Conditions: Neovascular Age-Related Macular Degeneration
Keywords: nAMD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1011
Healthy volunteers: no

Brief summary:
In this study researchers want to learn more about changes in visual acuity (clarity of vision) with a high dose treatment with Aflibercept (Eylea) in patients suffering from neovascular age-related macular degeneration (nAMD). Neovascular AMD is an eye disease that causes blurred vision or a blind spot due to abnormal blood vessels that leak fluid or blood into the light sensitive lining inside the eye (retina). The fluid buildup causes the central part of the retina (macula) responsible for sharp, straight-ahead vision to swell and thicken (edema), which distorts vision.

Detailed description:

Arms:
arm 1: In the double-masked study part (Years 1 and 2), Aflibercept 2 mg administered every 8 weeks after a loading phase. (Active Comparator) In Year 3, high dose aflibercept administered according to individual patient response. (Experimental) arm 2: Aflibercept high dose (HD) administered every 12 weeks after an initiation phase. Treatment intervals adjusted according to individual patient response. arm 3: Aflibercept high dose administered every 16 weeks after an initiation phase. Treatment intervals adjusted according to individual patient response.

Interventions: intervention 1: Aflibercept High Dose VEGF Trap-Eye (BAY86-5321) intervention 2: Aflibercept VEGF Trap-Eye (Eylea, BAY86-5321)
Intervention descriptions: intervention 1: Solution in Vial, intravitreal (IVT) injection intervention 2: Solution in Vial, 2 mg, intravitreal (IVT) injection

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Clinical Study Protocol 
Official Title: 
Randomized, Double-Masked, Active-Controlled, Phase 3 Study of 
the Efficacy and Safety of High Dose Aflibercept in Patients With 
Neovascular Age-Related Macular Degeneration 
NCT Number: 
NCT04562155 
Document Date: 
27 FEB 2023 
 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  1 of 109 
 
 
 
Title Page 
Protocol Title: Randomized, Double-Masked, Active-Controlled, Phase 3 Study of the 
Efficacy and Safety of High Dose Aflibercept in Patients With Neovascular Age-Related 
Macular Degeneration 
Protocol Number: 
 
20968 
Protocol Version: 
 
5.0 
Amendment Number: 
4 
Compound Number:  
BAY 86-5321 / aflibercept 
Short Title:  
Efficacy and Safety of High Dose Aflibercept in Patients With 
Neovascular Age-Related Macular Degeneration (nAMD) 
Study Phase:  
 
3 
Acronym: 
 
 
PULSAR 
Sponsor Name: 
Bayer AG 
Legal Registered Address: 
Bayer AG, 51368 Leverkusen, Germany  
Regulatory Agency Identifier Numbers:  
 
Investigational New Drug (IND): 12462 (Regeneron Pharmaceuticals, Inc.) 
European Clinical Trials Database (EudraCT): 2019-003851-12  
 
Protocol Date: 27-February-2023 
 
Name: 
 
 
 
 
 
 
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 TMF 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


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  2 of 109 
 
 
 
Document History Table 
DOCUMENT HISTORY 
Document 
Version 
Date 
Comments (if applicable) 
Amendment 4 
5.0 
27 FEB 2023 
- 
Amendment 3 
4.0 
13 SEP 2022 
Version approved by health authorities and 
used in the study 
Amendment 2 
3.0 
26 APR 2022 
Version approved by health authorities and 
used in the study 
JPN-1 
 
06 MAY 2021 
- 
FRA-2 
 
11 MAR 2021 
- 
SS-1 
 
23 FEB 2021 
- 
FRA-1 
- 
17 SEP 2020 
- 
DEU-1 
- 
03 AUG 2020 
- 
USA-1 
- 
12 MAY 2020 
- 
Amendment 1 
2.0 
14 FEB 2020 
Version approved by health authorities and 
used in the study 
Clinical Study Protocol 
1.0 
09 DEC 2019 
- 
 




CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  4 of 109 
 
 
 
Section # 
and Name 
Description of Change 
Brief Rationale 
6.6.3 Year 3 (Masked Transition Period and 
Open-label Extension Part): Week 96 to 
Week 156 (End of Study) / E-DRM Criteria 
Added clarifying 
language. 
To provide detail on 
E-DRM Criteria 
9.5 Interim Analyses 
Clarification added that 
additional exploratory 
analyses may be 
performed before 
Week 96 (but after the 
completion of the 
confirmatory analyses at 
Week 48 and Week 60) 
as necessary. 
To be able to address 
potential health 
authority requests 
and queries 
DRM=dose regimen modification, E-DRM=dose regimen modification criteria for extension period, 
FBR=future biomedical research, ICF=informed consent form 
 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  5 of 109 
 
 
 
Table of Contents 
Title Page ................................................................................................................................... 1 
Document History Table .......................................................................................................... 2 
Protocol Amendment Summary of Changes Table ............................................................... 3 
Table of Contents ..................................................................................................................... 5 
Table of Tables ......................................................................................................................... 8 
Table of Figures ........................................................................................................................ 8 
1. 
Protocol Summary ............................................................................................................ 9 
1.1 
Synopsis ........................................................................................................................... 9 
1.2 
Schema ........................................................................................................................... 13 
1.3 
Schedule of Activities (SoA) ......................................................................................... 16 
2. 
Introduction ..................................................................................................................... 25 
2.1 
Study Rationale .............................................................................................................. 25 
2.2 
Background .................................................................................................................... 25 
2.3 
Benefit/Risk Assessment ............................................................................................... 26 
3. 
Objectives and Endpoints ............................................................................................... 28 
4. 
Study Design .................................................................................................................... 30 
4.1 
Overall Design ............................................................................................................... 30 
4.2 
Scientific Rationale for Study Design ........................................................................... 33 
4.3 
Justification for Dose ..................................................................................................... 34 
4.4 
End of Study Definition ................................................................................................. 35 
5. 
Study Population ............................................................................................................. 35 
5.1 
Inclusion Criteria ........................................................................................................... 35 
5.1.1 
Additional Inclusion Criteria for the Extension Period .............................................. 37 
5.2 
Exclusion Criteria .......................................................................................................... 37 
5.2.1 
Additional Exclusion Criteria for the Dense PK Substudy ........................................ 39 
5.3 
Lifestyle Considerations ................................................................................................ 40 
5.4 
Screen Failures and Re-Screening ................................................................................. 40 
6. 
Study Intervention .......................................................................................................... 40 
6.1 
Study Intervention(s) Administered ............................................................................... 41 
6.1.1 
Medical Devices ......................................................................................................... 41 
6.2 
Preparation/Handling/Storage/Accountability ............................................................... 42 
6.3 
Measures to Minimize Bias: Randomization and Masking ........................................... 43 
6.3.1 
Intervention Assignment ............................................................................................ 43 
6.3.2 
Masking ...................................................................................................................... 43 
6.3.2.1 
Masked Part (Screening to Week 96) and Masked Transition Period for Extension 
(Week 96 to Week 108) .......................................................................................... 43 
6.3.2.2 
Open-label Part (After Week 108 to Week 156) ..................................................... 46 
6.4 
Study Intervention Compliance ..................................................................................... 46 
6.5 
Concomitant Therapy .................................................................................................... 46 
6.5.1 
Allowed and Prohibited Medications ......................................................................... 46 
6.5.2 
Fellow Eye Treatment ................................................................................................ 47 
6.6 
Dose Regimen Modification/Rescue Regimen .............................................................. 47 
6.6.1 
Year 1: Baseline to Week 48 ...................................................................................... 48 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  6 of 109 
 
 
 
6.6.2 
Year 2: Week 52 to Week 96 (End of Masked Part of Study) ................................... 48 
6.6.3 
Year 3 (Masked Transition Period and Open-label Extension Part): Week 96 to Week 
156 (End of Study) / E-DRM Criteria ........................................................................ 49 
6.7 
Intervention After the End of the Study ......................................................................... 50 
7. 
Discontinuation of Study Intervention and Participant Discontinuation/Withdrawal
 ........................................................................................................................................... 50 
7.1 
Discontinuation of Study Intervention ........................................................................... 50 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................... 50 
7.3 
Lost to Follow-Up .......................................................................................................... 51 
8. 
Study Assessments and Procedures ............................................................................... 52 
8.1 
Efficacy Assessments .................................................................................................... 52 
8.1.1 
Ophthalmic and General Examinations ...................................................................... 52 
8.1.1.1 
Best Corrected Visual Acuity (BCVA) ................................................................... 52 
8.1.1.2 
Intraocular Pressure (IOP) ....................................................................................... 53 
8.1.1.3 
Slit Lamp Examination ............................................................................................ 53 
8.1.1.4 
Indirect Ophthalmoscopy ........................................................................................ 53 
8.1.1.5 
Fundus Photography (FP) and Fluorescein Angiography (FA) .............................. 53 
8.1.1.6 
Spectral Domain Optical Coherence Tomography (SD-OCT) ............................... 54 
8.1.1.7 
Indocyanine Green Angiography (ICGA) ............................................................... 54 
8.1.1.8 
Optical Coherence Tomography Angiography (OCT-A) ....................................... 54 
8.1.2 
National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) ........... 55 
8.2 
Safety Assessments ........................................................................................................ 55 
8.2.1 
Physical Examinations ................................................................................................ 55 
8.2.2 
Vital Signs .................................................................................................................. 55 
8.2.3 
Electrocardiograms ..................................................................................................... 55 
8.2.4 
Clinical Safety Laboratory Assessments .................................................................... 55 
8.3 
Adverse Events and Serious Adverse Events ................................................................ 56 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information....................... 56 
8.3.2 
Method of Detecting AEs and SAEs .......................................................................... 57 
8.3.3 
Follow-up of AEs and SAEs ...................................................................................... 57 
8.3.4 
Regulatory Reporting Requirements for SAEs .......................................................... 57 
8.3.5 
Pregnancy ................................................................................................................... 58 
8.3.6 
Adverse Events of Special Interest ............................................................................. 58 
8.3.7 
Medical Device Deficiencies ...................................................................................... 58 
8.3.7.1 
Time Period for Detecting Medical Device Deficiencies ....................................... 58 
8.3.7.2 
Follow-up of Medical Device Deficiencies ............................................................ 58 
8.3.7.3 
Prompt Reporting of Medical Device Deficiencies to Sponsor .............................. 59 
8.3.7.4 
Regulatory Reporting Requirements for Medical Device Deficiencies .................. 59 
8.4 
Treatment of Overdose .................................................................................................. 59 
8.5 
Pharmacokinetics ........................................................................................................... 59 
8.6 
Pharmacodynamics ........................................................................................................ 60 
8.7 
Genetics ......................................................................................................................... 60 
8.7.1 
Optional Genomic Substudy ....................................................................................... 60 
8.8 
Future Biomedical Research .......................................................................................... 60 
8.9 
Biomarkers ..................................................................................................................... 60 
8.10 Immunogenicity Assessments ........................................................................................ 60 
8.11 Medical Resource Utilization and Health Economics ................................................... 61 
9. 
Statistical Considerations ............................................................................................... 61 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  7 of 109 
 
 
 
9.1 
Statistical Hypotheses .................................................................................................... 61 
9.2 
Sample Size Determination ........................................................................................... 63 
9.3 
Populations for Analyses ............................................................................................... 64 
9.4 
Statistical Analyses ........................................................................................................ 65 
9.4.1 
General Considerations............................................................................................... 65 
9.4.2 
Primary Efficacy Endpoint ......................................................................................... 65 
9.4.3 
Secondary Efficacy Endpoints.................................................................................... 67 
9.4.4 
Secondary Safety Endpoints ....................................................................................... 67 
9.4.4.1 
Adverse Events ........................................................................................................ 67 
9.4.4.2 
Immunogenicity Data .............................................................................................. 68 
9.4.5 
Other Safety Analyses ................................................................................................ 68 
9.4.5.1 
Vital Signs ............................................................................................................... 68 
9.4.5.2 
Laboratory Tests ...................................................................................................... 68 
9.4.6 
Pharmacokinetics Endpoints....................................................................................... 68 
9.4.7 
Other Analyses ........................................................................................................... 69 
9.5 
Interim Analyses ............................................................................................................ 69 
9.5.1 
Data Monitoring Committee (DMC) and Other Committees ..................................... 70 
10. Supporting Documentation and Operational Considerations .................................... 71 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........................ 71 
10.1.1 Regulatory and Ethical Considerations ...................................................................... 71 
10.1.2 Financial Disclosure ................................................................................................... 71 
10.1.3 Informed Consent Process .......................................................................................... 71 
10.1.3.1 Informed Consent for Study Extension ................................................................... 72 
10.1.4 Data Protection ........................................................................................................... 72 
10.1.5 Dissemination of Clinical Study Data ........................................................................ 72 
10.1.6 Data Quality Assurance .............................................................................................. 73 
10.1.7 Source Documents ...................................................................................................... 73 
10.1.8 Study and Site Start and Closure ................................................................................ 74 
10.2 Appendix 2: Clinical Laboratory Tests .......................................................................... 75 
10.3 Appendix 3: Adverse Events (AEs): Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................... 77 
10.3.1 Definition of AE ......................................................................................................... 77 
10.3.2 Definition of SAE ....................................................................................................... 78 
10.3.3 Recording and Follow-Up of AE and/or SAE ............................................................ 79 
10.3.4 Reporting of SAEs ...................................................................................................... 81 
10.4 Appendix 4: Medical Device Adverse Events (AEs), Adverse Device Effects (ADEs), 
Serious Adverse Events (SAEs) and Device Deficiencies: Definition and Procedures 
for Recording, Evaluating, Follow-up, and Reporting .................................................. 82 
10.4.1 Definition of Medical Device AE and ADE ............................................................... 82 
10.4.2 Definition of Medical Device SAE, Serious ADE (SADE) and Unexpected SADE 
(USADE) .................................................................................................................... 82 
10.4.3 Definition of Device Deficiency................................................................................. 83 
10.4.4 Recording and Follow-Up of Medical Device AE and/or SAE and Device 
Deficiencies ................................................................................................................ 83 
10.4.5 Reporting of Medical Device SAEs ........................................................................... 85 
10.4.6 Reporting of Medical Device SADEs ........................................................................ 86 
10.4.7 Medical Device AE, ADE, SAE, SADE Determination Flow Chart ......................... 87 
10.5 Appendix 5: Contraceptive Guidance and Collection of Pregnancy Information ......... 88 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  8 of 109 
 
 
 
10.6 Appendix 6: Genetics ..................................................................................................... 90 
10.7 Appendix 7: Study Intervention Administration and Procedures .................................. 91 
10.7.1 Preparation of Study Intervention............................................................................... 91 
10.7.1.1 Aflibercept HD and 2 mg ........................................................................................ 91 
10.7.1.2 Sham ........................................................................................................................ 91 
10.7.2 Injection Procedure ..................................................................................................... 91 
10.7.2.1 Preparation .............................................................................................................. 91 
10.7.2.2 Study Intervention Administration .......................................................................... 92 
10.7.2.3 Post-injection Procedures ........................................................................................ 92 
10.7.2.4 Discharge ................................................................................................................. 93 
10.8 Appendix 8: Abbreviations ............................................................................................ 94 
10.9 Appendix 9: Protocol Amendment History ................................................................... 97 
11. References ...................................................................................................................... 109 
 
 
Table of Tables 
Table 1–1 Schedule of Activities – Year 1 ............................................................................. 16 
Table 1–2 Schedule of Activities – Year 2 ............................................................................. 18 
Table 1–3 Schedule of Activities – Extension Period (Year 3) .............................................. 20 
Table 1–4 Schedule of Activities – Dense PK Substudy ....................................................... 24 
Table 6–1 Study Interventions ................................................................................................ 41 
Table 6–2: Masked and Unmasked Site Personnel ................................................................. 45 
Table 9–1 Testing Order of Hierarchical Testing Procedure in G-SAP and EP‑SAP ............ 63 
Table 10–1: 
Protocol-Required Safety Laboratory Assessments ......................................... 75 
 
 
Table of Figures 
Figure 1–1 Study Flow Diagram ............................................................................................. 13 
Figure 1–2 Dosing Schedule .................................................................................................... 14 
 
 
 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  9 of 109 
 
 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title: 
Randomized, Double-Masked, Active-Controlled, Phase 3 Study of the 
Efficacy and Safety of High Dose Aflibercept in Patients With 
Neovascular Age-Related Macular Degeneration 
Short Title: 
Efficacy and Safety of High Dose Aflibercept in Patients With 
Neovascular Age-Related Macular Degeneration (nAMD) 
Regulatory Agency Identifier Numbers: 
Investigational New Drug (IND): 
 
 
12462 (Regeneron Pharmaceuticals, Inc.) 
European Clinical Trials Database (EudraCT): 
2019-003851-12 
 
