermore, tables for 
patient validity status and disposition will contain COVID-19 pandemic associated findings 
and reasons. 
Additionally, the following summary tables will be displayed: 
• Study sample sizes by trial unit: Patients affected by COVID-19 pandemic related 
study disruption for all enrolled patients 
• Number of patients by country/region for all patients affected by COVID-19 pandemic 
related study disruption 
• Number of patients affected by COVID-19 pandemic related study disruption. 
Additional analyses may be added due to regulatory requirements or requests. 
 
 


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4.2 
Primary Endpoint/Estimand Analysis 
All analyses described below for the primary efficacy variable will be analyzed on the FAS 
by randomized treatment arm, regardless of any changes to dose interval. As a supplementary 
analysis, the primary endpoint will also be evaluated based on the PPS. 
All efficacy analyses will be based on the injection visits mapped to weeks as specified in 
Table 4-1 from Section 4.1.8. If the visit windowing causes issues with any statistical models, 
then wider visit windows may be considered. 
4.2.1 
Definition of Endpoint 
ETDRS charts present a series of five letters of equal difficulty on each row, with 
standardized spacing between letters and rows; there is a total of 14 lines (70 letters). The 
ETDRS letter score can be calculated when 20 or more letters are read correctly at 4.0 m, the 
visual acuity (VA) letter score is equal to the total number of letters read correctly at 4.0 m 
plus 30. If fewer than 20 letters are read correctly at 4.0 m, the VA letter score is equal to the 
total number of letters read correctly at 4.0 m (the number recorded on line 1.0), plus the total 
number of letters read correctly at 1.0 m in the first six lines. The ETDRS letter score could 
therefore result in a maximum score of 100. BCVA is measured by the ETDRS letter score 
for the study eye. 
The estimand of primary interest will be based on a hypothetical strategy. It describes the 
change in BCVA from baseline for all patients that started treatment assuming all patients 
have stayed on treatment until Week 36. 
The estimand is specified through the following definitions of population, variable, treatment 
condition, intercurrent events (ICEs), and population-level summary: 
Population: 
Defined by the inclusion/exclusion criteria in the study protocol. 
Variable: 
Absolute change from baseline to Week 36 in BCVA as 
measured by the ETDRS letter score for the study eye. 
Treatment condition: 
Aflibercept customized treatment interval arm vs. aflibercept 
standard T&E 2-week adjustment arm. 
Intercurrent events: 
Premature discontinuation from treatment/study. 
Use of a prohibited medication / start of alternative anti-VEGF 
treatment, prior to treatment and/or study discontinuation. 
Shortening/extension of the dosing interval will not be 
considered an ICE, but as part of the randomized treatment 
regimen. 
Details for other potential ICEs and the handling of ICEs in the 
analysis are given in Appendix 8.2. 
Population-level summary:  Difference in mean change from baseline to Week 36 in BCVA 
between the customized treatment interval arm and standard 
T&E 2-week adjustment arm. 
The hypothesis described in Section 2 will be tested in the primary analysis to assess non-
inferiority in the primary efficacy endpoint at a one-sided significance level of 2.5%. 


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4.2.2 
Main Analytical Approach 
For the analysis of the primary efficacy variable, a mixed-effect model repeated measure 
(MMRM) analysis making use of all observed BCVA data in the study eye from baseline up 
to Week 36 (after censoring for ICEs as defined in Appendix 8.2) will be used. Visit windows 
will be applied to the BCVA data as described in Section 4.1.8. The MMRM will include the 
fixed categorical effects of treatment, visit, treatment-by-visit interaction and stratification 
variable (BCVA gains in the study eye from treatment initiation to study start, captured 
during screening [<8 vs. ≥8 letters gain]); the fixed continuous covariate of baseline BCVA 
score in the study eye; and visit as a repeated measure. Restricted maximum likelihood 
estimation will be used. A Kenward-Roger approximation will be used for the denominator 
degrees of freedom. An unstructured covariance structure will be used to model the 
within-patient error, assuming different covariance parameters per group. If the fit of the 
unstructured covariance structure fails to converge, the following covariance structures will 
be tried in order until convergence is reached: 
• Toeplitz with heterogeneity 
• Autoregressive with heterogeneity 
• Toeplitz 
• Autoregressive 
• Compound symmetry. 
The model can be written as: 
𝑌𝑖𝑗= 𝛽0 + 𝑥𝑖𝛽𝑏𝑎𝑠𝑒+ 𝛽𝑠𝑡𝑟𝑎𝑡
(𝑙)
+ 𝛽𝑡𝑟𝑒𝑎𝑡
(𝑘)
+ 𝛽𝑣𝑖𝑠𝑖𝑡
(𝑗)
+ 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝑘,𝑗)
+ 𝑏𝑖+ 𝜖𝑖𝑗 
with 
• 𝑌𝑖𝑗 being the change in BCVA from baseline to visit j for the ith patient 
• 𝛽0 being the intercept 
• 𝑥𝑖 being the baseline BCVA measurement in the study eye of patient i 
• 𝛽𝑏𝑎𝑠𝑒 the fixed effect of the baseline BCVA measurement 
• 𝛽𝑠𝑡𝑟𝑎𝑡
(𝑙)
 the fixed effect of stratification variable (BCVA gains in the study eye from 
treatment initiation to study start, captured during screening [<8 vs. ≥8 letters 
gain]), as recorded on the IXRS system 
• 𝛽𝑡𝑟𝑒𝑎𝑡
(𝑘)  the fixed effect of treatment arm k 
• 𝛽𝑣𝑖𝑠𝑖𝑡
(𝑗)  the fixed effect of visit j 
• 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝑘,𝑗)
 the interaction between treatment arm k and visit j 
• 𝑏𝑖 the random effect of patient i 
• 𝜖𝑖𝑗 the residual error with 𝜖𝑖𝑗~𝑁(0, 𝜎2) and 𝑐𝑜𝑟𝑟(𝜖𝑖𝑗,𝜖𝑖′𝑗′) = 𝜌𝑖𝑗 and 𝜖𝑖𝑗 and 𝑏𝑖 
mutually independent. 
In terms of the model parameters, the estimate of the population-level summary of the 
estimand (i.e., the treatment effect at Week 36) can then be expressed as 
𝑑𝑖𝑓𝑓
̂𝑡𝑟𝑒𝑎𝑡= [𝛽̂𝑡𝑟𝑒𝑎𝑡
(𝐶𝑢𝑠𝑡𝑜𝑚𝑖𝑧𝑒𝑑) + 𝛽̂𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝐶𝑢𝑠𝑡𝑜𝑚𝑖𝑧𝑒𝑑,𝑤36)] − [𝛽̂𝑡𝑟𝑒𝑎𝑡
(𝑇&𝐸 2𝑤𝑒𝑒𝑘) + 𝛽̂𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝑇&𝐸 2𝑤𝑒𝑒𝑘,𝑤36)]. 


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In line with the definition of estimands (see above), the primary analysis will be performed on 
the FAS and patient will be analyzed within their original randomized group (regardless of 
any changes to dose interval). 
The analysis described above will be repeated on the PPS as a supplementary analysis. 
The customized treatment interval arm will be considered to be non-inferior to the standard 
T&E 2-week adjustment arm if this analysis is statistically significant. Statistical significance 
will be achieved if the estimated lower limit of the one-sided 97.5% CI of the treatment 
difference lies entirely above the value of -5 letters, where a positive difference favors the 
customized treatment interval arm. 
Summary tables will include number of patients, least-square mean (LSmean) change, 
(unadjusted) mean change and SD and baseline means of each treatment arm. For non-
inferiority testing, the estimate expressed as LSmean change including the one-sided 97.5% 
CI, the test statistics, the degrees of freedom and corresponding p-value will be presented. 
The two-sided 95% CI will be provided as well. 
The MMRM assumes missing at random (MAR) for patients who discontinue the study 
prematurely, i.e., missingness only depends on observed data. 
Descriptive summary tables will be provided by treatment arm and visit for: 
• All observed cases until the occurrence of an ICE (primary estimand strategy for 
continuous endpoints) in the FAS population 
• All observed cases until the occurrence of an ICE (primary estimand strategy for 
continuous endpoints) in the PPS population 
• All observed cases until the occurrence of an ICE with imputation of missing values 
with Last Observation Carried Forward (LOCF) in the FAS population. 
• All observed cases until the occurrence of an ICE with imputation of missing values 
with LOCF in the PPS population. 
4.2.3 
Sensitivity Analyses 
The following sensitivity analyses will be analyzed for the FAS with patient analyzed within 
their original randomized group (regardless of any changes to dose interval). 
4.2.3.1 
Analysis of Covariance with Last Observation Carried Forward 
The sensitivity analysis of the primary efficacy endpoint using an analysis of covariance 
(ANCOVA) with LOCF follows the same estimand strategy as the primary analysis. 
For this sensitivity analysis of the primary efficacy variable, an ANCOVA will be used, with 
the BCVA measure in the study eye at baseline as a covariate, and the treatment arm and the 
stratification variable (BCVA gains in the study eye from treatment initiation to study start, 
captured during screening [<8 vs. ≥8 letters gain]) as fixed effect factors. Missing data will be 
imputed using LOCF method. Observed values from both scheduled and unscheduled post-
baseline visits will be used for the LOCF imputation. For patients who experience an ICE as 
defined in Appendix 8.2, the efficacy data will be censored at the time of the ICE as defined 
in Appendix 8.2, prior to implementation of the LOCF approach. 
The observation at Week 36 of patient i in treatment arm t can be written as follows: 
𝑌𝑖𝑡𝑏= 𝛽0 + 𝜇𝑡+ 𝜂𝑏+ 𝑥𝑖𝛽𝑏𝑎𝑠𝑒+ 𝜖𝑖𝑡𝑏 