Rationale: 
There remains an unmet medical need in the treatment of neovascular (wet) age-related 
macular degeneration (nAMD). Although many patients benefit from treatment with currently 
available anti-vascular endothelial growth factor (VEGF) agents, a sizable proportion of 
patients still need intravitreal (IVT) injections as frequently as every 4 to 8 weeks, specifically 
in the first year of treatment. A continued need for treatment in intervals as short as 4 to 
8 weeks poses significant treatment burden to patients, physicians, and to healthcare systems. 
In addition, long-term data in patients with nAMD suggest that visual benefits achieved in the 
first year of treatment may be lost if regular dosing is not maintained. In real-world settings, 
visual loss also occurs to patients being treated under a treat-and-extend regimen with 
inappropriate dosing interval extension strategy. In fact, in nAMD, lost vision may not be 
regained, even with increases of treatment frequency after the vision loss has occurred. 
Furthermore, dosing with an insufficient frequency may result in a patient’s vision 
deteriorating below certain visual thresholds that would preclude certain activities of daily 
living, e.g., driving a car or reading.  
EYLEA® (also known as aflibercept 2 mg) is a VEGF antagonist approved as of 
07 OCT 2019 in over 109 countries for the treatment of nAMD at a dosage level of 2 mg 
(administered at a concentration of 40 mg/mL injected IVT) administered every 8 (q8) weeks. 
This study will investigate the efficacy and safety of a high dose (HD) aflibercept (8 mg; 
provided at a concentration of 
 mg/mL) with the intent of achieving non-inferior best 
corrected visual acuity (BCVA), while extending the dosing interval and potentially 
improving visual and/or anatomic outcomes for HD versus the currently approved aflibercept 
2 mg dose regimen. The study will compare HD aflibercept administered every 12 (q12) or 
every 16 (q16) weeks, after 3 initial injections at 4-week intervals (HDq12 and HDq16) 
versus aflibercept 2 mg administered q8 weeks (2q8), after 3 initial injections at 4-week 
intervals in participants with nAMD. 
In order to investigate the long-term efficacy and safety of HD aflibercept beyond 2 years of 
treatment, this study will be extended in an open-label part (after a masked transition period 
of 12 weeks) for approximately one additional year (60 weeks) in countries and sites selected 
by the sponsor. The reason for the masked transition period is to prevent study staff and 
participants from being able to determine the participant’s treatment assignment during the 
masked part of the study before data cleaning is completed for the masked part, preserving 
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  10 of 109 
 
 
 
data quality for the Week 60 database lock, and giving a time frame for data cleaning. During 
this third year of treatment, 
 who consent to continue in the study, 
 
. The 
treatment intervals for all groups will be adjusted according to individual participant response 
as determined by the E-DRM criteria in Year 3. 
 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
To determine if treatment with 
aflibercept 8 mg (HD) at intervals 
of 12 or 16 weeks provides non-
inferior BCVA change compared 
to aflibercept 2 mg every 
8 weeks in participants with 
nAMD 
Primary Endpoint  
• 
Change from baseline in BCVA measured by the Early 
Treatment Diabetic Retinopathy Study (ETDRS) letter 
score at Week 48 
Secondary - Efficacy 
 
To determine the effect of HD 
versus 2 mg aflibercept on other 
visual and anatomic measures of 
response 
Key Secondary Efficacy Endpoints 
• 
Change from baseline in BCVA measured by the 
ETDRS letter score at Week 60 (for regulatory 
submissions to European Medicines 
Agency/Pharmaceuticals and Medical Devices Agency 
[EMA/PMDA] Analysis Plan only, see Section 9) 
• 
Proportion of participants with no intraretinal fluid (IRF) 
and no subretinal fluid (SRF) in central subfield at 
Week 16 
Additional Secondary Efficacy Endpoints 
• 
Proportion of participants gaining at least 15 letters in 
BCVA from baseline at Week 48 
• 
Proportion of participants achieving an ETDRS letter 
score of at least 69 (approximate 20/40 Snellen 
equivalent) at Week 48  
• 
Change in choroidal neovascularization (CNV) size 
from baseline to Week 48 
• 
Change in total lesion area from baseline to Week 48 
• 
Proportion of participants with no IRF and no SRF in 
the center subfield at Week 48  
• 
Change from baseline in central subfield retinal 
thickness (CST) at Week 48  
To assess the efficacy of HD 
compared to 2 mg aflibercept on 
vision-related quality of life 
• 
Change from baseline in National Eye Institute Visual 
Functioning Questionnaire-25 (NEI-VFQ-25) total 
score at Week 48 
Secondary - Safety 
 
To evaluate the safety of 
aflibercept 
• 
Treatment-emergent adverse events (AEs) and 
serious AEs (SAEs) through Week 48, 60, 96 and, for 
participants who continue in the study extension, 
through Week 156 
Secondary - Other 
 
To evaluate the 
pharmacokinetics (PK) and 
immunogenicity of aflibercept 
• 
Systemic exposure to aflibercept as assessed by 
plasma concentrations of free, adjusted bound and 
total aflibercept from baseline through Week 48 
• 
Assessment of immunogenicity to aflibercept through 
end of masked study (Week 96) 
 
CCI
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  11 of 109 
 
 
 
Overall Design 
Disclosure Statement: This is a randomized, double-masked (participant and investigator 
masked), active-controlled, multi-center study with 3 groups. After completion of the 
double-masked part (Week 96), this study will be extended through a masked transition 
period (Week 96 to Week 108) to an open-label part until Week 156. 
Intervention Model: Parallel. 
Primary Purpose: Treatment. 
Number of Groups: 3 
Masking: In the masked part (up to Week 96): participant and investigator masked; in the 
transition period of study extension (Week 96 to Week 108): participant and investigator 
masked; in the open-label part of study extension (after Week 108 to Week 156): participant 
and investigator unmasked to treatment intervals in the extension period (
 
) (refer to Section 6.3.2 for details). 
Number of Participants: Approximately 960 participants will be randomly assigned in a 
1:1:1 ratio (320 in each group) such that approximately 288 evaluable participants per 
treatment group complete the primary endpoint evaluation. Refer to Section 9.2 for 
justification of the sample size. Randomization will be stratified by geographic region (Japan 
vs. Rest of World), and baseline (Day 1) BCVA (<60 vs. ≥60). Approximately 24 participants 
(12 Japanese participants from Japan sites and 12 non-Asian participants from Europe or US 
sites, distributed across all 3 treatment groups) will undergo additional pharmacokinetic (PK) 
testing in a Dense PK Substudy.  
Approximately 380 sites in approximately 36 countries in Europe, North America, Latin 
America, Australia, and Asia Pacific (including at least 10% of participants in Japan [n=96]) 
will participate in the masked part of this study (up to Week 96). 
A total of 660 participants (220 per group) are estimated to consent to continue in the study 
extension. 
Approximately 160 sites in approximately 18 countries in Europe, North America, Australia, 
and Asia Pacific will participate in the extension period of this study. 
Intervention Groups and Duration: 
In the double-masked study part (Years 1 and 2), treatment groups and duration will be as 
follows: 
• 2q8: aflibercept 2 mg administered every 8 weeks, after 3 initial injections at 
4-week intervals.  
• HDq12: high dose aflibercept 8 mg administered every 12 weeks, after 3 initial 
injections at 4-week intervals. 
• HDq16: high dose aflibercept 8 mg administered every 16 weeks, after 3 initial 
injections at 4-week intervals.  
Only one eye can be treated within the study. Sham procedures will be done on visits when an 
active injection is not planned. No sham procedures will be done at the non-treatment visit at 
Week 12. At all subsequent visits, all participants will receive either active study treatment 
injection or sham procedure (for masking purposes), depending on their assigned treatment 
schedule and eligibility for dose regimen modification (DRM). All participants will be 
followed every 4 weeks through Week 96. 
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  12 of 109 
 
 
 
For each participant, the total duration of participation in the double-masked study part will be 
approximately 99 weeks, including a 3-week screening period, Year 1 (48 weeks), and Year 2 
(48 weeks). 
At sites where the study will be extended, participants who are planned to complete the 
masked part of the study (i.e., the end of masked study visit at Week 96) will be asked to 
provide their informed consent to continue in the study for a 1-year extension until the end of 
Year 3. Participants must complete the Week 96 visit to be eligible to enter the extension. 
In this extension period (Year 3), treatment groups and duration will be as follows: 
• 2q8: For participants 
 assigned to 2q8 at the beginning of the study, 
thereafter, 
 according to individual participant 
response as determined by the E-DRM in Year 3. If the E-DRM criteria are met at 
, these participants will receive a dose at 
 and their subsequent 
treatment interval will be 
. 
• HDq12: For participants 
 assigned to HDq12 at the beginning of the 
study, 
 according to individual participant 
response as determined by the E-DRM in Year 3. 
• HDq16: For participants 
 assigned to HDq16 at the beginning of the 
study, 
 according to individual participant 
response as determined by the E-DRM in Year 3. 
Study eye and fellow eye assignments will be kept the same in the extension period as in the 
core study. The study extension will start immediately after completion of the end of masked 
study visit at Week 96 for Year 2 and consists of a masked transition period of 12 weeks, 
during which study intervention will still be administered in a masked fashion, followed by an 
open-label treatment part with duration of 44 weeks, and an end of study visit 4 weeks after 
the last treatment at Week 156 for Year 3. During the masked transition period, from Week 96 
through Week 108, sham injections will be done at visits when an active injection is not 
planned. 
Thereafter, in the open-label part, no sham injections will be done. At any visit, participants 
will receive either active or no study treatment. All participants in the open-label part will 
have treatment visits according to their treatment schedule. At treatment visits, if E-DRM 
criteria are met, treatment intervals will be modified
 
. In addition, there will be mandatory monitoring visits for all participants at 
Weeks 
 to ensure that data collection occurs at least every 
weeks. If 
shortening criteria are met at any treatment, monitoring or unscheduled visit, the participant 
will be dosed at the same visit, unless the previous dose was administered less than 8 weeks 
before, and the subsequent treatment interval will be shortened to the time from the most 
recent dose 
. 
For each participant in the extension period, the total duration of participation in the whole 
study will be approximately 159 weeks, including the initial 3-week screening period, Year 1 
(48 weeks), Year 2 (48 weeks), and Year 3 (60 weeks). 
Data Monitoring Committee: Yes 
The independent data monitoring committee (DMC) oversight will continue through the last 
participant’s completion of the end of masked study visit (Week 96) and until completion of 
the masked transition period (Week 108). 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI






CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  15 of 109 
 
 
 
For masking purposes, DRM assessments will be performed in all participants at all visits (through the IXRS) starting from Week 16. 
a HDq12 group: If DRM criteria are met, participants will continue on q8 rescue regimen.  
b HDq16 group: If DRM criteria are met at Week 16 or 20, participant will continue on q8 rescue regimen. If DRM criteria are met at Week 24, participant will 
continue on q12 regimen. 
c For participants remaining on a dosing interval of q12 or q16 weeks after Week 24, if DRM criteria are met at an active injection visit, the next dosing 
interval will be reduced by 4 weeks (to a minimum of q8). 
d From Week 52, all participants in HD groups will be eligible for dose interval shortening (to a minimum of q8) or extension (by 4-week increments) 
according to pre-specified DRM criteria. If DRM criteria are met at an active injection visit, the next dosing interval will be changed by 4 weeks. 
e Decision on treatment interval shortening at 
. If E-DRM shortening criteria in Year 3 are met, interval will be shortened to 8 weeks and the 
participants will be dosed 
 at the same visit, and thus will not be dosed at 
. 
f 
 will be administered according to individual participant response as determined by the E-DRM in Year 3. 
g During the open-label part: 
 will be administered according to individual participant response as determined by the E-DRM in Year 3. Visit 
windows will be increased to 
 to allow 
 apart. Decision on treatment interval 
shortening can be done at any visit: If E-DRM shortening criteria in Year 3 are met, dosing should be done at the same visit. Decision on treatment interval 
extension can only be done at treatment visits. 
h Mandatory monitoring visits must be performed to ensure that data collection occurs at least every 12 weeks. They will be performed with or without 
treatment according to individual participant response as determined by the E-DRM in Year 3. 
 
This figure does not reflect all available dosing options, once a participant’s dose regimen is shortened or extended. 
X=active injection, o=sham procedure 
2q8=aflibercept 2 mg administered every 8 weeks until Week 92, after 3 initial injections at 4-week intervals. Participants who consent to continue in the 
extension period from Week 96 in Year 3 
 
according to individual participant response as determined by the E-DRM in Year 3. If the E-DRM criteria are met at Week 104, these participants will 
receive a dose at 
 and their subsequent treatment interval will be shortened to every 8 weeks. 
HDq12=high dose aflibercept 8 mg administered every 12 weeks until Week 92, after 3 initial injections at 4-week intervals. Participants who consent to 
continue in the extension period from Week 96 in Year 3 
 according to individual participant response as determined by the E-
DRM in Year 3. 
HDq16=high dose aflibercept 8 mg administered every 16 weeks until Week 92, after 3 initial injections at 4-week intervals. Participants who consent to 
continue in the extension period from Week 96 in Year 3 
 according to individual participant response as determined by the 
E-DRM in Year 3. 
1º=primary, 2º=secondary, DRM=dose regimen modification, E-DRM=dose regimen modification criteria for extension period, EOMS=end of masked 
study, HD=high dose, IXRS=Interactive Response System, q8=every 8 weeks, q12=every 12 weeks, q16=every 16 weeks, Wk=Week 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI








CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  19 of 109 
 
 
 
BCVA=best corrected visual acuity, DRM=dose regimen modification, ECG=electrocardiogram, ED=Early Discontinuation, EOMS=End of Masked Study, 
ETDRS=Early Treatment Diabetic Retinopathy Study, FA=fluorescein angiography, FP=fundus photography, ICF=informed consent form, 
ICGA=indocyanine green angiography, IOP=Intraocular pressure, NEI-VFQ-25=National Eye Institute Visual Functioning Questionnaire-25, 
OCT-A=optical coherence tomography angiography, PK=pharmacokinetics, SD-OCT=spectral domain optical coherence tomography, UPCR=urine 
protein:creatinine ratio, WOCBP=women of childbearing potential 
 
 






CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  22 of 109 
 
 
 
main study with a 96 week duration. 
d 
The optional genomic substudy ICF should be presented to participants at the screening visit and may be signed at any subsequent visit at which the 
participant chooses to participate after screening. The genomic DNA blood sample should be collected on Day 1/baseline (pre-injection) or at any time 
during the study, only from participants who consent to participate in the genomic substudy. Participants from China will not be enrolled in this optional 
substudy. 
e 
The optional FBR ICF should be presented to participants and signed at the screening visit. No additional blood sample is required – remaining blood 
samples (from e.g., PK or anti-drug antibody [ADA] sampling) may be used.  
f 
Inclusion/exclusion criteria will be evaluated at screening and baseline to confirm subject’s eligibility. The investigator is responsible for confirming that any 
changes between screening and baseline do not affect the participant’s eligibility. 
g 
Refer to Section 10.7 for study intervention injection guidelines. Following study intervention injection or sham procedure, participants will be observed for 
at least 30 minutes. 
h 
For masking purposes, assessments for dose regimen modification (DRM) will be performed in all participants at all visits starting from Week 16 through 
Week 92. At Week 96 no interval adjustments will be performed. Thereafter, E-DRM assessments will be performed in all participants at all individually 
scheduled visits (including treatment and mandatory monitoring visits) and unscheduled visits through Week 152. Actual DRMs and E-DRMs will be 
implemented as described in Section 6.6. 
i 
NEI-VFQ-25 to be administered in a quiet room by a masked study-related person trained to administer this type of questionnaire, preferably before other 
visit procedures are performed. 
j 
IOP will be measured at all study visits (bilateral). On days when study intervention is administered, IOP should be measured pre-injection (bilaterally) and 
approximately 30 to 60 minutes after administration of study intervention (study eye only). The exact timing is left to the discretion of the unmasked 
investigator. IOP will be measured using Goldmann applanation tonometry, rebound tonometry Icare, or Tonopen and the same method of measurement 
must be used in each participant throughout the study. For visits after Week 108, no distinction between masked and unmasked study teams (or tasks) 
will be made. 
k 
Slit lamp examination will be performed bilaterally. 
l 
Indirect ophthalmoscopy will be performed bilaterally at all visits. On days when study intervention is administered, it should also be performed as soon as 
possible, approximately 0 to 15 minutes after administration of study intervention (study eye only). The exact timing is left to the discretion of the 
unmasked investigator. If the indirect ophthalmoscopy cannot be performed immediately after injection, see Section 10.7.2.3. For visits after Week 108, no 
distinction between masked and unmasked study teams (or tasks) will be made. 
m The same SD-OCT/FA/FP imaging system used at screening and Day 1 must be used at all follow-up visits in each participant. Images will be taken in 
both eyes before dosing (active or sham injection). 
n 
Optional at all sites that have the relevant equipment. ICGA will be used to diagnose and characterize the polypoidal choroidal vascularization (PCV) 
subtype of nAMD. If ICGA cannot be performed at screening visit, it may be done at baseline visit.  
o 
OCT-A is optional at all sites that have the relevant equipment. If OCT-A cannot be performed at screening visit, it may be done at baseline visit. 
p 
Vital signs (temperature, blood pressure, heart rate) should be measured per the procedure outlined in the study manual. At Visit 5, only blood pressure 
and heart rate are required. Vital signs should be measured prior to injection and any blood sampling. When possible, timing of all blood pressure 
assessments should be within 2 hours of clock time of dosing on Day 1. Measurements will be taken pre-dose (active or sham injection). 
q 
All samples collected for laboratory assessments should be obtained prior to administration of fluorescein and/or indocyanine green, and prior to 
administration of study intervention. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  23 of 109 
 
 
 
r 
For women of childbearing potential, a negative serum 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. 
s 
Sparse PK sampling will be performed in all participants (optional for participants in China). Any PK sampling will be done prior to dosing if scheduled at 
the sampling time point.  
t 
Anti-drug antibody sample collection is optional for participants in China. 
u 
Treatment visits during the mandatory masked transition period (Week 96 to Week 108): 
2q8 group: For participants originally assigned to 2q8 at the beginning of the study, 
 
starting at Week 96; thereafter, 
 administered according to individual participant response as determined by E-DRM in Year 3. If 
the E-DRM criteria are met at Week 
 these participants will receive a dose at Week 
 and their subsequent treatment interval will be shortened to 
every 8 weeks. 
HDq12 and HDq16 groups: For participants originally assigned to HDq12 and HDq16 at the beginning of the study, 
 participants will 
 
 according to their individual participant response as determined by the E-DRM in Year 3.  
Visit E01 at Week 96: All participants from selected countries/sites will be asked for consent to continue in the 1-year extension period of the study starting 
at Week 96. For all other procedures scheduled for the first extension visit, every effort should be made to ensure that they are performed on the same 
date as the end of Year 2, Week 96 visit. In cases where this is not possible, the procedures for the first extension visit may be conducted up to 4 weeks 
after the date of the end of Year 2, Week 96 visit. The schedule for subsequent extension visits will be adjusted to start counting from the actual date 
when initial extension procedures were performed. 
Any visit scheduled for Week 110 will actually be combined with the visit at Week 108 by making use of the overlapping visit windows (i.e., no visits with 
2-week intervals will occur). 
v 
Treatment visits during the open-label part (to be modified 
): 
 will be administered open label according to individual 
participant response as determined by the E-DRM in Year 3. If E-DRM shortening criteria are met at any visit in Year 3, treatment interval shortening and 
dosing should be done at the same visit. Treatment intervals may not be adjusted to less than 8 weeks. Decision on treatment interval extension can only 
be done at treatment visits. 
w 
Mandatory monitoring visits: these must be performed to ensure that data collection occurs at least every 12 weeks. They will be performed with or without 
treatment. If E-DRM shortening criteria in Year 3 are met at a monitoring visit, dosing should be done at the same visit. Dosing visits should be scheduled 
as close to the planned dosing date as possible, but should be combined with mandatory visits when visit windows overlap. 
x 
ICF has to be signed before or at Visit 1 of the Extension Period. 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  24 of 109 
 
 
 
Table 1–4 
Schedule of Activities – Dense PK Substudy 
Visit 
Dose 
Assessment Day 
Assessment Time (h) 
PK Sample  
Heart Rate and Blood 
Pressurea 
Screening 2b 
 
-21 to -1 
±2h 
 
X 
Visit 2 
(Baseline) 
 
1 
Pre-dosec 
X (pre-injection) 
X 
X 
4c 
X 
 
 
8c 
X 
 
 
 
2 
±2hc 
X 
X 
 
3 
±2hc 
X 
X 
 
5 
±2hc 
X 
X 
 
8 
±2hc 
X 
X 
 
15 
±2hc 
X 
X 
 
22 
±2hc 
X 
X 
PK=pharmacokinetics 
Participants enrolled in the Dense PK Substudy will also have blood pressure and heart rate assessed at each visit within the substudy. 
a 
Timing of all blood pressure assessments must be within ±2 hours of the clock time of dosing on Day 1. Blood pressure assessments for participants in 
the Dense PK Substudy will be taken prior to blood sample collection using automated office blood pressure (AOBP) measurement with the Omron 
Model HEM 907XL (or comparable). Measures will be recorded in the electronic case report form (eCRF). Detailed instructions can be found in the 
study manual. 
b 
Additional blood pressure assessment between screening and baseline, to confirm eligibility for participants in the Dense PK Substudy. Screening 2 
may occur on the same day as the screening visit. 
c 
On Day 1, the 4 hour and 8 hour PK sampling is to be within ±30 minutes and ±2 hours, respectively, of the scheduled time. For subsequent days, PK 
sampling is to be performed within ±2 hours of the clock time of dosing on Day 1.  
 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  25 of 109 
 
 
 
2. 
Introduction 
2.1 
Study Rationale 
There remains an unmet medical need in the treatment of neovascular (wet) age-related 
macular degeneration (nAMD). Although many patients benefit from treatment with currently 
available anti-vascular endothelial growth factor (VEGF) agents, a sizable proportion of 
patients still need intravitreal (IVT) injections as frequently as every 4 to 8 weeks, specifically 
in the first year of treatment. A continued need for treatment in intervals as short as 4 to 
8 weeks poses significant treatment burden to patients, physicians, and to healthcare systems. 
In addition, long-term data in patients with nAMD suggest that visual benefits achieved in the 
first year of treatment may be lost if regular dosing is not maintained. In real-world settings, 
visual loss also occurs to patients being treated under a treat-and-extend regimen with 
inappropriate dosing interval extension strategy. In fact, in nAMD, lost vision may not be 
regained, even with increases of treatment frequency after the vision loss has occurred. 
Furthermore, dosing with an insufficient frequency may result in a patient’s vision 
deteriorating below certain visual thresholds that would preclude certain activities of daily 
living, e.g., driving a car or reading. 
EYLEA (also known as aflibercept 2 mg) is a VEGF antagonist approved as of 07 OCT 2019 
in over 109 countries for the treatment of nAMD at a dosage level of 2 mg (administered at a 
concentration of 40 mg/mL injected IVT) administered every 8 (q8) weeks. This study will 
investigate the efficacy and safety of a high dose (HD) aflibercept (8 mg; provided at a 
concentration of 
 mg/mL) with the intent of achieving non-inferior best corrected visual 
acuity (BCVA), while extending the dosing interval and potentially improving visual and/or 
anatomic outcomes for HD versus the currently approved aflibercept 2 mg dose regimen. The 
study will compare HD aflibercept administered every 12 (q12) or every 16 (q16) weeks, after 
3 initial injections at 4-week intervals (HDq12 and HDq16) versus aflibercept 2 mg 
administered q8 weeks (2q8), after 3 initial injections at 4-week intervals in participants with 
nAMD. 
In order to investigate the long-term efficacy and safety of HD aflibercept beyond 2 years of 
treatment, this study will be extended in an open-label part (after a masked transition period 
of 12 weeks) for approximately one additional year (60 weeks) in countries and sites selected 
by the sponsor. The reason for the masked transition period is to prevent study staff and 
participants from being able to determine the participant’s treatment assignment during the 
masked part of the study before data cleaning is completed for the masked part, preserving 
data quality for the Week 60 database lock and giving a time frame for data cleaning. During 
this third year of treatment, 
 participants who consent to continue in the study, 
 
, will be treated with 
. The 
treatment intervals for all groups will be adjusted according to individual participant response 
as determined by E-DRM criteria in Year 3. 
2.2 
Background 
Neovascular (wet) AMD 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. In 
elderly patients affected by nAMD, vision loss frequently has an even greater impact, as it 
substantially reduces the visual compensation of functional impairment by other age-related 
comorbidities, such as arthritis and osteoporosis. 
CCI
CCI
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  26 of 109 
 
 
 
IVT-administered anti-VEGF therapies like EYLEA (aflibercept) inhibit neovascular vessel 
growth and leakage in the retina, and they are currently the standard of care for patients with 
nAMD. 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 choroidal neovascularization (CNV). Although the globally 
approved IVT anti-VEGF therapies are efficacious and well tolerated, the need for IVT 
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. Despite the 
recent US Food and Drug Administration (FDA) approval of brolucizumab for q8 to q12 use 
following 3 initial monthly loading doses in nAMD, there is limited clinical experience with 
this drug and the proposed dosing regimen. 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. 
Increasing the concentration of aflibercept in the dosing solution allows a greater amount of 
drug to be delivered via IVT administration. To achieve an optimized IVT aflibercept 
injection, a HD formulation has been developed with an aflibercept concentration of 
 mg/mL, allowing a dose of 8 mg in an injection volume of 
 µL. Quadrupling the IVT 
dose to 8 mg is estimated to increase the duration of exposure relative to the 2 mg formulation 
(see Section 4.3). This increased exposure and putative prolonged duration of 
pharmacological action carries the potential to extend treatment intervals in the maintenance 
phase to
, which will provide meaningful additional benefit to patients with 
nAMD.  
High dose aflibercept offers the potential for a similar efficacy benefit compared to aflibercept 
2 mg, with a reduced number of IVT injections per time period. Extending the treatment 
interval to injections
 will reduce the burden on patients, physicians, 
and healthcare systems. In addition, higher aflibercept concentrations over a longer period of 
time may provide better visual outcomes and/or control of the anatomic features of nAMD. 
Refer to Section 4.2 for a discussion on the rationale for study design and Section 4.3 for dose 
justification. 
This study will investigate the safety and efficacy of HD aflibercept at treatment intervals of 
12 weeks or longer. 
2.3 
Benefit/Risk Assessment 
Aflibercept is marketed for the treatment of adult patients with several retinal diseases that are 
characterized by upregulation of VEGF, are related to pathological neovascularization 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.  
CCI
CCI
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  27 of 109 
 
 
 
Anticipated Benefits of HD Aflibercept 
High dose IVT aflibercept may provide improved patient benefit through: 
• Longer treatment intervals (every 12 weeks or longer for most patients after initial 
monthly dosing). 
• Potential for improved visual, functional and/or anatomic efficacy. 
• Lower injection-related risk over time. 
• Increased patient compliance due to reduced treatment burden on patients, 
caregivers, physicians, and healthcare systems. 
Participation in the extension period may provide benefits to participants 
 
, allowing extension of treatment intervals for these 
participants with the aforementioned advantages. Additionally, participants 
 
d, may benefit from continued treatment on HD aflibercept 
with potential for 
 of their treatment intervals. 
Risks and Risk Management of Treatment with HD Aflibercept 
The safety profile of HD aflibercept is expected to be similar to that of the currently approved 
regimen of IVT aflibercept, 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. Potential risks for aflibercept include 
embryofetotoxicity and the development of arterial thromboembolic events (ATEs). For a 
dedicated assessment and categorization, a masked Anti-Platelet Trialists’ Collaboration 
(APTC) adjudication committee will centrally evaluate all potential ATE reports in this study 
(see Section 9.5.1). 
Pharmacokinetic (PK) and clinical safety data of IVT aflibercept have indicated that the 
known potential risks from systemic administration of anti-VEGF treatments in oncology 
indications were not identified with local treatment with IVT aflibercept. Studies performed 
with intravenous (IV) administration of aflibercept demonstrated that increases in blood 
pressure were the earliest pharmacodynamic indicator of systemic effects. Estimated exposure 
margins for free aflibercept after an 8 mg IVT dose, derived from linear extrapolation of 
available PK data for IVT-administered 2 mg IVT aflibercept, suggest adequate safety 
margins will be observed and maintained.  
Nonclinical pharmacology evidence from the chronic DL-alpha-aminoadipic acid toxin 
induced leakage model in rabbits (1) and additional clinical extrapolation data collectively 
suggest that a higher dose of aflibercept could extend the dosing interval on average by 
approximately 
(see also Section 4.3) and thereby 
reduce the number of injections needed for successful treatment.  
In initial clinical trials, doses of up to 4 mg per eye in monthly intervals with injection 
volumes up to 100 µL and isolated cases of unintentional dosing with 8 mg per eye, which 
occurred in early studies of the development program of aflibercept 2 mg, were generally well 
tolerated in participants with nAMD. 
The recently completed Phase 2 proof-of-concept study, CANDELA, evaluated for the first 
time the efficacy and safety of the 8 mg aflibercept dose compared to the 2 mg dose for the 
treatment of nAMD. The study met the primary safety endpoint and no new safety signals 
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  28 of 109 
 
 
 
were seen through Week 44. Moreover, results favored aflibercept 8 mg in visual acuity, 
drying and other anatomical measures through Week 44 (2). 
Hence, with a safety profile expected to be consistent with aflibercept 2 mg, the overall 
risk/benefit profile for HD should be maintained or improved over the currently approved 
dose of aflibercept (EYLEA 2 mg). 
As risk minimization measures, participants and investigators will be informed about the 
anticipated safety profile of HD and exclusion criteria will be applied to account for potential 
safety concerns such as hypersensitivity, pregnancy, and uncontrolled hypertension. 
Overall Risk-Benefit Balance: 
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with HD aflibercept are justified by the anticipated 
benefits that may be afforded to participants 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 Investigator’s Brochure. 
3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To determine if treatment with 
aflibercept 8 mg (HD) at intervals 
of 12 or 16 weeks provides non-
inferior BCVA change compared 
to aflibercept 2 mg every 
8 weeks in participants with 
nAMD 
Primary Endpoint  
• 
Change from baseline in BCVA measured by the Early 
Treatment Diabetic Retinopathy Study (ETDRS) letter 
score at Week 48 
Secondary - Efficacy 
 
To determine the effect of HD 
versus 2 mg aflibercept on other 
visual and anatomic measures of 
response 
Key Secondary Efficacy Endpoints 
• 
Change from baseline in BCVA measured by the 
ETDRS letter score at Week 60 (for regulatory 
submissions to European Medicines 
Agency/Pharmaceuticals and Medical Devices Agency 
[EMA/PMDA] Analysis Plan only, see Section 9) 
• 
Proportion of participants with no intraretinal fluid (IRF) 
and no subretinal fluid (SRF) in central subfield at 
Week 16 
Additional Secondary Efficacy Endpoints 
• 
Proportion of participants gaining at least 15 letters in 
BCVA from baseline at Week 48 
• 
Proportion of participants achieving an ETDRS letter 
score of at least 69 (approximate 20/40 Snellen 
equivalent) at Week 48 
• 
Change in choroidal neovascularization (CNV) size 
from baseline to Week 48 
• 
Change in total lesion area from baseline to Week 48 
• 
Proportion of participants with no IRF and no SRF in 
the center subfield at Week 48  
• 
Change from baseline in central subfield retinal 
thickness (CST) at Week 48  
To assess the efficacy of HD 
compared to 2 mg aflibercept on 
vision-related quality of life 
• 
Change from baseline in National Eye Institute Visual 
Functioning Questionnaire-25 (NEI-VFQ-25) total 
score at Week 48 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  29 of 109 
 
 
 
Objectives 
Endpoints 
Secondary - Safety 
 
To evaluate the safety of 
aflibercept 
• 
Treatment-emergent adverse events (AEs) and 
serious AEs (SAEs) through Week 48, 60, 96, and 
through Week 156 
Secondary - Other 
 
To evaluate the 
pharmacokinetics (PK) and 
immunogenicity of aflibercept 
• 
Systemic exposure to aflibercept as assessed by 
plasma concentrations of free, adjusted bound and 
total aflibercept from baseline through Week 48 
• 
Assessment of immunogenicity to aflibercept through 
end of masked study (Week 96) 
Exploratory 
 