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with 
• 𝑌𝑖𝑡𝑏 being the change from baseline to Week 36 for the ith patient 
• 𝛽0 being the intercept 
• 𝜇𝑡 being the treatment arm effect 
• 𝜂𝑏 being the categorical stratification variable (BCVA gains in the study eye from 
treatment initiation to study start, captured during screening [<8 vs. ≥8 letters 
gain]), as recorded on the IXRS system 
• 𝑥𝑖 being the baseline BCVA in the study eye of patient i 
• 𝛽𝑏𝑎𝑠𝑒 the fixed effect of the baseline BCVA measurement 
• 𝜖𝑖𝑡𝑏 the residual error with 𝜖𝑖𝑡𝑏~𝑁(0, 𝜎𝑡
2 ) being the residual error for treatment 
arm t. 
In terms of the model parameters, the estimate of the population-level summary of the 
estimand (i.e., the treatment effect at Week 36) can then be expressed as 
𝑑𝑖𝑓𝑓
̂𝑡𝑟𝑒𝑎𝑡= 𝛽̂𝑡𝑟𝑒𝑎𝑡
(𝐶𝑢𝑠𝑡𝑜𝑚𝑖𝑧𝑒𝑑) − 𝛽̂𝑡𝑟𝑒𝑎𝑡
(𝑇&𝐸 2𝑤𝑒𝑒𝑘). 
Summary tables will include number of patients, LSmean change, (unadjusted) mean change 
and SD and baseline means of each treatment arm and the estimate of the treatment difference 
expressed as LSmean difference including the corresponding two-sided 95% CI. 
The analysis described above will be repeated on the PPS as a supplementary analysis. 
4.2.3.2 
Complete Case (ANCOVA without imputation) 
The same methodology of the first sensitivity analysis (i.e., ANCOVA) will be applied but 
without imputation of missing data and with censoring due to ICEs as defined in Appendix 
8.2. Patients with missing BCVA assessment in the study eye at Week 36 will be excluded 
from the analysis. Analysis will be performed only on patients with available observed BCVA 
assessments in the study eye at both baseline and Week 36. 
The complete case approach assumes missing completely at random for patients with missing 
data i.e., missingness does not depend on any observed or unobserved data. 
For the model specification, please refer to Section 4.2.3.1. 
Summary tables will include number of patients, LSmean change, (unadjusted) mean change 
and SD, baseline means of each treatment arm, and the estimate of the treatment difference 
expressed as LSmean difference including the corresponding two-sided 95% CI. 
4.3 
Secondary Endpoints/Estimands Analysis 
4.3.1 
Key Secondary Endpoint/Estimand 
All analyses described below for the key secondary efficacy variable will be analyzed on the 
FAS by randomized treatment arm, regardless of any changes to dose interval. As a 
supplementary analysis, the key secondary efficacy variable will also be evaluated based on 
the PPS. 
4.3.1.1 
Definition of Endpoint 
The estimand of key secondary endpoint interest will be based on a “while on treatment” 
strategy. 


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It describes the number of injections in the study eye per patient up to study Week 52, for all 
patients that started treatment until the timepoint when they had an ICE as defined in 
Appendix 8.2. 
The estimand is specified through the following definitions of population, variable, treatment 
condition, ICEs, and population-level summary: 
Population: 
Defined by the inclusion/exclusion criteria. 
Variable: 
Number of IVT aflibercept injections in the study eye per patient 
in the time frame from baseline to Week 52. 
Treatment condition: 
Aflibercept customized treatment interval arm vs. aflibercept 
standard T&E 2-week adjustment arm. 
Intercurrent events: 
Premature discontinuation from treatment/study. 
Use of a prohibited medication / start of alternative anti-VEGF 
treatment, prior to treatment and/or study discontinuation. 
Shortening/extension of the dosing interval will not be 
considered an ICE, but as part of the randomized treatment 
regimen. 
Details for other potential ICEs and the handling of ICEs in the 
analysis are given in Appendix 8.2. 
Population-level summary:  Difference in mean number of injections in the study eye per 
patient in the time frame from baseline to Week 52 between the 
customized treatment interval arm and T&E 2-week adjustment 
arm. 
No hypothesis testing will be performed for the key secondary efficacy endpoint. Analyses 
will be performed in a descriptive manner, although 95% CI of the treatment difference will 
be estimated, as a reference. 
4.3.1.2 
Main Analytical Approach 
For the main analysis of the key secondary efficacy variable, an ANCOVA will be used, with 
the treatment arm and the stratification variable (BCVA gains in the study eye from treatment 
initiation to study start, captured during screening [<8 vs. ≥8 letters gain]) as fixed factors. 
No imputation of missing data will be performed, therefore the actual/observed number of 
injections in the study eye per patients from baseline to Week 52, performed prior to the 
occurrence of any ICE, will be analyzed. 
The actual number of injections in the study eye at Week 52 of patient i receiving treatment t 
can be written as follows: 
𝑌𝑖𝑡𝑏= 𝛽0 + 𝜇𝑡+ 𝜂𝑏+ 𝜖𝑖𝑡𝑏 
with 
• 𝑌𝑖𝑡𝑏 being the number of injections received in the study eye at Week 52 for the ith 
patient 
• 𝛽0 being the intercept 
• 𝜇𝑡 being the treatment arm effect 