To determine the effect of HD 
versus 2 mg aflibercept on 
functional and anatomic 
measures of response as well as 
on vision-related quality of life 
• 
Change from baseline in BCVA measured by the 
ETDRS letter score at Week 96 and through 
Week 156 
• 
Change from baseline in BCVA averaged over the 
period from Week 36 to Week 48 and from Week 48 to 
Week 60 
• 
Proportion of participants gaining at least 15 letters in 
BCVA from baseline at Week 60, Week 96, and 
through Week 156 
• 
Proportion of participants achieving an ETDRS letter 
score of at least 69 (approximate 20/40 Snellen 
equivalent) at Week 60, Week 96, and through 
Week 156 
• 
Proportions of participants gaining and losing at least 5 
or at least 10 letters in BCVA from baseline at 
Week 48, Week 60, Week 96, and through Week 156 
• 
Proportion of participants losing at least 15 letters in 
BCVA from baseline at Week 48, Week 60, Week 96, 
and through Week 156 
• 
Change in CNV size from baseline to Week 60, 
Week 96, and through Week 156 
• 
Change in total lesion area from baseline to Week 60, 
Week 96, and through Week 156 
• 
Change from baseline in CST at Week 60, Week 96, 
and through Week 156 
• 
Proportion of participants with no IRF and no SRF in 
the center subfield at Week 96 and through Week 156 
• 
Proportion of participants without retinal fluid (total 
fluid, IRF, and/or SRF) and subretinal pigment 
epithelium fluid in center subfield at Week 48, 
Week 60, Week 96, and through Week 156 
• 
Time to fluid-free retina over 48 weeks, 60 weeks, 
96 weeks, and 156 weeks (total fluid, IRF, and/or SRF 
in the center subfield) 
• 
Proportion of participants with sustained fluid-free 
retina over 48 weeks, 60 weeks, 96 weeks, and 
through 156 weeks (total fluid, IRF, and/or SRF in the 
center subfield)  
• 
Change from baseline in NEI-VFQ-25 total score at 
Week 60, Week 96, and through Week 156 
• 
Proportion of participants without leakage on 
fluorescein angiography (FA) at Week 48, Week 60, 
Week 96, and through Week 156 
To evaluate the duration of effect 
of HD after 3 initial doses at 
• 
Proportion of participants with q16 or longer treatment 
interval through Week 48, Week 60, and Week 96 in 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  30 of 109 
 
 
 
Objectives 
Endpoints 
4-week intervals followed by 
dosing q12 or q16 
HDq16 group 
• 
Proportion of participants with q12 or longer treatment 
interval through Week 48, Week 60, and Week 96 in 
the HDq12 and HDq16 groups 
• 
Proportion of participants with q12 or longer treatment 
interval as the last treatment interval at Week 48, 
Week 60, and Week 96 in HDq12 and HDq16 groups, 
respectively 
• 
Proportion of participants with q12 or longer treatment 
interval during Year 3 in the HDq12 and HDq16 groups 
To evaluate the duration of effect 
of HD after switching from 
treatment with 2 mg 
• 
Proportion of participants extended to q12 or longer 
treatment intervals during Year 3 in 2q8 group 
• 
Proportion of participants with q12 or longer treatment 
interval as the last treatment interval at Week 156 in 
2q8 group 
Based on dense PK sampling, 
characterize the concentrations 
in plasma over time, and 
corresponding PK parameters 
for aflibercept  
• 
Concentrations of free, adjusted bound and total 
aflibercept over time, and PK parameters 
For all participants, explore the 
relationship between PK and 
selected systemic and ocular 
response variables 
• 
Relationship of free aflibercept concentrations and 
blood pressure 
• 
Dose and/or exposure-response analyses for select 
safety and efficacy endpoints, as appropriate. 
Other Pre-specified Objectives 
 
To study molecular drivers of 
nAMD or related diseases, 
clinical efficacy of aflibercept, 
and affected molecular pathways 
• 
Evaluation of clinical efficacy parameters by repertoire 
or frequency of genetic alterations (genomics 
substudy) 
• 
Treatment related changes in circulating biomarkers 
(future biomedical research [FBR]) 
 
4. 
Study Design 
4.1 
Overall Design 
This phase 3, multi-center, randomized, double-masked, active-controlled study will 
investigate the efficacy, safety, and tolerability of IVT administration of aflibercept 8 mg 
(HD) versus aflibercept 2 mg in participants with treatment-naïve nAMD. 
The masked part of the study (up to Week 96) consists of a screening/baseline period, a 
treatment period with duration of 92 weeks, and a last study visit at Week 96 for Year 2 (i.e., 
end of main study visit). The extension period of the study starts immediately after the last 
scheduled procedure at the end of the Week 96 study visit and consists of a transition period 
of 12 weeks, during which study intervention will still be administered in a masked fashion, 
an open-label treatment period with duration of 48 weeks, and an end of study visit at 
Week 156 for Year 3. 
No study intervention will be administered at the end of masked study visit at Week 96 for 
Year 2 for participants who do not consent to participate in the extension period part of the 
study in Year 3 and complete the study at that visit. In contrast, participants who consent to 
continue in the extension period in Year 3 will receive masked study intervention at that visit, 
which will be considered the first visit for Year 3. 
 
 
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  31 of 109 
 
 
 
. All participants will continue 
to receive masked study intervention during the transition period of 12 weeks (through 
Week 108). Thereafter, 
 participants who remain in the extension period of the study will 
receive 
t in an open-label fashion according to their individual dosing 
schedule. 
Approximately 960 eligible participants with nAMD will be randomly assigned to receive 
IVT injections of HD or 2 mg in a 1:1:1 ratio to 3 parallel treatment groups for 2 years: 
• 2q8: aflibercept 2 mg administered every 8 weeks until Week 92, after 3 initial 
injections at 4-week intervals. 
• HDq12: aflibercept 8 mg administered every 12 weeks until Week 92, after 3 
initial injections at 4-week intervals. Participants in this group can move to q8 
dosing regimen at Weeks 16 or 20 according to pre-specified criteria. 
• HDq16: aflibercept 8 mg administered every 16 weeks until Week 92, after 3 
initial injections at 4-week intervals. Participants in this group can move to q8 
dosing regimen at Weeks 16 or 20, or q12 dosing regimen at Week 24, according 
to pre-specified criteria. 
Upon approaching completion of the first 2 years, all participants from selected countries/sites 
will be asked for consent to continue in the 1-year extension period of the study starting at 
Week 96. For all other procedures scheduled for the first extension visit, every effort should 
be made to ensure that they are performed on the same date as the end of Year 2, Week 96 
visit. In cases where this is not possible, the procedures for the first extension visit may be 
conducted up to 4 weeks after the date of the end of Year 2, Week 96 visit. The schedule for 
subsequent extension visits will be adjusted to start counting from the actual date when initial 
extension procedures were performed. During this extension period, 
 participants – 
 according to 
individual participant response as determined by the E-DRM in Year 3. 
For initial randomization at the beginning of the study, participants will be stratified based on 
baseline BCVA and geographical region, to ensure balanced distribution of the treatment 
groups within each stratum. Only one eye can be treated within the study. In the masked study 
part, sham procedures will be done on visits when an active injection is not planned. No sham 
procedures will be done at the non-treatment visit at Week 12. At all subsequent visits up 
until Week 92, all participants will receive either active study treatment injection or sham 
procedure (for masking purposes), depending on their assigned treatment schedule and 
eligibility for dose regimen modification. Participants who consent to continue in the 
extension period of the study from Week 96 in Year 3 will continue to receive either active 
study treatment injection or sham procedure, depending on their assigned treatment schedule, 
for masking purposes during the transition period. The reason for this masked transition 
period is to prevent study staff and participants from being able to determine the participant’s 
treatment assignment before data cleaning is completed, preserving data quality for the 
Week 60 database lock, and giving a time frame for data cleaning. 
Starting at Week 52, all participants randomized to HDq12 or HDq16 will be eligible for 
adjustments of their treatment intervals (shortening or extension) based on pre-specified DRM 
criteria, with the dose interval adjustments (shortening or extension) becoming effective at or 
after Week 60 (after data collection for key secondary efficacy endpoint). All participants will 
be followed every 4 weeks through Week 96. After completion of the last scheduled 
procedure at the end of masked study visit at Week 96 for Year 2, all participants in the 2q8, 
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  32 of 109 
 
 
 
HDq12, and HDq16 groups who consent to continue in the extension period of the study will 
be eligible for DRM to be followed for the extension period in Year 3 (E-DRM criteria). 
During the open-label extension, no sham procedures will be done at any visit so that all 
participants will receive either active or no study treatment injection according to their 
individual treatment and visit schedule. All participants will have treatment visits according to 
their treatment schedule and eligibility for DRM, as well as mandatory monitoring visits at 
Weeks 
 and 
 to ensure synchronized observations, participant monitoring, 
and data capture at least once every
weeks. In the open-label part, the visit schedule will be 
individualized and dependent on the injection schedule in multiples of 
 visit schedule required during the masked part of the study. 
An analysis of data up to Week 48 (including the primary efficacy analysis) will take place 
once all participants have completed Week 48 (or prematurely discontinued). Another 
analysis of data up to Week 60 (including a confirmatory analysis at this timepoint for 
regulatory submissions to EMA and PMDA) will take place once all participants have 
completed Week 60 (or prematurely discontinued). Furthermore, an analysis of all data will 
be conducted after all participants have completed the study at Week 96 (or prematurely 
discontinued). In addition, exploratory analyses may be performed at earlier time points (after 
the completion of the confirmatory analyses at Week 48 and Week 60) as necessary, e.g. to 
address health authority requests and queries. A final exploratory analysis of all data will be 
conducted after all participants who continued the study beyond Week 96 have completed the 
study at Week 156 (or prematurely discontinued). In addition, exploratory analyses may be 
performed at earlier time points during the extension phase as necessary. Masking of the study 
site personnel will continue until the end of the masked transition period of the study (see 
Section 6.3.2). Masking/unmasking of the study team will be described in a blinding 
maintenance plan. 
The exact test sequence for confirmatory testing is outlined in Section 9.4 and will be 
described in detail in the study’s statistical analysis plan (SAP).  
Indocyanine green angiography (ICGA) will be used to diagnose and characterize the 
polypoidal choroidal vascularization (PCV) subtype of nAMD at sites that have the 
appropriate equipment. 
Safety will be assessed by ophthalmic examinations, vital signs (including heart rate, blood 
pressure and temperature), electrocardiogram (ECG), AEs, and laboratory assessments. All 
AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  
In all participants, blood samples for measurement of drug concentrations (for PK) will be 
obtained prior to the first treatment and at pre-specified time points throughout the course of 
the study (see Schedule of Activities [SoA] in Section 1.3). In addition, a deoxyribonucleic 
acid (DNA) blood sample will be collected from those who sign the informed consent form 
(ICF) for the optional genomic substudy.  
The study also includes a PK substudy, with dense PK blood sampling for systemic drug 
concentrations and PK assessments for approximately 12 Japanese participants from Japan 
sites and 12 non-Asian participants from Europe or US sites (distributed across all 3 treatment 
groups). All participants in the PK substudy will participate in the main study but will have 
extra visits as outlined in Table 1–4. Participants in the PK substudy will also be eligible to 
participate in the extension period. Blood pressure and heart rate measurements will also be 
taken in these participants at the same time points as for the PK sampling. 
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  33 of 109 
 
 
 
A total of 960 participants (320 per group) is planned to be enrolled in this study. Refer to 
Section 9.2 for justification of the sample size. A total of 660 participants (220 per group) are 
estimated to consent to continue in the study extension. 
For each participant, the total duration of participation in the double-masked study part (up to 
Week 96) will be approximately 99 weeks, including a 3-week screening period, Year 1 
(48 weeks), and Year 2 (48 weeks). For each participant in the extension period, the total 
duration of participation will be approximately 155 weeks, including the initial 3-week 
screening period, Year 1 (48 weeks), Year 2 (48 weeks), and Year 3 (60 weeks). 
Approximately 380 sites in approximately 36 countries in Europe, North America, Latin 
America, Australia, and Asia Pacific (including at least 10% of participants in Japan [n=96]) 
will participate in the masked part of the study. 
This study includes an independent DMC to monitor safety. A Steering Committee will be 
established to guide all aspects of the study. An adjudication committee will evaluate all 
potential ATEs. Refer to Section 9.5.1 for details. 
4.2 
Scientific Rationale for Study Design 
The general patient population included in this study is considered to be representative of the 
population under treatment in the clinic, while the eligibility criteria minimize population 
variability and maximize the potential to measure clinically meaningful outcomes relevant to 
the study. 
This study includes an active control group, rather than placebo/sham control. Aflibercept, 
administered according to a widely approved dose and regimen (2 mg, q8 weeks) is the active 
control, as this treatment regimen provides outcomes and an appropriate control for 
assessment of this HD regimen. 
This study uses a double-masked design, with sham procedures at visits where active study 
intervention is not scheduled, to prevent participant and investigator bias during assessment of 
the safety and effectiveness of treatment. 
The primary endpoint (change from baseline in BCVA measured by the ETDRS letter score at 
Week 48) was chosen as BCVA is a clinically relevant and well accepted measure of efficacy 
in clinical trials of patients with nAMD. For EMA and PMDA, confirmatory analysis at 
Week 60 will include the key secondary endpoint change from baseline in BCVA measured 
by the ETDRS letter score at Week 60. 
Anatomic measures of retinal thickness and retinal fluid are well-known markers of disease 
activity. These parameters are used by clinicians to determine treatment success and/or the 
timing of further re-treatment. These measures will be used as secondary endpoints in this 
phase 3 study to help to determine the degree to which HD can extend the dosing interval 
relative to aflibercept 2 mg. Additional endpoints are included to determine whether higher 
aflibercept concentrations over a longer period of time may also provide potential additional 
functional benefits to patients with nAMD. 
The extension period aims to further evaluate the efficacy and safety of 
. It 
will evaluate 
 
 
It will also allow evaluation of potential benefits experienced by participants 
 
. 
CCI
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  34 of 109 
 
 
 
4.3 
Justification for Dose 
Based on considerations of manufacturing capabilities, formulation, stability, and the 
likelihood of achieving a meaningful extension of the duration of effect, an 8 mg IVT dose 
was selected for evaluation in the present study.  
In a nonclinical rabbit model of chronic retinal neovascularization and vascular leak, 
dose-dependent duration of leak suppression was observed after single IVT doses equivalent 
of up to 8 mg in humans. Pharmacokinetic simulations of free aflibercept concentration-time 
profiles in human vitreous using a
 (assuming a vitreous humor 
volume of  mL and half-life of
) predicted that the concentration at the end of an 
-week dosing interval for a 2 mg IVT dose would be achieved 
later for an 8 mg IVT 
dose, suggesting a longer duration of pharmacological activity for this dose relative to 2 mg 
IVT dose. This increase in IVT exposure and duration of pharmacological effect is expected 
to allow clinical treatment intervals of 
. 
Clinical studies with intravenous aflibercept indicated that blood pressure increase was the 
earliest pharmacodynamic indicator of systemic effect. Two studies (PDY6655 and 
PDY6656) evaluated the effects of IV and subcutaneous aflibercept on blood pressure via 
24-hour ambulatory monitoring in healthy subjects. At the lowest IV dose tested in these 
studies (1 mg/kg; PDY6656), a maximal increase of about 5 mmHg in 24-hour mean change 
from baseline in systolic blood pressure occurred by Day 6 after a single dose, returning to 
baseline by about 30 days post-dose. Assuming
 PK and extrapolating maximum 
concentration (Cmax) and area under the curve to the last quantifiable concentration (AUClast) 
values (for both mean and maximum individual patient values) from 2 mg IVT, estimated free 
aflibercept systemic Cmax and AUClast for an 8 mg IVT dose are approximately 
 times 
and 
 times 
respectively, than the corresponding values associated with a 
1 mg/kg IV dose. Although systemic concentrations of free aflibercept at these IVT doses are 
appreciably lower than those required to saturate the target-mediated elimination pathway, 
. A 
threshold dose and/or concentration of free aflibercept associated with blood pressure increase 
has not yet been determined.  
In the early phase 1 and 2 clinical studies, 93 patients have been exposed to 4 mg of IVT 
aflibercept, with dosing for up to approximately 1 year and injection volumes up to 
 µL. 
Furthermore, 3 patients (4 injections) were erroneously treated with a  mg aflibercept dose 
instead of the intended dose of  mg VEGF Trap-Eye, in an injection volume of
 μL 
instead of the protocol-specified 50 μL in the phase 1 study VGFT-OD-0603. Adverse events 
reported in these patients were consistent with the adverse event profile observed for patients 
receiving EYLEA 2 mg. 
The target for the current development plan is to achieve at least similar efficacy to the 
current standard of care (EYLEA 2 mg) while allowing for a reduced frequency of treatment 
by increasing the dose. Building on the established safety profile of EYLEA 2 mg, the 8 mg 
IVT aflibercept may provide additional patient benefits through longer treatment intervals 
(12 weeks or 16 weeks after initial dosing at 4-week intervals), improved anatomical efficacy 
(better and/or more durable retinal drying), lower injection-related risk over time related to 
longer treatment intervals with need for fewer injections over time and increased patient 
compliance due to reduced treatment burden on patients, caregivers, physicians, and 
healthcare systems. Better patient compliance in practice is thought to translate to better 
visual outcomes due to maintaining an adequate injection frequency. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  35 of 109 
 
 
 
With the expectation of both a longer dosing interval, resulting in a lower annualized number 
of injections, similar safety profile, and relatively small increase in injection volume, the 8 mg 
dose was selected for evaluation in this study. Although the planned dose intervals in the HD 
groups are q12 and q16, DRM is allowed on an individual basis according to pre-specified 
criteria (see Section 6.6), tailoring the interval to the needs of the participant. 
4.4 
End of Study Definition 
A participant is considered to have completed the masked part of the study if he/she has 
completed all phases of the study up until and including the last scheduled procedure for 
Year 2 at the end of masked study visit at Week 96, as shown in the SoA in Table 1–2 
(Section 1.3). 
A participant is considered to have completed the extension period of study if he/she has 
completed all phases of the study including the last scheduled procedure at the end of study 
visit at Week 156, as shown in the SoA in Table 1–3 (Section 1.3). 
The end of the study as a whole is defined as the date of the last visit of the last participant in 
the study in all centers of 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. 
The participants’ eligibility to be included in the study in terms of optical coherence 
tomography (OCT) and fluorescein angiography (FA) will be confirmed by the central 
reading center before randomization. 
Re-screening is permitted under certain conditions (see Section 5.4). 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply at 
both screening and baseline: 
Age 
1. At least 50 years of age at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Active subfoveal CNV secondary to nAMD, including juxtafoveal lesions that affect 
the fovea as assessed in the study eye.  
3. Total area of CNV (including both classic and occult components) must comprise 
greater than 50% of the total lesion area in the study eye. 
4. BCVA ETDRS letter score of 78 to 24 (corresponding to a Snellen equivalent of 
approximately 20/32 to 20/320) in the study eye.  
5. Decrease in BCVA determined to be primarily the result of nAMD in the study eye. 
6. Presence of IRF and/or SRF affecting the central subfield of the study eye on OCT. 
The central subfield is defined as a circle with diameter 1 mm, centered on the fovea. 




CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  37 of 109 
 
 
 
5.1.1 
Additional Inclusion Criteria for the Extension Period 
All randomized participants that complete Week 96 are eligible for the extension period, as 
long as the following criteria apply: 
1. The participant provides signed informed consent to participate in the extension period 
as described in Section 10.1.3.1, and no treatment for nAMD has been given in the 
study eye outside of the randomized study treatment. 
2. At least one BCVA value and one central subfield retinal thickness (CST) value from 
measurements at one of the following visits: Visit 24 (Week 84), Visit 25 (Week 88) 
or Visit 26 (Week 92). 
3. Participant is enrolled at a site that participates in the extension period. 
5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply at either 
screening or baseline: 
Medical Conditions – Per Eye 
1. Causes of CNV other than nAMD in the study eye. 
2. Prior or concomitant conditions in the study eye: 
a. Subretinal hemorrhage that is at least 50% of the total lesion area, or if the blood 
under the fovea is 1 or more disc areas in size in the study eye.  
b. Scar or fibrosis making up more than 50% of the total lesion in the study eye.  
c. Scar, fibrosis, or atrophy involving the central subfield in the study eye.  
d. Presence of retinal pigment epithelial tears or rips involving the central subfield in 
the study eye.  
e. Total lesion size >12 disc areas (30.5 mm2, including blood, scars, and 
neovascularization) as assessed by FA in the study eye.  
f. Uncontrolled glaucoma (defined as IOP >25 mmHg despite treatment with anti-
glaucoma medication) in the study eye. 
g. History of idiopathic or autoimmune uveitis in the study eye.  
h. Vitreomacular traction or epiretinal membrane in the study eye evident on 
biomicroscopy or OCT that is thought to affect central vision.  
i. Any history of macular hole of stage 2 and above in the study eye. 
j. Structural damage to the center of the macula in the study eye that is likely to 
preclude improvement in BCVA following the resolution of retinal fluid including 
but not limited to, atrophy of the retinal pigment epithelium, subretinal fibrosis or 
scar or significant macular ischemia. 
k. History of, or likely future need of, filtration or tube shunt surgery on the study 
eye.  
l. Aphakia, or pseudophakia with absence of posterior capsule (unless it occurred as 
a result of a yttrium-aluminum-garnet [YAG] posterior capsulotomy performed 
more than 30 days before screening), in the study eye. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  38 of 109 
 
 
 
m. Myopia of a spherical equivalent of at least 8 diopters in the study eye prior to any 
refractive or cataract surgery.  
n. Significant media opacities, including cataract, that interfere with BCVA 
assessment, fundus photography or OCT imaging in the study eye. 
o. History of corneal transplant or corneal dystrophy in the study eye. 
p. History of irregular astigmatism or amblyopia with chronic limitation of BCVA in 
the study eye. 
Medical Conditions – Per Participant 
3. Prior or concomitant conditions: 
a. History or clinical evidence of diabetic retinopathy, diabetic macular edema, or 
any retinal vascular disease other than nAMD in either eye.  
b. Evidence of extraocular or periocular infection or inflammation (including 
infectious blepharitis, keratitis, scleritis, or conjunctivitis) in either eye at the time 
of screening/randomization. 
c. Any intraocular inflammation/infection in either eye within 12 weeks (84 days) of 
the screening visit. 
d. Only 1 functional eye, even if that eye was otherwise eligible for the study (e.g., 
BCVA of counting fingers or less in the eye with worse vision). 
e. Ocular conditions with poorer prognosis in the fellow eye. 
4. Uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic 
>95 mmHg).  
Participants may be treated with up to 3 agents known to have anti-hypertensive 
effects for arterial hypertension to achieve adequate blood pressure control. This limit 
applies to drugs that could be used to treat hypertension even if their primary 
indication in the participant was not for blood pressure control. Any recent changes in 
medications known to affect blood pressure need to be stable for 12 weeks prior to 
screening. 
5. History of cerebrovascular accident or myocardial infarction within 24 weeks 
(168 days) before the screening visit. 
6. Renal failure requiring dialysis, or renal transplant at screening or potentially during 
the study. 
7. Allergy or hypersensitivity to any of the compounds/excipients in the study 
interventions formulations. 
8. Presence of any contraindications indicated in the locally approved label for 
aflibercept. 
9. History of other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug, might affect interpretation of the 
results of the study, or renders the participant at high risk for treatment complications. 
10. Members of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the sponsor. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  39 of 109 
 
 
 
11. Pregnant or breastfeeding women. 
Prior Therapy  
12. Any prior or concomitant ocular (in the study eye) or systemic treatment (with an 
investigational or approved, anti-VEGF or other agent) or surgery for nAMD, except 
dietary supplements or vitamins.  
13. Prior treatment of the study eye with any of the following drugs (any route of 
ophthalmic administration) or procedures before baseline visit (Day 1): 
a. Anti-angiogenic drugs at any time including investigational therapy (e.g., with 
anti-angiopoietin/anti-VEGF bispecific monoclonal antibodies). 
b. Long-acting steroids, within 16 weeks (112 days) before the screening visit, or any 
treatment with IVT implant, gene therapy, or cell therapy at any time. 
c. Ocriplasmin (Jetrea®) at any time. 
d. Vitreoretinal surgery and/or including scleral buckling at any time. 
e. Any other intraocular surgery within 90 days before the screening visit. 
f. Panretinal laser photocoagulation or macular laser photocoagulation within 
90 days before the screening visit. 
g. YAG capsulotomy in the study eye within 30 days before the screening visit. 
14. Prior treatment of the fellow eye with any of the following: 
a. Investigational therapy (e.g., with anti-angiopoietin/anti-VEGF bispecific 
monoclonal antibodies) within 180 days before the screening visit. 
b. IVT implant, gene therapy, or cell therapy at any time. 
Prior treatment in the fellow eye with approved anti-VEGF therapy is allowed. Prior 
treatment in the fellow eye with bevacizumab (although not approved but a component 
of standard of care in some countries) is also allowed. 
Prior/Concurrent Clinical Study Experience 
15. Participation in other clinical trials requiring administration of investigational 
treatments (other than vitamins and minerals) at the time of screening, or within 
30 days or 5 half-lives of administration of the previous study intervention, whichever 
is longer. 
5.2.1 
Additional Exclusion Criteria for the Dense PK Substudy 
Participants who meet any of the following criteria will be not be eligible for the Dense PK 
Substudy: 
1. Prior treatment with IVT aflibercept in the fellow eye within 12 weeks (84 days) 
before the screening visit. 
2. Active CNV in the fellow eye requiring anti-VEGF treatment at the time of screening 
visit. 
3. Other IVT anti-VEGF treatment (ranibizumab, bevacizumab, brolucizumab, 
conbercept, pegaptanib sodium) in the fellow eye within 4 weeks (28 days) before the 
screening visit. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  40 of 109 
 
 
 
4. Systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg. 
5. Known cardiac arrhythmia, based on medical history and/or outcome of ECG at 
screening. 
6. Variation by more than 10% in the 3 pre-randomization blood pressure measures 
recorded at the screening visits and at randomization (see Table 1–4). 
7. Participants who, in the opinion of the investigator, are unlikely to have stable blood 
pressure over the course of the study (e.g., due to known or suspected non-compliance 
with medication). 
5.3 
Lifestyle Considerations 
No lifestyle restrictions are required during the study. 
5.4 
Screen Failures and Re-Screening 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, and eligibility criteria.  
Re-starting the defined set of screening procedures to enable a “screening failure” participant 
to re-screen at a later time point is not allowed, with the following exceptions: 
• The participant had successfully passed the screening procedures, but was not 
randomized and could not start subsequent treatment on schedule. 
• Initial screening occurred too early to fulfil the requirements for time intervals 
after specific therapeutic interventions specified in the exclusion criteria. 
• The in/exclusion criteria preventing the participant’s initial attempt to participate 
have been changed (via protocol amendment). 
• The reason for the screening failure (e.g., uncontrolled glaucoma or arterial 
hypertension) was subsequently resolved.  
 
Under any of the above exceptions, a participant may be re-screened once only. To be 
eligible, the re-screened participant must meet all inclusion criteria and none of the exclusion 
criteria at the re-screening visit. 
In any case, the investigator must ensure that the repeated screening procedures do not expose 
the participant to an unjustifiable health risk. Also, for re-screening, the participant must 
re-sign the ICF, even if it was not changed since the participant’s previous screening. 
Re-screened participants should be assigned the same participant number as for the initial 
screening. 
6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  41 of 109 
 
 
 
6.1 
Study Intervention(s) Administered 
Table 6–1 
Study Interventions 
Masked part of study (up to Week 96) 
Group Name 
HDq12, HDq16 
2q8 
Sham 
Intervention Name 
Aflibercept HD 
Aflibercept 2 mg 
Sham 
Type  
Drug 
Drug 
Not applicable 
Dose Formulation 
Solution in Vial 
Solution in Vial 
Not applicable 
Unit Dose Strength(s) 
 mg/mL  
40 mg/mL 
Not applicable 
Dosage Level(s) 
8 mg (
 µL)  
2 mg (50 µL)  
Not applicable 
Route of 
Administration 
IVT injection 
IVT injection 
Not applicable 
Use 
Experimental 
Active comparator 
Sham procedure 
Packaging and 
Labeling 
Study Intervention will 
be provided in sterile 
3 mL glass vials. Each 
vial will be labeled as 
required per country 
Study Intervention will 
be provided in sterile 
2 mL glass vials. Each 
vial will be labeled as 
required per country 
Empty kit 
2q8=aflibercept 2 mg administered every 8 weeks until Week 92, after 3 initial injections at 
4-week intervals. Participants who consent to continue in the extension period from Week 96 in 
Year 3 
 starting at Week 96; thereafter, 
 
 to individual participant response as determined by dose regimen 
modification criteria for extension period (E-DRM) in Year 3. If the E-DRM criteria are met at 
Week 
, these participants will receive a dose at Week 
 and their subsequent treatment 
interval will be shortened to every 8 weeks. 
HDq12=high dose aflibercept 8 mg administered every 12 weeks until Week 92, after 3 initial 
injections at 4-week intervals. Participants who consent to continue in the extension period from 
Week 96 in Year 3 receive 
 according to individual participant response as 
determined by the E-DRM in Year 3. 
HDq16=high dose aflibercept 8 mg administered every 16 weeks until Week 92, after 3 initial 
injections at 4-week intervals. Participants who consent to continue in the extension period from 
Week 96 in Year 3 receive 
 according to individual participant response as 
determined by the E-DRM in Year 3. 
HD=high dose, IVT=intravitreal 
a Only applicable during the masked transition period (Week 96 to Week 108). 
Each vial is for single use only. 
6.1.1 
Medical Devices 
Medical devices used in this study include both devices that help prepare and deliver the study 
intervention (study drug and comparator), as well as devices that are used to gather additional 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  42 of 109 
 
 
 
clinical data. These devices are CE marked (or FDA cleared) according to the regulatory 
requirements specific for the country where the study site is located. 
Sponsor provides an 18-gauge filter needle for use preparing the study medication in this 
study. Other medical devices (not manufactured by or for Bayer) to be used in this study to 
deliver the medication according to Table 6–1 include syringes and injection needles. 
Instructions for use of these medical devices are provided by the legal manufacturer of these 
devices. Deficiencies (including malfunctions, use error, and inadequate labelling) related to 
the filter needles, injection needles, and syringes 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. 
Additional devices (Omron Model HEM 907XL (or comparable), Goldmann applanation 
tonometry / rebound tonometry Icare / Tonopen, standard digital 12-Lead ECG, etc.) are used 
for gathering additional clinical data (measuring blood pressure, IOP, heart rate, etc.). 
Instructions for use of these medical device are provided by the legal manufacturer of these 
devices. Deficiencies related to these devices should be reported directly to the legal 
manufacturer of the deficient medical device.  
6.2 
Preparation/Handling/Storage/Accountability 
The investigator or designee must 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 participants enrolled 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 (study drug and comparator) will be supplied in kits that include the 
following: 
• Sterile study intervention in sealed glass vials (see Table 6–1)  
• Filter needle (18-gauge) 
Study intervention (study drug and comparator) 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 medication (study drug and 
comparator) 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. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  43 of 109 
 
 
 
Sham kits will assigned for visits requiring sham procedures. The sham kits are empty but 
should be handled same as a study intervention kit. 
Sham procedure will be given on visits when an active injection is not planned. No sham 
procedures will be given at the non-treatment visit at Week 12. Thereafter, all participants in 
the masked part of study and the masked transition period will receive either active study 
treatment or sham procedure (for masking purposes) following their assigned treatment group 
and eligibility for DRM. 
Details on the administration of aflibercept IVT injection, sham procedure, and post-injection 
procedures are provided in Section 10.7. 
After study intervention injection or sham procedure, participants will be observed for at least 
30 minutes. 
Dose modification procedures are detailed in Section 6.6. 
6.3 
Measures to Minimize Bias: Randomization and Masking 
6.3.1 
Intervention Assignment 
Participants will be randomly assigned in a 1:1:1 ratio to 1 of 3 parallel treatment groups as 
described in Section 4.1. Randomization will be stratified by geographic region (Japan vs. 
Rest of World), and baseline (Day 1) BCVA (<60 vs. ≥60), to ensure balanced distribution of 
the treatment groups within each stratum. 
Participants will be centrally assigned to randomized study intervention using an Interactive 
Response System (IXRS). 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 SoA (Section 1.3).  
6.3.2 
Masking 
6.3.2.1 
Masked Part (Screening to Week 96) and Masked Transition Period 
for Extension (Week 96 to Week 108) 
All study site personnel (except for those performing the unmasked roles as described below 
and in Table 6–2), must remain masked to treatment assignment of participants in order to 
ensure an unbiased assessment of visual acuity, safety, and ancillary study measures. Masking 
will continue until the end of the masked transition period of the study extension. Any visit 
scheduled for Week 110 will actually be combined with the visit at Week 108 by making use 
of the overlapping visit windows (i.e., 
). At the end 
of Week 108 visit, only the date of the next planned visit will be known. On the actual date of 
the visit subsequent to Week 108, the date of the immediate previous treatment will also be 
disclosed to allow accurate interval adjustment. Subsequently (after a participant reaches 
Visit E04, Week 108), only the BCVA examiners will remain masked throughout the study 
(i.e., with no access to the participant file, only to the BCVA file); all other tasks for that 
participant previously assigned to masked or unmasked teams can be performed by any study 
personnel. 
Masking/unmasking of the study team will be described in a blinding maintenance plan. 
An unmasked monitor will be responsible for unmasked site visits and will be unmasked to 
study treatment. Participants, all other study personnel, central reading center, and Steering 
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  44 of 109 
 