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• 𝜂𝑏 being the categorical stratification variable (BCVA gains in the study eye from 
treatment initiation to study start, captured during screening [<8 vs. ≥8 letters 
gain]), as recorded on the IXRS system 
• 𝜖𝑖𝑡𝑏 the residual error with 𝜖𝑖𝑡𝑏~𝑁(0, 𝜎𝑡
2 ) being the residual error for treatment 
arm t. 
In terms of the model parameters, the estimate of the population-level summary of the 
estimand (i.e., the treatment effect at Week 52) can then be expressed as 
𝑑𝑖𝑓𝑓
̂𝑡𝑟𝑒𝑎𝑡= 𝛽̂𝑡𝑟𝑒𝑎𝑡
(𝐶𝑢𝑠𝑡𝑜𝑚𝑖𝑧𝑒𝑑) − 𝛽̂𝑡𝑟𝑒𝑎𝑡
(𝑇&𝐸 2𝑤𝑒𝑒𝑘). 
Summary tables will include number of patients, LSmean, (unadjusted) mean and SD of each 
treatment arm, and the estimate of the treatment difference expressed as LSmean difference 
including the corresponding two-sided 95% CI. 
A descriptive summary table, including the mean number of injections up to Week 52 as well 
as the frequencies for the number of injections up to Week 52, will be provided by treatment 
arm. 
The analysis described above will be repeated on the PPS as a supplementary analysis. 
4.3.1.3 
Sensitivity Analysis 
The same methodology of the main analysis for the key secondary efficacy endpoint (i.e., 
ANCOVA) will be applied but considering only data of patients who stay on treatment until 
Week 52. Patients who have an ICE that leads to exclusion of data as described in 
Appendix 8.2 will be excluded from the analysis. 
The complete case approach assumes missing completely at random for patients with missing 
data i.e., missingness does not depend on any observed or unobserved data. 
For the model specification and the corresponding summary tables, please refer to 
Section 4.3.1.2. 
4.3.2 
Supportive Secondary Endpoints 
The other secondary efficacy endpoints are: 
• Mean number of IVT aflibercept injections in the study eye per patient until study 
Week 36. 
• Proportion of patients achieving pre-defined treatment intervals (≥4, ≥8, ≥10, ≥12, 
≥14, and 16 weeks) at Weeks 36 and 52. 
• Mean change in BCVA (ETDRS letters score in the study eye) from baseline to 
Week 52. 
Analyses on the other secondary efficacy endpoints will be conducted on the FAS by 
randomized treatment arm, regardless of any changes to dose interval. As a supplementary 
analysis, the other secondary efficacy endpoints except fro the mean change in BCVA from 
baseline to Week 52, will also be evaluated based on the PPS. No hypothesis testing will be 
performed for the other secondary efficacy endpoints. Analyses will be performed in a 
descriptive manner, adjusting for the stratification factors as described in Sections 4.3.2.1, 
4.3.2.2 and 4.3.2.3. This may include 95% CIs for treatment differences in an exploratory 
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4.3.2.1 
Number of injections in the study eye per patient until Week 36 
The same methodology of the main analysis for the key secondary efficacy endpoint (i.e., 
ANCOVA) will be applied. 
No imputation of missing data will be performed, therefore the actual/observed number of 
injections in the study eye per patient from baseline to Week 36, performed prior to the 
occurrence of any ICE, will be analyzed. 
For the model specification and the corresponding summary tables, please refer to 
Section 4.3.1.2 and Section 4.3.1.3. 
4.3.2.2 
Proportion of patients achieving pre-defined treatment intervals (≥4, 
≥8, ≥10, ≥12, ≥14, and 16 weeks) for the study eye at Weeks 36 and 52 
For the analysis of the proportion of patients achieving pre-defined treatment intervals (≥4, 
≥8, ≥10, ≥12, ≥14, and 16 weeks) for the study eye at Weeks 36 and 52, a logistic regression 
with a binomial probability distribution and the identity link function will be used, with the 
treatment arm and the stratification variable (BCVA gains in the study eye from treatment 
initiation to study start, captured during screening [<8 vs. ≥8 letters gain]) as fixed factors. 
No imputation of missing data will be performed. Only exposure data prior to the occurrence 
of any ICE will be considered for the analysis. 
Achievement of the pre-defined treatment interval at the mandatory visit of Week 36 and at 
Week 52 will be based on the duration between the last 2 injections received prior to or on 
Week 36 and Week 52 respectively. This will be derived as follows: 
• If last administration of study treatment occurs on the same date of (i.e., during) the 
mandatory visit, only if required per treatment schedule, difference in days between 
the date of the administration performed at the mandatory visit and the date of the 
previous administration of study treatment 
• If last administration of study treatment occurs prior to the date of the mandatory visit, 
difference in days between the last administration date and the penultimate 
administration date. 
Achievement of the pre-defined treatment interval at the mandatory visit of Week 36 and at 
Week 52 will be declared: 
• ≥4 weeks flag achieved, if the length of the last injection interval prior to or on the 
mandatory visit is ≥28 - 7 days 
• ≥8 weeks flag achieved, if the length of the last injection interval prior to or on the 
mandatory visit is ≥56 - 7 days 
• ≥10 weeks flag achieved, if the length of the last injection interval prior to or on the 
mandatory visit is ≥70 - 7 days 
• ≥12 weeks flag achieved, if the length of the last injection interval prior to or on the 
mandatory visit is ≥84 - 7 days 
• ≥14 weeks flag achieved, if the length of the last injection interval prior to or on the 
mandatory visit is ≥98 - 7 days 
• ≥16 weeks flag achieved, if the length of the last injection interval prior to or on the 
mandatory visit is ≥112 - 7 days. 


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The time window of 7 days is applied to allow for an early attendance of a mandatory visit. 
According to the study protocol, visit window for mandatory visits is +/-7 days. 
The pre-defined treatment intervals flags will not be mutually exclusive, which means that a 
patient achieving (according to the definition above) a pre-defined treatment interval at a 
given mandatory visit, will be considered also achieving shorter intervals at the same given 
visit. For example, a patient achieving a pre-defined treatment interval of ≥10 weeks at 
Week 36 will be considered achievers for ≥4 weeks, ≥8 weeks and ≥10 weeks intervals at 
Week 36. 
The model below applies for each of the pre-defined treatment interval at both timepoints of 
Weeks 36 and 52. 
In the example, the proportion of patients achieving the pre-specified treatment interval ≥4 
weeks at Week 36 can be written as follows: 
𝑃𝑟(𝑌≥4 𝑤𝑘 𝑎𝑡 𝑤𝑘 36 = 1) =
𝑒𝛽0+𝛽1𝑥1+𝛽2𝑥2
1 + 𝑒𝛽0+𝛽1𝑥1+𝛽2𝑥2 
with 
• 𝑌 being the response variable flag for patients achieving the pre-specified 
treatment interval (≥4 weeks) at Week 36 (i.e., 1 = achieved vs. 0 = not achieved) 
• 𝑃𝑟(𝑌≥4 𝑤𝑘 𝑎𝑡 𝑤𝑘 36 = 1) being the proportion of patients achieving the pre-
specified treatment interval (≥4 weeks) at Week 36 
• 𝛽0 being the intercept 
• 𝛽1,  𝛽2 being the coefficients of the explanatory variables/factors 
• 𝑥1 being the categorical stratification variable (BCVA gains in the study eye from 
treatment initiation to study start, captured during screening [<8 vs. ≥8 letters 
gain]), as recorded on the IXRS system 
• 𝑥2 being the treatment variable. 
In terms of the model parameters, the estimate of the treatment effect can then be expressed as 
𝑑𝑖𝑓𝑓
̂𝑡𝑟𝑒𝑎𝑡= 𝑃𝑟
̂(𝑌≥4 𝑤𝑘 𝑎𝑡 𝑤𝑘 36 = 1)(𝐶𝑢𝑠𝑡𝑜𝑚𝑖𝑧𝑒𝑑) − 𝑃𝑟
̂(𝑌≥4 𝑤𝑘 𝑎𝑡 𝑤𝑘 36 = 1)(𝑇&𝐸 2𝑤𝑒𝑒𝑘) 
The logistic model followed by use of the NLMeans macro allows the LSmean of proportions 
and difference in proportions to be calculated, rather than the default log odds and difference 
in the log odds. 
Summary tables will include number of patients, observed proportion, LSmean estimated 
proportion of patients achieving the pre-defined treatment intervals for each treatment arm 
and the estimate of the treatment difference in proportions expressed as LSmean difference 
including the corresponding two-sided 95% CI. 
The analysis described above will be repeated on the PPS as a supplementary analysis. The 
analysis will also be repeated on the FAS using the complete case approach. 
4.3.2.3 
Change in BCVA in the study eye from baseline to Week 52 
The same methodology of the primary analysis for the primary efficacy endpoint (i.e., 
MMRM) will be applied. 
Details for the management of data with regards to potential ICEs are given in Appendix 8.2. 