 
 
Committee members must remain masked to treatment assignment. A masked monitor will be 
responsible for the masked site visits. 
Site personnel must not change from unmasked to masked roles after the first participant is 
randomized at the site. Masked staff are allowed to change to unmasked role under 
exceptional circumstances, if approved by the sponsor. 
Active and sham treatments will be masked and will be administered by an unmasked 
investigator (or designee).  
Masked Roles 
The masked personnel are responsible to (i) assess AEs (except for the post-injection 
evaluation), (ii) perform the masked assessment of efficacy and safety, iii) assess if a 
participant has met pre-specified criteria for dose regimen shortening at Weeks 16, 20, and 24 
and for dose regimen shortening or extending at and after Week 52, (iv) report any medical 
device AEs/SAEs/device deficiencies relating to devices used for gathering clinical data (see 
Section 6.1.1).  
Depending on their function, masked personnel are also responsible for performing the 
masked assessments of visual acuity, ophthalmologic assessments, non-ophthalmologic 
assessments, and blood samples collection and laboratory assessments.  
Every effort will be made to ensure that the visual acuity examiner remains masked to 
treatment assignment in order to allow for an unbiased assessment of visual acuity. The visual 
acuity examiner should only perform the assigned task of visual acuity assessments and 
should make every effort to remain masked to participant’s previous letter score and study 
eye; another masked team member will document BCVA values in source and electronic case 
report form (eCRF). 
Unmasked Roles 
An unmasked investigator (or designee), separate from the masked personnel, will perform 
active injection / sham procedure (including rescue regimen), post-injection indirect 
ophthalmoscopy, and post-injection IOP assessment. The participant must remain unaware of 
the treatment assignment; thus, the study intervention and syringe must be covered and 
remain unidentifiable to the participant. The unmasked investigator will not have any role in 
the study beyond the i) receipt, tracking, preparation, destruction, and administration of study 
intervention, and ii) reporting any AEs relating to the injection procedure or medical device 
AEs/SAEs/device deficiencies relating to the filter needle, injection needle, or syringe, during 
the post-injection period until the next scheduled visit. An unmasked drug handler (e.g., 
pharmacist) may be assigned to handle receipt, storage, and preparation of active and sham 
kits. Unmasked personnel are also allowed to do screening/baseline procedures such as initial 
informed consent (reconsent must be undertaken by masked personnel). 
All individuals performing unmasked roles must be trained for maintenance of the masking 
measures required in the context of this study. 
An overview of the masked and unmasked site personnel is presented in Table 6–2. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  45 of 109 
 
 
 
Table 6–2: 
Masked and Unmasked Site Personnel  
Study Procedure 
Masked 
Study Staff a 
Unmasked 
Study Staff b 
Certification 
needed 
Study intervention: 
Study intervention (study drug) accountability 
 
X 
 
Injection-related procedures: 
IXRS access c 
X 
X 
 
(Pre-)injection procedures 
 
X 
 
IVT injection (active, sham) 
 
X 
 
Post-injection assessment (post-injection indirect 
ophthalmoscopy, and post-injection IOP) 
 
X 
 
AE reporting: 
AEs and device-related AEs/SAEs/deficiencies 
relating to filter needle, injection needle, or 
syringe during injection procedure and post-
injection assessment 
 
X 
 
All other AEs,  
device-related AEs/SAEs/ deficiencies for 
devices used for gathering clinical data 
X 
 
 
Ophthalmic assessment: 
BCVA examination 
BCVA recording in eCRF (different from BCVA 
examiner) 
X 
X 
 
X 
 
Full ophthalmic examination (IOP, slit lamp, 
indirect ophthalmoscopy) 
X 
 
 
FA, FP 
X 
 
X 
SD-OCT 
X 
 
X 
ICGA, if applicable 
X 
 
X 
OCT-A, if applicable 
X 
 
X 
NEI-VFQ-25 questionnaire 
X 
 
X 
Other procedures: 
Informed consent 
  X d  
  X d 
 
Demography, medical and ocular history 
  X d 
  X d 
 
Record concomitant medications / treatments / 
interventions e 
X 
 
 
Blood sampling (e.g., serum pregnancy test, 
immunogenicity, PK sampling)  
X 
 
 
Blood pressure measurement 
X 
 
 
Urine pregnancy test 
X 
 
 
AE=adverse event, BCVA=best corrected visual acuity, eCRF=electronic case report form, FA=fluorescein 
angiography, FP=fundus photography, ICGA=indocyanine green angiography, IOP=intraocular pressure, 
IVT=intravitreal, IXRS=Interactive Response System, NEI-VFQ-25=National Eye Institute Visual Functioning 
Questionnaire-25, OCT-A=optical coherence tomography angiography, PK=pharmacokinetic, SAE=serious 
adverse event, SD-OCT=spectral domain optical coherence tomography.  
a 
Includes masked investigator, masked study nurse/study coordinator, and study personnel for ocular 
assessments. 
b 
Includes, unmasked investigator administering active/sham study intervention and assessing post-injection 
ocular assessments, and drug handler/pharmacist dispensing active/sham study intervention. 
c 
For the purpose of treatment assignments/kit numbers, only the unmasked staff should have access to IXRS. 
Masked staff will have limited access to IXRS.  
d 
Masked or unmasked personnel are allowed to do screening/baseline procedures such as initial informed 
consent. Reconsent must be undertaken by masked personnel. 
e 
Except concomitant medications due to AE occurring during the injection or in the immediate post-injection 
period, which must be reported by unmasked investigator. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  46 of 109 
 
 
 
Masked study intervention kits coded with a medication numbering system will be used. In 
order to maintain the mask, lists linking these codes with product lot numbers will not be 
accessible to individuals involved in study conduct.  
In compliance with applicable regulations, in the event of a suspected unexpected serious 
adverse reactions (SUSAR) (see Section 8.3.4) related to the masked treatment, the 
participant’s treatment code will usually be unmasked before reporting to the health 
authorities, ethics committees and investigators (Section 10.3.4). 
Emergency Unmasking  
The IXRS will be programmed with mask-breaking instructions. In case of an emergency, the 
investigator has the responsibility for determining if unmasking of a participant’s intervention 
assignment is warranted. If the investigator is unavailable, and a treating physician not 
associated with the study requests emergency unmasking, the emergency unmasking requests 
are forwarded to the study specific emergency medical advice 24 hours/7 day service. 
Participant safety must always be the first consideration in making such a determination. If 
the investigator decides that unmasking is warranted, the investigator should make every 
effort to contact the sponsor or the sponsor representative prior to unmasking a participant’s 
intervention assignment unless this could delay emergency treatment of the participant. If a 
participant’s intervention assignment is unmasked, the sponsor must be notified within 
24 hours after breaking the mask. The date and reason that the mask was broken must be 
recorded in the source documentation and eCRF, as applicable. 
6.3.2.2 
Open-label Part (After Week 108 to Week 156) 
In the open-label part of the study,
 
according to their individual treatment schedule. The group assignment used during the 
masked part will not be disclosed. Sites are required to enter all available data from the 
masked part of the study before being able to see the treatment schedule for the open-label 
part. The BCVA examiner will remain masked to treatment received during the open-label 
part of the study. All other team members, as well as the study participants, will be aware of 
the treatment schedule starting from the first visit after Week
 
6.4 
Study Intervention Compliance 
Study intervention will be administered by a qualified ophthalmologist. Details of aflibercept 
injection will be recorded in the eCRF (e.g., time of injection, type of anesthesia, treatment 
site). 
6.5 
Concomitant Therapy 
6.5.1 
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.  
Participants 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.  
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  47 of 109 
 
 
 
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.  
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 participant is receiving at the time of enrollment or 
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 
If a pre-treatment concomitant medication is administered in the study eye before injection 
(e.g., antibiotic, topical anesthetic), it must be administered for sham procedures as well. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.2 
Fellow Eye Treatment 
Only 1 eye per participant may be enrolled in the study. If a participant’s fellow (non-study) 
eye requires anti-VEGF treatment during the participant’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 
participant. 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. Participants 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/aflibercept HD treatment), IVT injection-procedure, and other 
protocol-specified procedures.  
For participants enrolled in the Dense PK Substudy, if a participant’s fellow (non-study) eye 
requires anti-VEGF treatment prior to Week 12, PK sample(s) should be collected prior to 
administration of study intervention in the study eye and aflibercept (2 mg) in the fellow eye. 
6.6 
Dose Regimen Modification/Rescue Regimen 
For masking purposes, assessments for DRM will be performed in all participants at all visits 
(through the IXRS) starting from Week 16. Based on these assessments, participants in the 
HD groups may have their treatment intervals shortened or extended. The minimum interval 
between injections will be 8 weeks, which is considered a rescue regimen for participants 
randomized to HD aflibercept who are unable to tolerate a dosing interval greater than every 
8 weeks. Participants in the aflibercept 2 mg group will remain on fixed q8 dosing throughout 
the study until the end of masked study visit at Week 96 (i.e., will not have modifications of 
their treatment intervals regardless of the outcomes of the DRM assessments).  


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  48 of 109 
 
 
 
6.6.1 
Year 1: Baseline to Week 48 
Beginning at Week 16, participants in the HD groups will have the dosing interval shortened 
(at the visits described below) if BOTH the following DRM criteria are met: 
1. BCVA loss >5 letters from Week 12, AND 
2. >25 µm increase in central retinal thickness (CRT) from Week 12 OR new foveal 
hemorrhage OR new foveal neovascularization 
In case the Week 12 measurement is not available, the Week 8 measurement should be used 
instead. If both, Week 12 and Week 8 measurements are not available, the Week 4 
measurement should be used instead. 
If a participant in the HDq12 group or the HDq16 group meets both criteria at Week 16 or 
Week 20, the participant will be dosed with 8 mg aflibercept at that visit and will continue on 
rescue regimen (aflibercept 8 mg, every 8 weeks). If a participant in the HDq16 group who 
has not met the criteria at Week 16 or Week 20 meets both criteria at Week 24, the participant 
will be dosed with 8 mg aflibercept at that visit and will continue on q12 dosing.  
For participants whose interval was not shortened to q8 dosing at or before Week 24, the 
interval will be shortened if the DRM criteria are met at subsequent visits with active 
injection. Participants in the HDq12 group who meet the criteria will receive the planned dose 
at that visit and will then continue on rescue regimen (aflibercept 8 mg, every 8 weeks). 
Participants in the HDq16 group who meet these criteria will receive the planned dose at that 
visit and will then continue to be dosed every 12 weeks if they were on a 16-week interval, or 
switch to the rescue regimen (aflibercept 8 mg, every 8 weeks) if they were on a 12-week 
interval. Therefore, a participant randomized to HDq16 whose injection interval has been 
shortened to q12 will have their injection interval further shortened to q8 if these criteria are 
met at any subsequent assessment. 
6.6.2 
Year 2: Week 52 to Week 96 (End of Masked Part of Study) 
From Week 52 through the end of the masked part of study (Year 2), all participants in the 
HD groups will continue to have the interval shortened in 4-week intervals (to a minimum of 
q8) if the DRM criteria for shortening are met at visits with active injection, using the criteria 
described above for Year 1. 
In addition to shortening of the interval, all participants in the HD groups (including HD 
group participants whose interval was shortened during Year 1) may be eligible for interval 
extension (by 4-week increments) if the following DRM criteria are met at visits with active 
injection in Year 2: 
1. BCVA loss <5 letters from Week 12, AND 
2. No fluid at the central subfield on OCT, AND 
3. No new onset foveal hemorrhage or foveal neovascularization  
For participants who do not meet the criteria for shortening or extension of the interval, the 
dosing interval will be maintained.  
As in Year 1, all participants in all treatment groups (including the 2q8 group) will be 
evaluated against both DRM criteria at all visits through the IXRS for masking purposes. 
However, changes to dosing schedule will only be implemented as described above. No 
changes to the dosing schedule will be made to the 2q8 treatment group at any time. All 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  49 of 109 
 
 
 
anatomic criteria will be based on the site evaluations/OCT assessments, not on the reading 
center assessments. 
6.6.3 
Year 3 (Masked Transition Period and Open-label Extension Part): 
Week 96 to Week 156 (End of Study) / E-DRM Criteria 
The E-DRM criteria refer to new baseline (NB) which will be defined as the 
values 
). 
At Week 96, no interval adjustments will be performed for any group. 
Beginning at Week 
 all participants will have the dosing interval shortened if the 
following criteria are met at ANY visit (scheduled or unscheduled, with or without active 
injection): 
1. BCVA loss >5 letters from NB BCVA due to persistent or worsening AMD, 
AND 
2. Any of the following 
• >25 µm increase in CRT from NB CRT 
• new onset of foveal neovascularization 
• new foveal hemorrhage 
OR 
3. BCVA loss >10 letters NB due to worsening AMD 
If the E-DRM shortening criteria are met at any treatment, monitoring or unscheduled visit, 
the participant will be dosed at the same visit unless the previous dose was administered less 
than 8 weeks before. 
If the E-DRM criteria are met at a dosing visit the subsequent interval will be shortened by 
 weeks. If the E-DRM criteria are met at a non-dosing visit, the subsequent interval will be 
shortened to the time from the most recent dose minus  weeks. Participants can be seen for 
unscheduled visits at any time at the investigator’s discretion. Treatment intervals may not be 
adjusted to less than 8 weeks. Actual intervals may be slightly shorter due to the windows 
allowed for visits planned 8 weeks apart. 
Starting from Week 
, if a participant does not meet any of the E-DRM criteria but is 
deemed at high risk for vision loss, the participant should be brought back for evaluation 
within approximately 2 weeks. If E-DRM criteria are still not met, and the investigator feels 
there is high risk for irreversible disease progression, a dose can be given at that visit, and the 
subsequent interval will be shortened to the time from the most recent dose minus  weeks. 
The minimum dosing interval remains every 8 weeks (q8). 
Similarly to Year 2, all participants in all groups (including participants whose interval was 
shortened during Year 1, Year 2, or Year 3) are eligible for interval extension 
 to a 
 interval of 
 weeks, but in contrast to Year 2, intervals will now be modified by 
, if all of the following E-DRM criteria are met at visits 
with active injection: 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  50 of 109 
 
 
 
1. BCVA loss <5 letters from the NB, AND 
2. No fluid at the central subfield on OCT, AND 
3. No new onset foveal hemorrhage or foveal neovascularization  
For participants who do not meet the criteria for shortening or extension of the interval, the 
dosing interval will be maintained. 
For E-DRM adjustment purposes, similar to the masked study part, all anatomic criteria will 
be based on the local site evaluations/OCT assessments, not on the assessments of the central 
reading center. 
6.7 
Intervention After the End of the Study 
Intervention will not be supplied after the end of the study. Participants will not be restricted 
with regard to pursuing available approved treatments for nAMD. 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1 
Discontinuation of Study Intervention  
Study intervention (study drug or comparator) discontinuation can be triggered by the 
participant (or legally authorized representative) or by the treating investigator. 
Participants 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. 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for safety evaluation. See the SoA for data 
to be collected at the time of intervention discontinuation and follow-up and for any further 
evaluations that need to be completed. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
A participant 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, compliance, 
or administrative reasons. This is expected to be uncommon. 
Participants 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 nonocular) that, from the participant’s or the investigator’s view, is 
potent enough to require withdrawal from the study. The investigator must notify 
the sponsor immediately if a participant is withdrawn because of an AE/SAE.  
• At the discretion of the treating investigator. The development of conditions, 
which would have prevented a participant’s entry into the study according to the 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  51 of 109 
 
 
 
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 sponsor that termination is in the participant’s best 
medical interest or administrative decision for a reason other than an AE/SAE.  
• A female participant 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.  
Participants 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 participant must be withdrawn from the 
study. 
• Systemic anti-angiogenic agents were taken by the participant during the study.  
• If, in the investigator's opinion, continuation of the study would be harmful to the 
participant's well-being. 
• 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. 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 participant will be permanently discontinued both from the study intervention and from 
the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
Participants who withdraw from the study will not be replaced. 
7.3 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or 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 participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last known 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  52 of 109 
 
 
 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• Should the participant 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. Protocol waivers or 
exemptions are not allowed. Participants 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 participant 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 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) 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 time frame defined in the SoA. 
The maximum amount of blood collected from each participant over the duration of the study, 
including safety laboratory assessments, sparse PK, Dense PK Substudy, optional genomic 
substudy, and any extra assessments that may be required, will not exceed 120 mL. 
Additional repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.  
8.1 
Efficacy Assessments  
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 (BCVA) 
Visual function will be assessed using the ETDRS protocol (3) starting at 4 meters. 
Refraction is to be done at each visit.  