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For the model specification and the corresponding summary tables, please refer to 
Section 4.2.2. 
The sensitivity analyses – ANCOVA with LOCF and complete case (ANCOVA without 
imputation) – specified in Section 4.2.3 will be performed and associated summary tables 
presented. 
4.4 
Exploratory Endpoints Analysis 
The exploratory efficacy endpoints are: 
For both treatment arms: 
• Change in BCVA in the study eye from Week -16 to Week 52. 
• Change in CST (μm) from baseline to Weeks 36 and 52 in the study eye. 
• Change in CST compared to treatment initiation (i.e., 16 weeks before baseline) at 
Weeks 36 and 52 in the study eye. 
• Proportion of patients without any fluid/without IRF/SRF at 8 weeks before baseline, 
baseline, Weeks 36 and 52 in the study eye. 
For the customized treatment interval arm only: 
• Change in retinal fluid volume and in volume by compartment (IRF and SRF) in the 
study eye. 
• Area under the curve (AUC) of fluid volumes in the study eye. 
• Agreement of home monitoring findings with SD-OCT in-office monitoring 
performed at the closest time prior to the office visit. 
For both treatment arms: 
• Change in CNV size using OCT-A (optional for center) in the study eye at study 
visits. 
• Number of patients with newly developed CNV in fellow eye in OCT-A at Weeks 36 
and 52 in eyes with dry AMD signs at baseline. 
For the customized treatment interval arm only: 
• Number of patients for agreement levels 1 to 5 assessed at Week 36. 
There is no scoring system/algorithm for the patient home OCT user experience 
questionnaire. Summary statistics will be presented for each of the 15 items of the 
questionnaire. See Section 8.1.1 for full details. 
Analyses on the exploratory efficacy endpoints will be conducted on the FAS by randomized 
treatment arm, regardless of any changes to dose interval. No hypothesis testing will be 
performed for these endpoints. Analyses will be performed in a descriptive manner. 
No imputation of missing data will be performed for the exploratory efficacy endpoints, with 
the exception of the change in BCVA in the study eye from Week -16 to Week 52 where 
summary statistics will include a table where LOCF is used if there is an ICE. For all other 
exploratory efficacy endpoints, available and observed data will be analyzed irrespective of 
the occurrence of ICEs. 
The agreement of home monitoring findings with SD-OCT in-office monitoring will be 
evaluated by calculating the percentage of visits instigated by a home monitoring findings 
alert where a patient received an early injection, from all the clinic visits instigated by a home 
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4.5 
Safety Analyses 
The analysis of safety variables will be conducted descriptively on the SAF population for the 
data up to Week 36 and up to Week 52/end of study, unless otherwise stated. 
4.5.1 
Extent of Exposure 
Exposure to the study intervention will be analyzed for SAF, FAS and PPS. Descriptive 
statistics will be used for analysis. For the analyses at Week 36 only study intervention data 
prior to Week 36 will be used (as described in Section 6.2). 
For each patient, the following variables for the study eye will be used to summarize exposure 
to study intervention (including scheduled and unscheduled study interventions): 
Based on actual injections: 
• Total number of injections 
• Proportion of patients with at least one treatment interval reduction 
• Number of treatment interval reductions per patient 
• Proportion of patients with at least one treatment interval extension 
• Number of treatment interval extensions per patient 
• Proportion of patients achieving a last completed treatment interval of ≥4 weeks at 
Weeks 36 and 52 – secondary endpoint 
• Proportion of patients achieving a last completed treatment interval of ≥8 weeks at 
Weeks 36 and 52 – secondary endpoint 
• Proportion of patients achieving a last completed treatment interval of ≥10 weeks at 
Weeks 36 and 52 – secondary endpoint 
• Proportion of patients achieving a last completed treatment interval of ≥12 weeks at 
Weeks 36 and 52 – secondary endpoint 
• Proportion of patients achieving a last completed treatment interval of ≥14 weeks at 
Weeks 36 and 52 – secondary endpoint 
• Proportion of patients achieving a last completed treatment interval of ≥16 weeks at 
Weeks 36 and 52 – secondary endpoint 
• Duration of study intervention calculated in weeks as: [(date of last study intervention 
[prior to Week 36/up to and including Week 52]) – (date of first study intervention) 
+28]/7; 28 days are added because of the minimum 4-week dosing interval in the 
study 
These exposure variables do not consider if the study intervention is temporarily interrupted. 
Exposure to study intervention will be summarized for the following periods: 
• From Baseline to Week 36 (excluding intervention data at Week 36) – summary to be 
displayed at Week 36 and final analysis 
• From Baseline to end of study (Week 52). 
For each patient who received concomitant fellow eye treatment (as defined in 
Section 4.1.11), the following variables will be shown for SAF only: 
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• Participants with concomitant fellow eye treatment and corresponding biosimilars 
(available in the Biosimilars, Medical Histories and Definition of Grouped Adverse 
Event Terms document) 
o Aflibercept (trade name: Eylea) 
o Bevacizumab (trade name: Avastin) 
o Brolucizumab (trade name: Beovu) 
o Ranibizumab (trade name: Lucentis) 
o Faricimab (trade name: Vabysmo) 
o Conbercept (trade name: Lumitin) 
o Pegaptanib sodium (trade name: Macugen) 
• Duration of fellow eye treatment in weeks calculated as: [(date of last treatment of 
fellow eye) – (date of first treatment of fellow eye) +28]/7 
Summaries for fellow eye treatment will be displayed for all patients with any fellow eye 
injection during the study. 
Listings will show the patients’ exposure duration and the number of injections. 
A treatment interval pattern figure, showing the next treatment interval at each injection visit, 
will be created for the FAS at Week 36 and Week 52. 
4.5.2 
Adverse Events 
An AE is any untoward medical occurrence in a clinical study patient, associated with the use 
of study intervention, whether or not considered related to the study intervention. All reported 
AEs will be coded using the currently available version of the MedDRA at time of analysis. 
Coding will be to lowest level terms according to Bayer global standards. 
Adverse events will be collected from the time of informed consent signature and at each visit 
until the end of the study. If the patient withdraws from the study during the screening, AEs 
will be collected up until the patient withdraws. If the patient is withdrawn after receiving the 
first injection of study medication, AEs will be collected up until 30 days after the last dose of 
study intervention or the termination visit, whichever is later. 
Adverse events will be summarized as: 
• Pre-treatment AE: Pre-treatment AEs are defined as AEs that start after the patient 
has signed the informed consent, but prior to the first injection at baseline (i.e., date of 
informed consent ≤ AE onset date < date of the patient’s first injection of study 
intervention). 
• Treatment-emergent adverse event (TEAE): TEAEs are defined as AEs that started 
in the time frame from first injection to the last injection in the study plus 30 days (i.e., 
date of the patient’s first injection ≤ AE onset date ≤ date of the patient’s last injection 
of study intervention + 30 days). For the patients who have not discontinued study 
treatment prematurely (i.e., are “ongoing”) at the Week 36 analysis, all AEs that 
started at first injection or later will be considered treatment-emergent, even if they 
started more than 30 days after the latest injection. 
• Post-treatment AE: Post-treatment AEs are defined as AEs that started more than 
30 days after the last injection in the study (i.e., AE onset date > date of the patient’s 
last dose of study intervention + 30 days). For the patients who have not discontinued 
study treatment prematurely (i.e., are “ongoing”) at the Week 36 analysis, no AEs will 


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be considered post-treatment, even if they started more than 30 days after the latest 
injection. 
The data cut-off rules for Week 36 AE reporting are described in Section 6.2. 
The proportions of patients with AEs will be used as safety variables for AE summary. 
Other variables for AE description and analysis will include AE Verbatim Term, AE start 
date/time and end date/time/ongoing and corresponding study day, AE duration, relationship 
of AE to study drug, relationship of AE to fellow eye treatment (as defined in Section 4.1.11), 
relationship of AE to intravitreal injection, relationship of AE to protocol required procedure, 
seriousness, intensity, action due to AE, treatment of AE, and outcome. 
Summaries that include frequencies and proportions of patients reporting AEs will include the 
PTs and the SOCs. A patient who has multiple events in the same SOC and PT will be 
counted only once for each SOC and PT for the patient counts but all events will be included 
for the event counts. 
Evaluations for TEAE will be mainly done for the following categories, which will be 
identified from the information of the CRF: 
• Ocular TEAEs in the treated study eye 
• Ocular TEAEs in the fellow eye 
• Non-ocular TEAEs 
AE summaries will be provided displaying AEs within each SOC in decreasing order of total 
percentage of patients reporting the AE. 
For overall characterization of the AE profile for aflibercept in this study, an AE summary 
will include AEs within each SOC listed in decreasing order of total percentage of patients 
reporting the AE, with columns for treatment arm and a pooled arm. 
TEAEs in the study eye assessed by the investigator as being related to the injection 
procedure, related to protocol required procedures and those related to the study medication 
will be summarized separately. 
TEAEs in the fellow eye assessed by the investigator as being related to the injection 
procedure, related to protocol required procedures, related to the study medication and those 
related to fellow eye treatment (as defined in Section 4.1.11) will be summarized separately. 
A listing will be constructed that includes the patient identification, the treatment arm, 
category of AE (ocular study eye, non-ocular), AE, MedDRA term, seriousness, severity, 
causality, elapsed time to onset, duration, and outcome. 
Serious Adverse Events (SAEs) will be summarized in the same way as described for 
TEAEs. 
A frequency table of TEAEs of intraocular inflammation terms, cross-tabulated with related 
MedDRA PT, will be displayed by treatment arm (see the Biosimilars, Medical Histories and 
Definition of Grouped Adverse Event Terms document for definition of terms). 
A frequency table of TEAEs of intraocular pressure increase terms, cross-tabulated with 
related MedDRA PT, will be displayed by treatment arm (see the Biosimilars, Medical 
Histories and Definition of Grouped Adverse Event Terms document for definition of terms). 
No AEs of special interest are defined. 


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4.5.3 
Additional Safety Assessments 
4.5.3.1 
Surgeries 
All surgeries after informed consent are collected on the eCRF. All surgeries and diagnostic 
procedures will be displayed in listings. 
4.5.3.2 
Clinical Laboratory Variables 
No collection of chemistry, hematology, urinalysis and biomarker parameters is foreseen. 
Only urine pregnancy testing is performed at each visit for women of childbearing potential. 
Results of pregnancy tests will be listed only. 
4.5.3.3 
Vital Signs 
Vital signs will be collected pre-injection at each visit during the study. Variables for analysis 
of vital signs include body temperature, heart rate, systolic blood pressure, and diastolic blood 
pressure. Vital signs will be summarized by baseline and change from baseline to each visit 
by treatment arm for the SAF. 
Heart rate and blood pressure assessments will also be displayed as figures with mean change 
from baseline for SAF. 
4.5.3.4 
Indirect Ophthalmoscopy 
The number and proportion of patients with vitreous cells will be summarized by treatment 
arm for the SAF, according to the following categories: 
• 0: clear (0-1 cells) 
• Trace: few opacities (2-20 cells) 
• 1+: scattered opacities (21-50 cells) 
• 2+: moderate opacities (51-100 cells) 
• 3+: many opacities (101-250 cells) 
• 4+: dense opacities (>251 cells). 
4.5.3.5 
Slit Lamp Biomicroscopy 
The number and proportion of patients with anterior chamber cells and anterior chamber flare 
will be summarized by treatment arm for the SAF, according to the following categories: 
• Proportion of patients with anterior chamber cells 
o 0: no cells 
o Trace: less than 5 cells 
o 1+: 5 to 10 cells 
o 2+: 10 to 20 cells 
o 3+: 20 to 30 cells 
o 4+: cells too numerous to count. 
• Proportion of patients with anterior chamber flare 
o 0: no protein 


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o Trace: trace amount of protein 
o 1+: mild amount of protein 
o 2+ and 3+: moderate amount of protein (continuum) 
o 4+: severe amount of protein. 
4.5.3.6 
Intraocular Pressure 
The number and proportion of patients with increased IOP will be summarized by treatment 
arm for the SAF, according to the following categories: 
• ≥10 mmHg increase in IOP measurement from baseline to any (i.e., pre-dose or post-
dose) measurement 
• >21 mmHg for any (i.e., pre-dose or post-dose) measurement at any time during the 
study 
• ≥25 mmHg for any (i.e., pre-dose or post-dose) measurement at any time during the 
study 
• ≥35 mmHg for any (i.e., pre-dose or post-dose) measurement at any time during the 
study. 
Summary statistics will also be displayed by visit and by treatment arm for the SAF for: 
• change from baseline to pre-dose values 
• change from pre-dose to post-dose values. 
4.6 
Other Analyses 
4.6.1 
Subgroup Analyses 
4.6.1.1 
Efficacy Analyses 
The following subgroups will be considered for efficacy analyses: 
• Age at enrollment: <65 years, ≥65 to <75 years, ≥75 years to <80 years, ≥80 years to 
<85 years, ≥85 years 
• Sex: male, female 
• Baseline BCVA: <35 letters, 35-69 letters, ≥70 letters 
• Treatment start (Week -16, first pre-study treatment) BCVA: <35 letters, 35-69 letters, 
≥70 letters 
• Stratification factor – visual outcomes as determined at the screening visit by gain in 
BCVA relative to aflibercept initiation prior to study enrollment: <8 letters, ≥8 letters 
• Actual gain in BCVA relative to aflibercept initiation prior to study enrollment as 
determined at screening visit (to address potential errors in the stratification factor): <8 
letters, ≥8 letters 
All subgroup analyses will be descriptive only, i.e., no statistical testing of treatment effects 
or treatment interactions will be performed. 
All statistical analyses for primary and key secondary efficacy endpoints will be conducted 
for the FAS by each subgroup defined above for efficacy analyses. The number of IVT 


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aflibercept injections in the study eye from baseline to Week 36, a secondary efficacy 
endpoint, will be analysed using the FAS by each subgroup defined above. 
The purpose of the subgroup analyses is to assess the consistency of treatment effect across 
expected prognostic factors. 
No adjustment to the significance level for testing will be made, since all these subgroup 
analyses will be considered exploratory and descriptive. For each subgroup, the estimate of 
the treatment difference and 95% CI will be presented in tables. These will be presented on a 
forest plot including the results of the overall analyses. 
Analysis of subgroups for the primary endpoint will be done using the MMRM without 
imputation of missing values but with censoring for ICEs as described in Appendix 8.2, and 
the analyses of subgroups for the key secondary endpoint will be done using the ANCOVA 
without imputation of missing values but with censoring for ICEs as described in 
Appendix 8.2. 
Summary statistics for the primary efficacy endpoint will be conducted for the FAS by each 
subgroup, both for the observed cases until the occurrence of an ICE, and for where there is 
imputation of missing values after occurrence of an ICE with LOCF. 
Summary statistics for the key secondary efficacy endpoint will be conducted for the FAS, 
PPS and complete case FAS by each subgroup. 
Summary statistics for the number of IVT aflibercept injections in the study eye from baseline 
to Week 36, a secondary efficacy endpoint, will be conducted for the FAS. 
4.6.1.2 
Safety Analyses 
The following subgroups will be considered for safety analyses: 
• Age at enrollment: <65 years, ≥65 to <75 years, ≥75 years to <80 years, ≥80 years to 
<85 years, ≥85 years 
• Sex: male, female 
Subgroup analyses for TEAEs will be performed for the safety analysis subgroups described 
above, for each of the following types of TEAE: 
Number of patients with: 
• Ocular TEAEs in the study eye 
• Non-ocular TEAEs 
• Serious ocular TEAEs in the study eye 
• Serious non-ocular TEAEs 
4.7 
Interim Analyses 
No formal statistical interim analyses are planned. 
The primary endpoint/estimand will be analyzed and the summaries up to Week 36 will be 
provided when all patients have completed Week 36 (or withdrew). The analysis will only use 
data collected up to Week 36 or premature discontinuation, whichever occurs first. 
No decisions on the outcome and/or study will be made (e.g., terminating the study or 
changing the design). Therefore, no α-adjustment is necessary. 


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All the secondary and exploratory endpoints/estimands will be analyzed and the summaries 
up to Week 52 will be provided when all patients have completed the study (i.e., completed 
Week 52 or prematurely withdrew, whichever occurs first). The analysis will use all data 
collected. 
4.8 
Changes to Protocol-planned Analyses 
A clarification has been added in Section 4.1.7 of this document that for repeated 
measurements at a visit before the start of study treatment, the last non-missing repeated 
measurement would be used for data summarises and analysis. This does not match the 
unscheduled assessments paragraph of Section 9.3.1 of the study protocol. 
The definition of FAS in Section 3 of this document has been amended to remove reference to 
the BCVA assessment, which is included in the definition provided in Section 9.2 of the study 
protocol. Section 3 of this document specifies that the SAF will be analyzed “as randomized” 
rather than “as treated”, which is what was specified in Section 9.2 of the study protocol. The 
PPS has been included in Section 3 of this document but was not included in Section 9.2 of 
the study protocol. 
An additional exploratory analysis has been added in Section 4.4 for change in BCVA in the 
study eye from Week -16 to Week 52. 
There is no exploratory analysis of sub-RPE, which is included as an exploratory endpoint in 
Section 9.3.4 of the study protocol and Table 1-1 of this document. There is no exploratory 
analysis for the proportion of patients without any fluid/without IRF/SRF at treatment 
initiation (16 weeks before baseline), which is included as an exploratory endpoint in Section 
9.3.4 of the study protocol and Table 1-1 of this document. 
 