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  53 of 109 
 
 
 
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) and must remain masked to treatment 
assignment. For each participant, the same examiner must perform all assessments whenever 
possible. BCVA should be done before any other ocular procedures are performed. 
8.1.1.2 
Intraocular Pressure (IOP)  
IOP will be measured using Goldmann applanation tonometry, rebound tonometry Icare, or 
Tonopen and the same method of measurement must be used in each participant throughout 
the study.  
At all visits, IOP should be measured bilaterally by the masked investigator (or designee). 
On days when study intervention is administered, IOP should also be measured approximately 
30 to 60 minutes after administration of study intervention (study eye only) by the unmasked 
investigator (or designee). The exact timing is left to the discretion of the unmasked 
investigator. 
If multiple post-injection measurements are performed, the final measurement before the 
participant leaves should be documented in the eCRF. Any injection-related increase in IOP 
(and treatment) should be documented in a masked fashion. 
8.1.1.3 
Slit Lamp Examination 
The slit lamp examination will be performed according to local medical practice and 
applicable medical standards at the site. 
Participants’ 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 masked investigator, 
as specified in Table 6–2. 
8.1.1.4 
Indirect Ophthalmoscopy 
Indirect ophthalmoscopy will be performed according to local medical practice and applicable 
medical standards at the site.  
Participants’ posterior pole and peripheral retina will be examined by indirect 
ophthalmoscopy at each study visit pre-dose (bilateral) by the masked investigator and post-
dose (study eye) by the unmasked investigator, as specified in Table 6–2. Post-dose 
evaluation should be performed as soon as possible, approximately 0 to 15 minutes after 
injection. The exact timing is left to the discretion of the unmasked investigator. If the indirect 
ophthalmoscopy cannot be performed immediately after injection, see Section 10.7.2.3. 
8.1.1.5 
Fundus Photography (FP) and Fluorescein Angiography (FA) 
The anatomical state of the retinal vasculature of the study eye will be evaluated by FP and 
FA at visits specified in Table 6–2. The treating investigator may perform additional FA/FP at 
other times during the study based on his/her medical judgment and standard of care. 
Photographers must be masked to treatment assignment and must be certified by the reading 
center to ensure consistency and quality in image acquisition.  
FP and FA images will be read by the investigator for individual treatment decisions and sent 
to an independent reading center where images will be read by masked readers. The 
participants’ eligibility to participate in the study in terms of FA will be confirmed by the 
central reading center before randomization.  


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  54 of 109 
 
 
 
The same FA/FP imaging system used at screening and Day 1 must be used at all subsequent 
visits in each participant. Images will be taken in both eyes before dosing (active or sham 
injection). Detailed instructions can be found in the imaging manual. 
All FA and FP images will be archived electronically at the site as part of the source 
documentation.  
The study manual will further specify the acquisition and assessment for FA/FP during the 
study. 
8.1.1.6 
Spectral Domain Optical Coherence Tomography (SD-OCT) 
Retinal and lesion characteristics will be evaluated using SD-OCT. Technicians must be 
masked to treatment assignment and must be certified by the reading center to ensure 
consistency and quality in image acquisition and segmentation. 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 masked readers. The participants’ eligibility to take part in the 
study in terms of SD-OCT will be confirmed by the central reading center before 
randomization.  
The same SD-OCT imaging system used at screening and Day 1 must be used at all follow-up 
visits in each participant. Images will be taken in both eyes before dosing (active or sham 
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. 
8.1.1.7 
Indocyanine Green Angiography (ICGA) 
ICGA will be optional, performed at sites with the appropriate equipment. ICGA will be used 
to diagnose and characterize the PCV subtype of nAMD. Technicians must be masked to 
treatment assignment and must be certified by the reading center to ensure consistency and 
quality in image acquisition.  
The same imaging modality used at screening must be used at all follow-up visits in each 
participant. Images will be taken in both eyes before dosing (active or sham injection). 
All ICGAs 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 
ICGA during the study. 
8.1.1.8 
Optical Coherence Tomography Angiography (OCT-A) 
Optical coherence tomography angiography (OCT-A) will be optional, performed at sites with 
the relevant equipment. Technicians must be masked to treatment assignment and must be 
certified by the reading center to ensure consistency and quality in image acquisition.  
The same imaging modality used at screening must be used at all follow-up visits in each 
participant. Images will be taken in both eyes before dosing (active or sham injection). 
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. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  55 of 109 
 
 
 
8.1.2 
National Eye Institute Visual Functioning Questionnaire-25 
(NEI-VFQ-25) 
Vision-related quality of life (QoL) will be assessed using the NEI-VFQ-25 questionnaire (4) 
in the interviewer-administered format. It is a reliable and valid 25-item version of the 
51-item NEI-VFQ.  
The questionnaire will be presented in the local language and should be administered in a 
quiet room by a masked study-related person trained to administer this type of questionnaire, 
preferably before other visit procedures are performed.  
8.2 
Safety Assessments  
Planned time points 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 should be 
measured at Visit 1. The assessment will be based on the clinical judgment of the investigator 
and aim to evaluate the overall health of the participant.  
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, and before any blood draws, if applicable, per 
the procedure outlined in the study manual. When possible, timing of all blood pressure 
assessments should be within ±2 hours of clock time of dosing on Day 1.  
Where possible, blood pressure assessments will be taken using automated office blood 
pressure (AOBP) with the Omron Model HEM 907XL (or comparable). Measures will be 
recorded in the eCRF. Detailed instructions can be found in the study manual. 
Participants in the Dense PK Substudy will also have blood pressure and heart rate assessed at 
each visit within the substudy. These assessments must be within ±2 hours of the clock time 
of dosing on Day 1. 
Clinically significant abnormal findings will be reported as AEs in the eCRF. 
8.2.3 
Electrocardiograms 
A standard digital 12-lead ECG will be performed. Heart rate will be recorded from the 
ventricular rate and the PR, QRS, RR, and QT intervals will be recorded. The ECG strips or 
report will be retained with the source documentation.  
Electrocardiograms will be forwarded to a central reader. 
8.2.4 
Clinical Safety Laboratory Assessments 
See Section 10.2 for the list of clinical laboratory tests to be performed and to the SoA for the 
timing and frequency.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  56 of 109 
 
 
 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 4 weeks after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or the Medical Monitor.  
• If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.  
• All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA. 
• If laboratory values from non-protocol-specified laboratory assessments performed 
at the institution’s local laboratory require a change in participant management or 
are considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded in the eCRF. 
All samples collected for laboratory assessments should be obtained prior to administration of 
fluorescein and/or indocyanine green and prior to administration of study intervention. 
At visits at which FA or ICGA are performed, urinalysis samples must be collected before 
FA/ICGA to avoid false elevations in urine protein values. 
Laboratory (hematology, chemistry, and urinalysis) analyses will be performed and reviewed 
at screening (Visit 1). A sample is not needed if results from laboratory tests within 8 days 
prior to screening are available and there was no change in the clinical situation from the time 
of the sample to the screening visit. 
Additional samples, including blood samples for immunogenicity, may be collected at any 
time during the study as determined necessary by the investigator or required by local 
regulations. This might be true for participants receiving rescue regimen with aflibercept. 
8.3 
Adverse Events and Serious Adverse Events 
The definitions of an AE and SAE can be found in Section 10.3. The definitions of 
device-related safety events (adverse device effects [ADEs] and serious adverse device effects 
[SADEs]) can be found in Section 10.4. Device deficiencies are covered in Section 8.3.7. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’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 participant to discontinue the study intervention or the study 
(see Section 7). 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the moment when informed consent is obtained until the last 
follow-up visit at the time points specified in the SoA (Section 1.3). 
All AE will be collected from the moment when informed consent is obtained until the last 
follow-up visit at the time points specified in the SoA (Section 1.3). 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  57 of 109 
 
 
 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3. 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 AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant 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 AEs and SAEs 
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 10.3. 
For participants receiving fellow eye injections, AEs will also 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/aflibercept HD treatment), IVT 
injection-procedure, and other protocol-specified procedures. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in 
Section 10.3.  
8.3.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants 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 (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for SUSAR according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
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 Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  58 of 109 
 
 
 
8.3.5 
Pregnancy 
Details of all pregnancies in female participants or female partner of a male participant 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 should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.5. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
Outcome for all pregnancies should be reported to the sponsor. 
8.3.6 
Adverse Events of Special Interest  
No AEs of special interest are defined. 
8.3.7 
Medical Device Deficiencies 
Medical devices are being provided for use in this study as described in Section 6.1.1. In order 
to fulfil 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. 
Deficiencies should be reported by completing the product technical complaint (PTC) form 
and then sending PTC form via email ptc-imp@bayer.com. Included in this PTC reporting 
requirement are devices used to prepare the dose (filter needle / syringe) or deliver the dose 
(injection needle /syringe).  
Device deficiencies for all devices used for gathering additional clinical data (measuring 
blood pressure, IOP, heart rate, etc.) should be reported directly to the legal manufacturer of 
the medical device.  
The definition of a medical device deficiency can be found in Section 10.4. 
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.3 and Section 10.3 of the protocol.  
8.3.7.1 
Time Period for Detecting Medical Device Deficiencies 
Medical device incidents or malfunctions of the device that result in an incident will be 
detected, documented, and reported 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 participant has been 
discharged from the study, and such incident 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 participants, 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.  


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  59 of 109 
 
 
 
8.3.7.3 
Prompt Reporting of Medical Device Deficiencies to Sponsor 
For device deficiencies related to medical devices used to prepare, apply, or deliver the study 
medication: 
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 PTC 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 medical device deficiency reports. 
8.3.7.4 
Regulatory Reporting Requirements for Medical 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 fulfil 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. 
8.4 
Treatment of Overdose 
For this study, any administered dose of study intervention greater than 2 mg (for the 2q8 
group during the masked part of study up until Week 96) or greater than 8 mg (for the HDq12 
or HDq16 groups during the entire study; for the 2q8 group during the extension period of 
study from Week 96) 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: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis). 
4. 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 participant. 
8.5 
Pharmacokinetics 
Blood samples for analysis of systemic concentrations of aflibercept (bound and free) will be 
collected. Collection of PK samples for all participants (sparse schedule) will be optional in 
China. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  60 of 109 
 
 
 
A blood sample for plasma concentrations of aflibercept will be collected according to the 
time points in the SoA (Section 1.3). For participants in the Dense PK Substudy, blood 
samples will be collected as outlined in Table 1–4. 
Additional samples may be collected at any time during the study as determined necessary by 
the investigator or required by local regulations. PK (and anti-drug antibody [ADA]) samples 
may be collected in the event of an SAE. 
If the fellow eye needs to be treated with aflibercept on a day with PK sample collection, the 
PK sample should be collected first. 
To ensure accuracy of the PK analyses, it is critical to accurately record the exact date and 
time (24-hour clock) of all blood samples taken on the eCRF. 
Details about the collection, processing, storage and shipment of samples will be provided 
separately (e.g., sample handling sheets or laboratory manual). 
8.6 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. Blood pressure is considered 
under safety endpoints. 
8.7 
Genetics 
8.7.1 
Optional Genomic Substudy 
Optional participation in genomic substudy will be offered to all participants, except those in 
China, who will not be enrolled in this optional substudy. See Section 10.6 for details.  
8.8 
Future Biomedical Research 
Participation is optional. Participants who do not wish to participate in the FBR component of 
the study may still participate in the main study. Participants from China will not be enrolled 
in the optional FBR component of the study. 
No additional blood sample is required – analysis may be performed on remaining blood 
samples (from e.g., PK or ADA sampling).  
Samples will be banked in long-term storage. The unused PK samples will be stored for up to 
15 years after the final date of the database lock. The unused samples may be utilized for FBR 
of nAMD, related diseases or pathways blocked by study treatment, and any adverse reactions 
that may emerge. These samples may also be used for unrelated assay development and 
validation purposes. After 15 years, any residual samples will be destroyed.  
The results of these FBR analyses will not be presented in the clinical study report.  
8.9 
Biomarkers 
Not applicable.  
8.10 
Immunogenicity Assessments 
Antibodies to aflibercept will be evaluated in serum samples collected from all participants 
according to the SoA (Section 1.3). These samples will be tested by the sponsor or sponsor’s 
designee. Collection of ADA and neutralizing antibody (NAb) samples will be optional in 
China. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  61 of 109 
 
 
 
Serum samples will be screened for antibodies binding to aflibercept and the titer of 
confirmed positive samples will be reported. Other analyses may be performed to verify the 
stability of antibodies to aflibercept and/or further characterize the immunogenicity of 
aflibercept. 
The detection and characterization of antibodies to aflibercept will be performed using a 
validated assay method by or under the supervision of the sponsor. Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of the study 
intervention(s).  
Samples may be stored for a maximum of 15 years (or according to local regulations) 
following the last participant’s last visit for the study at a facility selected by the sponsor, to 
enable further analysis of immune responses to aflibercept. 
8.11 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.  
9. 
Statistical Considerations  
Due to differing requirements for the submission to regulatory authorities, 2 different testing 
strategies will be applied, which will be detailed in the SAP: a Global plan (G-SAP) and an 
EMA/PMDA plan (EP-SAP). This section provides the basis for these plans, which will be 
used to govern the detailed analysis of the study. The G-SAP plan will constitute the primary 
analysis for the study. The EP-SAP plan will be used for submission to the EMA/PMDA 
regulatory authorities. 
9.1 
Statistical Hypotheses 
The 2 primary hypotheses to be tested are the non-inferiority of HDq12 vs. 2q8 (control) and 
HDq16 vs. 2q8 (control) with respect to the primary endpoint of change from baseline in 
BCVA at Week 48. The non-inferiority margin is set at 4 letters for each of the primary 
hypotheses. 
Justification of the Non-inferiority Margin 
Previous studies with anti-VEGF therapies in other indications regarded a difference of 
5 letters as clinically relevant. For example, the CATT study in AMD, comparing 
ranibizumab and bevacizumab in a setting close to real life, used a non-inferiority margin of 
5 letters in the in BCVA (5). Recently, controlled phase 3 clinical trials studying AMD 
(HARBOR study (6) and HAWK and HARRIER (7)) were based on a reduced margin of 
4 letters.  
Null and Alternative Hypotheses 
The primary family of hypotheses (null vs. alternative) are stated as below. 
1. Change from baseline in BCVA at Week 48 (non-inferiority at a margin of 4 letters): 
H10: μ1 ≤ μ0 – 4 vs. H11: μ1 > μ0 – 4 (i.e., HDq12 vs. 2q8) 
H30: μ2 ≤ μ0 – 4 vs. H31: μ2 > μ0 – 4 (i.e., HDq16 vs. 2q8) 
where μ0, μ1, μ2 are the mean change from baseline in BCVA at Week 48 for 2q8, HDq12, 
and HDq16, respectively. In addition, the HDq12 and HDq16 treatment groups will be tested 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  62 of 109 
 
 
 
for non-inferiority or superiority against the control group of 2q8 with respect to the following 
key secondary endpoints. The hypotheses (null vs. alternative) are, respectively, stated as 
below: 
2. Only included in the EP-SAP for EMA and PMDA:  
Change from baseline in BCVA at Week 60 (non-inferiority at a margin of 4 letters)  
H20: μ1 ≤ μ0 – 4 vs. H21: μ1 > μ0 – 4 (i.e., HDq12 vs. 2q8) 
H40: μ2 ≤ μ0 – 4 vs. H41: μ2 > μ0 – 4 (i.e., HDq16 vs. 2q8) 
where μ0, μ1, μ2 are the mean change from baseline in BCVA at Week 60 for 2q8, 
HDq12, and HDq16, respectively.  
3. Proportion of participants with no IRF and no SRF in central subfield at Week 16 
(superiority)  
H50: p1 ≤ p0 vs. H51: p1 > p0 (i.e., pooled high dose vs. 2q8) 
where p0, p1 are the proportion of participants with no IRF and no SRF in central 
subfield at Week 16 for 2q8, and the pooled high dose groups (HDq12 and HDq16), 
respectively. HDq12 and HDq16 high dose groups have same dosing regimen up to 
Week 16. 
The HDq12 and HDq16 treatment groups will also be tested for superiority against the control 
group of 2q8 with respect to the change from baseline in BCVA at Week 48 (and Week 60, 
only for EP-SAP). 
4. Change from baseline in BCVA at Week 48 (superiority):  
H60: μ1 ≤ μ0 vs. H61: μ1 > μ0 (i.e., HDq12 vs. 2q8) 
H80: μ2 ≤ μ0 vs. H81: μ2 > μ0 (i.e., HDq16 vs. 2q8) 
where μ0, μ1, μ2 are the mean change from baseline in BCVA at Week 48 for 2q8, HDq12, 
and HDq16, respectively. 
5. Only included in the EP-SAP for EMA and PMDA:  
Change from baseline in BCVA at Week 60 (superiority)  
H70: μ1 ≤ μ0 vs. H71: μ1 > μ0 (i.e., HDq12 vs. 2q8) 
H90: μ2 ≤ μ0 vs. H91: μ2 > μ0 (i.e., HDq16 vs. 2q8) 
where μ0, μ1, μ2 are the mean change from baseline in BCVA at Week 60 for 2q8, HDq12, 
and HDq16, respectively. 
Control of Multiplicity 
The overall family-wise type 1 error will be controlled at 0.025 (one-sided tests) for testing 
the primary and key secondary endpoints. Adjustment for multiple comparisons in the 
primary and key secondary endpoints will be made with a hierarchical testing procedure (see 
Table 9–1). This approach allows the confirmatory testing of a hypothesis at the full alpha 
level of 0.025 after successful rejection of the hypotheses which are ranked higher in the 
hierarchy. Further details will be described in the SAP. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  63 of 109 
 