 


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5. 
Sample Size Determination 
In ARIES study, patients which were dry (as no intraretinal fluid [IRF] and no subretinal fluid 
[SRF]) at Weeks 8 and 16 in the early T&E arm (N=59) had a mean BCVA change of -0.5 
letters from Week 16 to Week 52 with a SD of 6.6 letters. 
In ALTAIR study, patients which were dry (as no IRF and no SRF) at Weeks 8 and 16 in the 
2-week adjustment arm (N=55) had a mean BCVA change of -0.7 letters from Week 16 to 
Week 52 with a SD of 7.2 and the 4-week adjustment arm (N=61) had a mean BCVA change 
of -0.5 letters from Week 16 to Week 52 with a SD of 6.1 letters. 
Under the assumptions that: 
• The customized treatment interval arm is similar to the 4-week adjustment arm from 
ALTAIR study (i.e., N=61 with a mean BCVA change of -0.5 letters from Week 16 to 
Week 52 with a SD of 6.1). 
• The standard T&E 2-week adjustment arm is similar to the 2-week adjustment arm 
from ALTAIR study (i.e., N=55 with a mean BCVA change of -0.7 letters from 
Week 16 to Week 52 with a SD of 7.2). 
• There is no true difference in mean BCVA change from baseline to Week 36 between 
both arms (which would be equal to the change from Week 16 to Week 52 in ALTAIR 
and ARIES studies). 
• Both arms will have SD of 7 letters for the mean change in BCVA from baseline to 
Week 36. 
A sample size of N=86 patients in total would be needed to show a non-inferiority of 
customized treatment interval arm compared to the standard T&E 2-week adjustment arm, 
using a non-inferiority margin of 5 letters, for the difference of the means change from 
baseline in BCVA at Week 36, achieving a power of 90% using a one-sided test with a 
significance level α of 2.5%. Assuming an expected dropout rate of 20%, a sample size of 
approximately N=108 patients in total (54 patients per arm) will be randomized. 
The sample size was calculated using NCSS PASS 13 “Non-Inferiority Tests for Two Means 
using Differences”. 
 
 


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6. 
Supporting Documentation 
6.1 
Population characteristic 
6.1.1 
Participant disposition 
The total number of patients who signed informed consent, were randomized, treated, 
completed study intervention and completed study for the respective analysis (Weeks 36 and 
52) will be summarized for all ES. Patients prematurely discontinuing the study/study 
intervention will be summarized by reason for discontinuation for all ES. 
The total number and percentage of patients who qualified as FAS and SAF (as defined in 
Section 3) including the reasons for exclusion from the respective analysis set will be 
summarized for all ES. 
The disposition of patients who signed the informed consent will be summarized overall and 
by study site including the date of first consent, date of last visit and the number of patients 
with informed consent and in each analysis set for all ES. 
The disposition of patients and the number of study sites in regions and countries will be 
presented for the FAS. Totals of all regions and within a country will be added. 
The number of patients with important PDs by country and study site will be presented for all 
ES. Number of screen failures will be included. A second summary will show the number and 
percentage of patients in each PD category for all randomized subjects. Important PDs will be 
listed for all randomized subjects. 
Additionally, a listing including all patients prematurely discontinuing from the study will be 
provided for all ES. 
6.1.2 
Demography and disease characteristics 
Demographics and baseline assessments of vital signs to be summarized for FAS and PPS 
will include: 
• Age (as entered in eCRF) 
• Age categorized (<65 years, ≥65 to <75 years, ≥75 years to <80 years, ≥80 years to 
<85 years, ≥85years) 
• Sex 
• Race and ethnicity 
• Weight (kg) 
• Height (cm) 
• Body mass index (BMI) (kg/m²) 
• BMI (≤25 kg/m², 25 kg/m² < BMI ≤30 kg/m², 30 kg/m² < BMI ≤35 kg/m², BMI 
>35 kg/m²) 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Heart rate (bpm) 
• Body temperature (°C) 
• Fellow eye with history of wet AMD (yes/no) 


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• Prior fellow eye treatment (as defined in Section 4.1.11) (yes/no) 
• Medical history of hypertension (as defined in the Biosimilars, Medical Histories and 
Definition of Grouped Adverse Event Terms document) (yes/no) 
• Medical history of cerebrovascular disease (as defined in the Biosimilars, Medical 
Histories and Definition of Grouped Adverse Event Terms document) (yes/no) 
• Medical history of ischemic heart disease (as defined in the Biosimilars, Medical 
Histories and Definition of Grouped Adverse Event Terms document) (yes/no) 
• Medical history of renal impairment (as defined in the Biosimilars, Medical Histories 
and Definition of Grouped Adverse Event Terms document) (yes/no) 
• Medical history of hepatic impairment (as defined in the Biosimilars, Medical 
Histories and Definition of Grouped Adverse Event Terms document) (yes/no) 
Baseline assessments of disease characteristics to be summarized for FAS and PPS will 
include: 
• Baseline BCVA (ETDRS letters score) 
• Categorized baseline BCVA (<35 letters, 35-69 letters, ≥70 letters) 
• Baseline intraocular pressure (IOP in mmHg) 
• Baseline CST (in µm as defined in Section 4.1.10) 
• Baseline CNV area (in mm2 as defined in Section 4.1.10) 
• Presence of IRF or SRF at baseline 
Demographic data and baseline characteristics variables will be summarized using descriptive 
statistics. Disease characteristics will be presented in a separate table. Only data of the study 
eye will be shown although most examinations are done bilaterally. 
6.1.3 
Medical history 
Medical history will be coded according to the version of Medical Dictionary for Regulatory 
Activities (MedDRA) available at DB lock. Medical history is evaluated by a frequency table, 
showing number of patients with medical history findings by primary system organ class 
(SOC) and preferred term (PT). Patients will be summarized for all medical history findings, 
along with separate summaries for ocular medical or surgical history of the study eye, ocular 
medical or surgical history of the fellow eye and non-ocular medical or surgical history. All 
summaries will be presented for the SAF. A listing of the medical history records will be 
provided. 
6.1.4 
Prior and concomitant medication 
Prior and concomitant medication or therapy will be coded to Anatomical Therapeutic 
Chemical (ATC) classification codes according to the version of the World Health 
Organization Drug Dictionary (WHO Drug Dictionary) available at DB lock. 
Prior and concomitant medication will be presented for the number and percentage of patients 
who took at least one prior and (new) concomitant medication and by ATC class (level 1) and 
subclass (level 2) for the SAF. Patients with prior and concomitant medication will be 
summarized for all medications. All medication will be included in a listing that includes 
reason for use, start and end dates and dosage information for the SAF. The following 
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• Concomitant medications are defined as medications that are ongoing at or began after 
the start and prior to the stop of study intervention. 
• Prior medications are defined as medications that began before the start of study 
intervention regardless of when they ended. 
Treatment of the fellow eye (as defined in Section 4.1.11) will be collected as concomitant 
medication. 
All prior and concomitant medication will be listed. 
6.2 
Data Cut-Off Specifications 
The aim of this section is to specify which data to include in the Week 36 and Week 52 
evaluations and which data to remove. It follows the principles and rules described in the 
sponsor’s best practice document “RD-SOP-1119 - Data cutting rules specification (for 
SDTM+)” (v2.0). 
As described in Section 1.2, the evaluation of data will be performed at two different time 
points: 
• After Week 36 (i.e. after all participants have prematurely discontinued or completed 
Week 36), the primary endpoint/estimand will be analyzed. 
• After Week 52 (i.e. after all participants have prematurely discontinued or completed 
Week 52). 
The database cut-off for this study will be based on the SDTM+ database (Study Data 
Tabulation Model provided by CDISC plus additional variables added by BAYER) and on the 
visit based cut-off approach. 
For Week 36 evaluations, a strategy for performing the data cut-off for the clinical database 
was developed, i.e. to include cumulative data up to Week 36. For Week 52 evaluations, all 
available data will be included and no data will be removed. 
6.2.1 
Definitions 
Screening Failures: 
Participants who have recorded “Did the subject complete Screening?” as “No” on the latest 
“End of Screening” form and who have not been randomized, will be considered Screening 
Failures. 
Participants considered as non-completer for Week 36: 
Participants who have 
• No Week 36 visit recorded (i.e. Week 36 “Subject Visit” form not available) and 
• “Did the subject complete the study?” = “No” recorded on the “End of Study” form, 
with a premature “Date of study completion/discontinuation” prior to the date of 
Week 36 visit (i.e. “Date of study completion/discontinuation” ≤ date of 
randomization + 252 days (+ 7 days visit window permitted by protocol)), 
will be considered non-completer for Week 36 in context of data cut-off logic. 
Participants considered as completer for Week 36: 
All participants who are neither screening failures nor discontinued study prior to Week 36 
will be considered Completer for Week 36 in context of data cut-off logic, i.e. 


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• Week 36 visit recorded (i.e. Week 36 “Subject Visit” form recorded, no matter if 
“Visit date” or “Not done”), or 
• Week 36 visit not recorded, but participant either discontinued study later than after 36 
weeks or is still in the study (i.e. “Date of study completion/discontinuation” > date of 
randomization + 252 days (+ 7 days visit window permitted by protocol)). 
Individual data cut-off date: 
Each participant will be assigned an individual data cut-off date/time, using the last available 
visit/assessment of the following: 
Screening Failures: 
The participant’s individual data cut-off date/time will be the “Date of discontinuation”, as 
recorded in the “End of Screening” folder. 
Non-completer for Week 36: 
The participant’s individual data cut-off date/time will be the “Date of study 
completion/discontinuation”, as recorded in the “End of Study” folder. 
Completer for Week 36: 
The participant’s individual data cut-off date/time will be one of the following: 
1. Date/time of study intervention at the Week 36 visit (if Week 36 visit performed, i.e. 
visit date available and study intervention was given) 
2. Last date/time from the Week 36 visit (if Week 36 visit performed, i.e. visit date 
available and no study intervention was given) 
3. Planned date/time of the Week 36 visit (if Week 36 visit was not performed, i.e. “Not 
done”; then planned date of Week 36 visit: date of randomisation + 252 days) 
Study intervention data at Week 36 and “post-intervention” data at Week 36 needs to be 
removed as well, i.e. for the cases 1) and 2) all assessments which are (as per protocol) to be 
taken after the study intervention at Week 36 should be removed. 
6.2.2 
Data cut-off rules 
6.2.2.1 
General remarks and rules 
• All variables which are calculated according to the timing guideline as well as the 
treatment emergent flag will be re-calculated after the cut-off is done. 
• Usually authorities request a special listing of all subjects who died after cut-off date. 
For this purpose, the information related to “death” (cause of death, death date) should 
not be removed even if after the cut-off date. This covers related information from 
Disposition and Death domains only. 
• If there is a domain, which depends on another, the parent domain is always cut first, 
the dependent domain will then be cut accordingly. 
• If an observation has a partial date, the observation will be cut only if the partial date 
is without any doubt after the cut-off date. 
• If an observation has a missing date and occurred up to the cut-off visit (based on the 
visit number), the observation will not be cut. 


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• If an observation is clearly related to a later visit (based on the visit number) it will 
also be removed. 
• If an observation has a missing time, “00:00” will be used for the cut-off process. 
• If for the data cut-off date/time no time is available, “23:59” (11:59pm) will be used 
for the cut-off process. 
• Different time zones will not be considered for comparison of dates. 
• Trial design domains are updated to reflect the content after cut-off. 
Study specific rules (described in more detail in the following sections): 
• At Week 36 visit only pre-intervention assessment data from that visit will be included 
(study intervention data, intraocular pressure [post-injection], indirect ophthalmoscopy 
[post-injection], will be removed) 
• Unscheduled visit data collected until the participant’s individual data cut-off 
date/time will be included 
• Further study specific rules will be defined throughout Section 6.2 
6.2.2.2 
Types of datasets to be considered for database cut-offs 
There are four different types of datasets regarding dates: 
A. Trial Design domains. 
B. Datasets without dates. 
C. Datasets with only start dates (xxSTDTC) but no end dates (xxENDTC) or 
collection/assessment dates (xxxxDTC) 
D. Datasets with start dates and respective end dates (xxSTDTC – xxENDTC). 
These four different types have different data handling rules with respect to cutting data. 
Trial Design domains 
Table 6-1 Comments for trial design domains 
Domain 
Comments (only datasets/variables listed where actions are expected) 
TS 
• 
DCUTDESC (Data Cut-off Description) and DCUTDTC (Data Cut-off Date) 
must be updated (see below) 
• 
SENDTC (Study End Date) will be re-calculated based on the definition of 
RFPENDTC but does not include time. 
TV 
To be changed if after cut-off not all planned visits were performed (e.g. for Week 36 
analysis all visits after the Week 36 vist need to be removed, except the End of 
Study/Week 52 visit if early termination information is captured there) 
Data Cut-off Description (DCUTDESC) 
For the Week 36 evaluation the following description will be used: “Analysis of data up to 
Week 36 (including the primary efficacy analysis)”. 
For the Week 52 evaluation the following description will be used: “Final analysis of data up 
to Week 52”. 
Data Cut-off Date 
The data cut-off date shall be the date when the database is locked. 


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Study End Date (SENDTC) 
The study end date shall be the date when the last study treatment up to Week 52 was given. 
At the Week 36 analysis, if this information is not available, this variable will be left blank. 
Datasets without dates 
Table 6-2 Comments for datasets without dates 
Domain 
Comments 
CO 
Comments are related to information given in other domains. If the information is 
removed by the cut-off process, the respective comment must be removed as well. 
RELREC 
Information in RELREC is related to information given in other domains. If the 
information is removed by the cut-off process, the respective RELREC lines must be 
removed as well. 
Single date variables (DTC – variables) and single start dates (SDTC – variables) 
Single date variables (DTC – variables) and single start dates (SDTC – variables), i.e. all 
variables with corresponding start and end date (##STDTC – ##ENDTC) are excluded. 
General rule: 
If a visit is clearly prior to the visit of the individual cut-off date/time, it will be kept. 
Otherwise, if date/time is after the subject’s individual cut-off date/time, the complete 
observation should be removed. Also visits that are clearly after the visit of the individual cut-
off date/time should be removed. 
Table 6-3 Comments for single date variables and single start dates 
Domain 
Variable 
Comments (only datasets/variables listed where actions are expected) 
DS 
DSSTDTC 
Keep all records where DSDECODN = 3 (Death) without any regard to date. 
 
For “Participants completed study intervention until Week 36”, “Participants 
started follow-up phase prior to Week 36”, “Participants completed follow-up 
phase until Week 36” and “Participants completed Week 36” records need to be 
created according to definition in Section 6.2.1. 
Single end dates (ENDTC – variables) and variables with corresponding start and end 
dates (##STDTC – ##ENDTC) 
General rules: 
If a visit is clearly prior to the visit of the individual cut-off date/time, it will be kept. If a visit 
is clearly after the visit of the individual cut-off date/time, it should be removed. Furthermore: 
a) If start date/time is after the subject’s individual cut-off date/time, remove the complete 
observation. 
b) If end date/time is before the subject’s individual cut-off date/time, keep the complete 
observation as is. 
c) If start date/time is before or on the subject’s individual cut-off date/time and end date/time 
is after the subject’s individual cut-off date/time, keep the observation and apply the rules in 
table below. 
d) If start date/time is before or on the subject’s individual cut-off date/time and end date/time 
is completely missing, keep the complete observation as is, except for CM/MH apply the rules 
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e) If end date is a partial date, the earliest plausible date should be taken and rules a) or c) in 
table below to be applied. 
f) For domains EX/EC: If start date/time is equal to or after the subject’s individual cut-off 
date/time, remove the complete observation. 
The table below covers tasks to be done for rule c) and d). 
Table 6-4 Comments for single end dates and variables with corresponding start and 
end date 
Domain 
Variable 
Specific actions for general rule c) and d) 
(all domains 
except EC, EX. 
PC, SV) 
##ENDTC 
End date ##ENDTC is set to “blank” 
AE 
AEOUT 
AE outcome should be set to missing 
CM 
CMENTPT 
Rule c) and d): 
 
CMENRTPT 
If Last Visit Date contained in CMENTPT is after cut-off date, 
CMENTPT will be set to cut-off date and CMENRTPT will be set to 
"ongoing" and the flag variable (CUTFL) should be set to “Y” to identify 
imputed information. Otherwise no change to CMENTPT and 
CMENRTPT. 
MH 
MHENTPT 
RULE c) and d): Same as CMENTPT / CMENRTPT 
 
MHENRTPT 
 
SV 
SVENDTC 
SVENDTC should be set to cut-off date/time and flag variable (CUTFL) 
to identify cut-off records. 
Dependent domains 
The dependent datasets do not have a date but if the related record from the parent domain is 
removed because of the cut-off process specified above, the related record in the dependent 
domain has to be removed as well. 
Dependent Domain 
Parent Domain 
PP 
PC 
CO 
Some Domains (AE, ...) 
RELREC 
Some Domains (AE, ...) 
TE 
TA 
6.2.2.3 
Database cut-off process (Overview) 
• Copy and zip the source data before cut-off to a pre-defined folder for traceability. 
• Cut all subject level data as specified above. 
• Add or update cut-off related information: Data Cut-off Date (DCUTDTC), Data 
Cut-off Description (DCUTDESC) and Study End Date (SENDTC) in TS domain. 
Note: There should be only one pair of DCUTDTC/DCUTDESC related to the current 
cut-off date and description. 
• Re-calculate SE domain and other timing information as well as information about 
treatment emergency. The following algorithm is to be applied: Keep the original 
elements of the pre-cut SE, create a temp DS with death and Survival Assessment 
Contact Date blanked out if those dates are after cut-off date, apply the timing concept 
rules on the temp DS and other cut datasets to populate the dates in SE and DM, delete 
records with blank SESTDTC from the new SE. Note: For Bayer in-house trials this 
can be done running the timing and the treatment emergent macro again. 
 
 


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7. 
References 
1. National Research Council (US) Panel on Handling Missing Data in Clinical Trials. 
The Prevention and Treatment of Missing Data in Clinical Trials. Washington (DC): 
National Academies Press (US); 2010. 
 
 


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8. 
Appendix 
8.1 
Handling of Questionnaires 
8.1.1 
Patient Home OCT User Experience Questionnaire 
Patient user experience with Home OCT device will be assessed with Notal Vision 
questionnaire (only applicable for patients in Home OCT-customized treatment interval arm). 
The purpose of the questionnaire is to get patients’ feedback on the Notal Home OCT device 
used during the study, with regards to the tutorial, ease of use and comfortability. 
The questionnaire, shown in Table 8-1, is made up of 15 self-administered questions with 
responses, assessing the patients’ level of agreement, ranging from 1=Strongly agree to 
5=Strongly disagree. Patients are required to check the box with the answer that best fits their 
level of agreement. 
 
 


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Table 8-1 Notal Vision Patient Home OCT User Experience Questionnaire 
 
1 - Strongly agree 
2 - Agree 
3 - Not sure/Irrelevant 
4 - Disagree 
5 - Strongly disagree 
1 
The setup material, demonstrating how to install the device, was clear, 
and after reading it I was able to setup the device. 
2 
Getting the device out of the box and setting it up was simple. 
3 
The video tutorial, demonstrating how to use the device, was clear, 
and after watching it I was able to operate the device without further 
assistance. 
4 
I understood the tasks I had to perform in order to scan my eyes, by 
myself. 
5 
The tasks I had to perform to scan my eyes were easy. 
6 
The time to scan each eye was short. 
7 
Daily use of the device was convenient (posture, head rest, etc.) 
8 
I did not feel my eyes get tired or hurt during the scans. 
9 
The face rest on the viewer was comfortable to use. 
10 The handles on the sides of the device helped me stabilize myself 
during the scans. 
11 Using the device on a daily basis was easy. 
12 After using the device for a few days, it got easier. 
13 The fact that I can check my eyes at home every day makes me feel 
like I am in good care. 
14 Based on the study I participated in, I would like to use the device to 
scan my eyes on a daily basis. 
15 If you used the service call assistance during the study (otherwise 
leave blank): 
The service call helped me to solve problems and questions I had 
during the study. 
 
 


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8.2 
Strategies for Occurrence of Intercurrent Events 
Analysis Strategies for ICEs for Primary Endpoint (i.e., Mean Change in BCVA from Baseline to Week 36) 
Table 8-2: Strategies for Occurrence of ICEs for Primary Endpoint (i.e., Mean Change in BCVA from Baseline to Week 36) 
 
 
Primary Estimand 
Sensitivity Analysis (LOCF) 
Sensitivity Analysis (Complete Case) 
Potential post-randomization 
event 
ICE 
Strategy 
Analysis 
Analysis 
Analysis 
Premature discontinuation of 
study intervention for any reason 
(and discontinuation of study) 
before Week 36 
Yes 
Hypothetical 
Non-observed data beyond 
discontinuation of study 
intervention will be covered 
implicitly in the MMRM 
Non-observed data beyond 
discontinuation of study intervention 
will be imputed by LOCF 
Patient excluded from analysis 
Premature discontinuation of 
study intervention for any reason 
(but continuation of study) before 
Week 36 
Yes 
Hypothetical 
Observed data beyond last 
injection + minimum treatment 
interval of 4 week +7 days will be 
excluded from analysis and 
resulting missing data will be 
covered implicitly in the MMRM 
Observed data beyond last injection 
+ minimum treatment interval of 4 
week +7 days will be excluded from 
analysis and resulting missing data 
will be imputed by LOCF 
Patient excluded from analysis data if 
the last observed data go beyond the 
last injection + minimum treatment 
interval of 4 week +7 days 
Use of a prohibited medication / 
start of alternative anti-VEGF 
treatment, prior to treatment 
discontinuation before Week 36 
Yes 
Hypothetical 
Observed data beyond first 
administration of the prohibited 
medication will be excluded from 
analysis and resulting missing 
data will be covered implicitly in 
the MMRM 
Observed data beyond first 
administration of the prohibited 
medication will be excluded from 
analysis and resulting missing data 
will be imputed by LOCF 
Patient excluded from the analysis 
Shortening/extension of dosing 
interval before Week 36 
No 
Not applicable 
Observed data beyond 
shortening/extension of dosing 
interval will be included in the 
analysis 
Observed data beyond 
shortening/extension of dosing 
interval will be included in the 
analysis 
Observed data beyond 
shortening/extension of dosing interval 
will be included in the analysis 
Any missing assessment of BCVA is not considered an ICE per se but is considered missing at random and covered implicitly in the MMRM or LOCF as applicable (or 
considered missing in the complete case). 
Any missed injections are not considered an ICE per se but are considered missing at random. 
 
 


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Analysis Strategies for ICEs for Key Secondary Endpoint (i.e., Number of Injections up to Week 52) 
Table 8-3: Strategies for Occurrence of ICEs for Key Secondary Endpoint (i.e., Number of Injections up to Week 52) 
 
 
Primary Estimand 
Sensitivity Analysis (Complete Case) 
Potential post-randomization 
event 
ICE 
Strategy 
Analysis 
Analysis 
Premature discontinuation of study 
intervention for any reason (and 
discontinuation of study) before 
Week 52 
Yes 
While on treatment Non-observed data beyond discontinuation of study 
intervention will not be imputed 
Patient excluded from the analysis 
Use of a prohibited medication / 
start of alternative anti-VEGF 
treatment, prior to treatment 
discontinuation before Week 52 
Yes 
While on treatment 
without prohibited 
medication 
Observed data beyond first administration of the 
prohibited medication will be excluded from analysis 
and resulting missing data will NOT be imputed 
Patient excluded from the analysis 
Shortening/extension of dosing 
interval before Week 52 
No 
Not applicable 
Observed data beyond shortening/extension of 
dosing interval will be included in the analysis 
Observed data beyond 
shortening/extension of dosing interval 
will be included in the analysis 
Any missing assessment of BCVA is not considered an ICE per se but is considered missing at random and covered implicitly in the MMRM or LOCF as applicable (or 
considered missing in the complete case). 
Any missed injections are not considered an ICE per se but are considered missing at random. 
 
Analysis Strategies for ICEs for Secondary Endpoint (i.e., Number of Injections up to Week 36) 
Intercurrent events for the analysis of this endpoint will be handled similarly to what is specified in the primary estimand columns in Table 8-3. 
 
Analysis Strategies for ICEs for Secondary Endpoint (i.e., Patients Achieving Pre-defined Treatment Intervals at Week 36 and at 
Week 52) 
Intercurrent events for the analysis of these endpoints will be handled similarly to what is specified in the primary estimand columns in Table 
8-3. 
 
Analysis Strategies for ICEs for Secondary Endpoint (i.e., Mean Change in BCVA from Baseline to Week 52) 
Intercurrent events for the analysis of this endpoint will be handled similarly to what is specified in the primary estimand columns in Table 8-2. 


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8.3 
Participating Regions and Countries 
The following regions and countries are participating in this study and are shown in Table 
8-4. 
Table 8-4: Participating Regions and Countries 
Region 
Country 
Europe 
FRANCE 
GERMANY 
SPAIN 
UNITED KINGDOM 
North America 
CANADA 
 


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