 
 
Table 9–1 
Testing Order of Hierarchical Testing Procedure in G-SAP and 
EP‑SAP 
G-SAP 
EP-SAP 
H10: non-inferiority of HDq12 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at 
Week 48” 
H10: non-inferiority of HDq12 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at 
Week 48” 
 
H20: non-inferiority of HDq12 vs. 2q8 in key 
secondary endpoint “Change from baseline in 
BCVA at Week 60” 
H30: non-inferiority of HDq16 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at 
Week 48” 
H30: non-inferiority of HDq16 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at 
Week 48” 
 
H40: non-inferiority of HDq16 vs. 2q8 in key 
secondary endpoint “Change from baseline in 
BCVA at Week 60” 
H50: superiority of pooled high dose vs. 2q8 in 
key secondary endpoint “Proportion of 
participants with no IRF and no SRF in central 
subfield at Week 16” 
H50: superiority of pooled high dose vs. 2q8 in 
key secondary endpoint “Proportion of 
participants with no IRF and no SRF in central 
subfield at Week 16” 
H60: superiority of HDq12 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at 
Week 48” 
H60: superiority of HDq12 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at 
Week 48” 
 
H70: superiority of HDq12 vs. 2q8 in key 
secondary endpoint “Change from baseline in 
BCVA at Week 60” 
H80: superiority of HDq16 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at 
Week 48” 
H80: superiority of HDq16 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at 
Week 48” 
 
H90: superiority of HDq16 vs. 2q8 in key 
secondary endpoint “Change from baseline in 
BCVA at Week 60” 
2q8=aflibercept 2 mg administered every 8 weeks, after 3 initial injections at 4-week intervals, 
BCVA=best corrected visual acuity, EMA=European Medicines Agency, EP-SAP=EMA/PMDA 
statistical analysis plan, G-SAP=global statistical analysis plan, HDq12=aflibercept 8 mg 
administered every 12 weeks, after 3 initial injections at 4-week intervals, HDq16=aflibercept 8 mg 
administered every 16 weeks, after 3 initial injections at 4-week intervals, IRF= intraretinal fluid, 
IVT=intravitreal, PMDA=Pharmaceuticals and Medical Devices Agency, SRF=subretinal fluid 
9.2 
Sample Size Determination  
The sample size calculation is based on the primary endpoint analysis, “change from baseline 
in BCVA in ETDRS letters to Week 48” in 2 comparisons to assess non-inferiority: HDq12 
versus 2q8, and HDq16 versus 2q8. 
The sample size has been calculated under the following assumptions: 
• The changes in BCVA letter score from baseline are normally distributed. 
• The true difference in the mean change in BCVA between HDq12 and 2q8, and 
between HDq16 and 2q8 is 0 letters. 
• The standard deviation of the residuals is 
(derived from the residuals of an 
analysis of covariance (ANCOVA) analysis of the 
studies). 
Under the hierarchical testing strategy, a sample size of 288 evaluable participants per group 
provides 94% power for rejecting the initial null hypothesis (HDq12 vs 2q8) for the primary 
endpoint assessing non-inferiority with a 1-sided t-test at significance level of 0.025. The 
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  64 of 109 
 
 
 
power to reject both primary null hypotheses (HDq12 vs 2q8 and HDq16 vs 2q8) is 88%. 
Under the prior testing strategy that was planned originally (before Protocol version 3.0, 
Global Amendment 2), a sample size of 288 evaluable participants per group provides 90% 
power for rejecting each of the null hypotheses for the primary endpoints assessing 
non‑inferiority (HDq12 vs 2q8 and HDq16 vs 2q8) with a 1-sided t-test at significance level 
of 1.25% (=2.5%/2 Bonferroni correction). 
Approximately 10% of the participants are assumed to drop out before Week 48 (time point of 
the primary endpoints). Therefore, approximately 320 participants are to be randomized in 
each group, leading to a total sample size of approximately 960 participants. 
Approximately 1600 participants will be screened to achieve 960 randomly assigned to study 
intervention and 864 evaluable participants for an estimated total of 288 evaluable 
participants per treatment group. 
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Justification of Japanese Sample Size 
Out of the total sample size of approximately 960 participants, at least 96 (10%) are to be 
enrolled in Japan in order to provide consistent results with a certain probability.  
For superiority trials, the PMDA guidance (8) proposes to determine the number of Japanese 
participants so that DJapan / Dall > π will occur with a probability of 80 % or higher, whereas 
Dall is the treatment difference in the entire study population across regions, and DJapan is the 
treatment difference within the Japanese sub-population. Furthermore, π = 0.5 is generally 
recommended.  
As the present study is a non-inferiority trial, this consistency criterion is adapted as follows: 
(DJapan + non-inferiority margin) / (Dall + non-inferiority margin) > π. 
With the sample size of at least 96 Japanese participants and π = 0.5:  
• the probability to show a consistent result in at least one of the 2 hypothesis tests 
for the primary endpoints assessing non-inferiority (HDq12 vs. 2q8 and HDq16 vs. 
2q8) is 81%.  
• the probability to show a consistent result in one particular hypothesis test for the 
primary endpoints is 71%.  
9.3 
Populations for Analyses 
The primary analysis is based on the estimand framework including the definition of the 
population which is of interest (see Section 9.4.1). The population of interest for the primary 
and key secondary endpoints is represented by the full analysis set (FAS). 
The following populations are defined: 
Population 
Description 
Full analysis set (FAS) 
All participants randomly assigned to study intervention and who 
received at least 1 dose of study intervention. 
Per protocol set (PPS) 
All participants in the FAS, who did not have an important 
deviation from the protocol affecting primary efficacy endpoint. 
Safety analysis set (SAF) 
All participants randomly assigned to study intervention and who 
received at least 1 dose of study intervention.  


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  65 of 109 
 
 
 
PK analysis set (PKS) 
The PK analysis population includes all participants who received 
any study intervention and who had a at least 1 non-missing result 
following the first dose of study intervention. Participants will be 
analyzed based on the actual treatment received. 
Immunogenicity analysis set 
The ADA analysis set includes all participants who received study 
intervention and had at least 1 non-missing result in the ADA 
assay following the first study dose.  
The NAb analysis set includes all participants who received any 
study intervention and who are negative in the ADA assay or with 
at least 1 non-missing result in the NAb assay [participants who 
are ADA negative are set to negative in the NAb analysis set]. 
Participants will be analyzed based on the actual treatment 
received. 
9.4 
Statistical Analyses 
The SAP for the masked part of the study (Years 1 and 2) will be finalized prior to unmasking 
and will include a more technical and detailed description of the statistical analyses described 
in this section (statistical analyses related to the study extension [Year 3] will present results 
split by initial treatment assignment, pooled groups and overall. The analysis is exploratory 
and details will be described in a SAP document). This section is a summary of the planned 
statistical analyses of the most important endpoints including primary and key secondary 
endpoints. 
9.4.1 
General Considerations 
The testing of the primary and key secondary endpoints is performed at an overall 
significance level of 2.5% for the one-sided tests. The confirmatory testing strategy for the 
primary and the key secondary endpoints is defined in Section 9.1. For descriptive purposes 
95% two-sided confidence intervals will be provided where applicable.  
More details (including any subgroup analyses) will be described in the SAP.  
9.4.2 
Primary Efficacy Endpoint 
The primary endpoint is the change in BCVA (as measured by ETDRS letter score) from 
baseline at Week 48.  
The primary analysis is based on the estimand concept. The estimand of primary interest will 
mainly be based on a hypothetical strategy. It describes the change from baseline for all 
participants that started treatment assuming all participants have stayed on treatment until 
Week 48. 
The estimand is specified through the following definitions of population, variable, treatment 
condition, intercurrent events, and population-level summary: 
Target population:  
Defined by the inclusion/exclusion criteria. 
Variable:  
Absolute change from baseline to Week 48 in BCVA. 
Treatment condition:  
HD aflibercept administered HDq12 with option for 
DRM/rescue regimen (Section 6.6), or HDq16 with option for 
DRM/rescue regimen (Section 6.6), versus aflibercept 2 mg 
administered 2q8. 
Intercurrent events:  
Premature discontinuation from treatment. Shortening/extension 
of the dosing interval (DRM/rescue regimen) will not be 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  66 of 109 
 
 
 
considered an intercurrent event but as part of the randomized 
treatment regimen. 
Population-level summary:  Difference in least squared (LS) change from baseline to 
Week 48 in BCVA between HDq12 and 2q8 (HDq16 and 2q8, 
respectively). 
The following 2 hypotheses will be tested in the primary analysis, to assess non-inferiority in 
the primary endpoint:  
• HDq12 is non-inferior to 2q8 regarding the mean change in BCVA from baseline 
to Week 48 using a non-inferiority margin of 4 letters. 
• HDq16 is non-inferior to 2q8 regarding the mean change in BCVA from baseline 
to Week 48 using a non-inferiority margin of 4 letters. 
For the analysis, a mixed model for repeated measurements (MMRM) will be used with 
baseline BCVA measurement as a covariate and treatment group and the stratification 
variables as fixed factors as well as terms for the interaction between baseline and the visit 
and for the interaction between treatment and visit. A Kenward-Roger approximation will be 
used for the denominator degrees of freedom. More details (including the handling of missing 
data as well as the missing at random assumption) will be described in the SAP. 
𝑌𝑖𝑗𝑘= 𝛽0 + 𝑥𝑖× 𝛽𝑏𝑎𝑠𝑒+ 𝛽𝑟𝑒𝑔
(𝑙) + 𝛽𝑏𝑎𝑠𝑒_𝑐𝑎𝑡
(𝑚)
+ 𝛽𝑡𝑟𝑒𝑎𝑡
(𝑘)
+ 𝛽𝑣𝑖𝑠𝑖𝑡
(𝑗) + 𝑥𝑖× 𝛽𝑏𝑎𝑠𝑒∗𝑣𝑖𝑠𝑖𝑡
(𝑗)
+ 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝑘,𝑗)
+ 𝜖𝑖𝑗𝑘 
with 
• 𝑌𝑖𝑗𝑘 being the change from baseline to visit j for the ith participant receiving 
treatment k 
• 𝛽0 being the intercept 
• 𝑥𝑖 being the baseline BCVA measurement of participant i 
• 𝛽𝑏𝑎𝑠𝑒 the fixed effect of the baseline BCVA measurement 
• 𝛽𝑟𝑒𝑔
(𝑙)  the fixed effect of region l 
• 𝛽𝑏𝑎𝑠𝑒_𝑐𝑎𝑡
(𝑚)
 the fixed effect of categorized baseline BCVA measurement m 
• 𝛽𝑡𝑟𝑒𝑎𝑡
(𝑘)  the fixed effect of treatment k 
• 𝛽𝑣𝑖𝑠𝑖𝑡
(𝑗)  the fixed effect of visit j 
• 𝛽𝑏𝑎𝑠𝑒∗𝑣𝑖𝑠𝑖𝑡
(𝑗)
 the interaction between baseline BCVA and visit j 
• 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝑘,𝑗)
 the interaction between treatment k and visit j 
• 𝜖𝑖𝑗𝑘 the residual error with 𝜖𝑖𝑗𝑘~𝑁(0, 𝜎𝑘
2) and 𝑐𝑜𝑟𝑟(𝜖𝑖𝑗𝑘,𝜖𝑖𝑗′𝑘) = 𝜌(𝑘)_{𝑗, 𝑗′}. 
In terms of the model parameters the population-level summary of the estimands (i.e., the 
treatment effect at Week 48) can then be expressed as 
[𝛽𝑡𝑟𝑒𝑎𝑡
(1)
+ 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(1,𝑤48)
] − [𝛽𝑡𝑟𝑒𝑎𝑡
(2)
+ 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(2,𝑤48)
]. 
In line with the definition of estimands (see above), the primary analysis will be performed on 
the FAS and participants will be analyzed within their original randomized group (regardless 
of any changes to dose interval). 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  67 of 109 
 
 
 
The analysis described above will be repeated on the PPS as supplementary analysis. 
Furthermore, the following 2 hypotheses will be tested (within the pre-defined testing 
strategy, see Section 9.1), using the MMRM described above, to assess superiority in the 
primary endpoint: 
• HDq12 is superior to 2q8 regarding the mean change in BCVA from baseline to 
Week 48. 
• HDq16 is superior to 2q8 regarding the mean change in BCVA from baseline to 
Week 48. 
To control the nominal family-wise type I error rate of 0.025, a hierarchical testing procedure 
will be applied that also includes the confirmatory testing of the key secondary endpoints (see 
Section 9.1) and the confirmatory testing of change from baseline in BCVA at Week 48 (and 
Week 60, only for EP-SAP) for superiority at the end of the confirmatory testing hierarchy. 
9.4.3 
Secondary Efficacy Endpoints 
Key Secondary Endpoints 
The key secondary endpoint “change from baseline to Week 60 in BCVA” will be analyzed 
with the same methodology as the primary endpoint under the EP-SAP only. The HDq12 and 
HDq16 treatment groups will be tested for non-inferiority and superiority against the control 
group of 2q8, according to the confirmatory testing strategy outlined in Section 9.1. 
The key secondary endpoint “the proportion of participants with no IRF and no SRF in central 
subfield at Week 16” will be analyzed by a Cochran-Mantel-Haenszel test stratified by 
geographic region (Japan vs. Rest of World) and baseline (Day 1) BCVA (<60 vs. ≥60). The 
pooled high dose groups (HDq12 and HDq16) will be tested for superiority against the control 
group of 2q8, according to the confirmatory testing strategy outlined in Section 9.1. 
Other Secondary Endpoints 
All other secondary efficacy endpoints will only be analyzed descriptively. Continuous 
variables will be analyzed by similar repeated measurement models as for the primary 
endpoint. Binary endpoints will be analyzed by Cochran-Mantel-Haenszel methodology.  
Two-sided 95% confidence intervals and p-values might be provided for descriptive purposes. 
Details will be provided in the SAP. 
9.4.4 
Secondary Safety Endpoints 
9.4.4.1 
Adverse Events 
Treatment-emergent AEs and SAEs will be summarized through Week 48, Week 60, 
Week 96, and through Week 156. 
Definitions 
Treatment-emergent AEs (TEAEs) are defined as AEs that occurred in the time frame from 
first injection to the last injection (active or sham) in the study plus 30 days. 
All AEs reported in this study will be coded using the currently available version of the 
MedDRA®. Coding will be to lowest level terms. 
The number and percentage of participants in the SAF with at least one TEAE (TESAE) will 
be summarized by System Organ Class (SOC) and Preferred Term (PT). 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  68 of 109 
 
 
 
9.4.4.2 
Immunogenicity Data  
Incidence of treatment-emergent ADA response will be provided by treatment groups, 
including characterization of the response with titers and NAb status.  
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on 
individual PK profiles evaluated. Assessment of impact of ADA and NAbs on safety and 
efficacy may be provided. 
9.4.5 
Other Safety Analyses 
All other safety variables will be analyzed in the SAF by descriptive methods. 
9.4.5.1 
Vital Signs 
Vital signs (temperature, heart rate, and blood pressure) will be summarized by baseline and 
change from baseline to each scheduled assessment time with descriptive statistics. 
9.4.5.2 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each 
scheduled assessment time with descriptive statistics. 
Number and percentage of participants with a potentially clinically significant value (PCSV) 
at any post-randomization time point will be summarized for each clinical laboratory test for 
all participants and separately for participants in whom the PCSV criterion was normal or 
missing at baseline.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may 
be used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
9.4.6 
Pharmacokinetics Endpoints 
Main Study: 
The concentrations of free, adjusted bound, and total aflibercept over time will be summarized 
by descriptive statistics for each treatment group. Concentrations may be further grouped by 
factors such as age, renal function, hepatic function, concomitant medications, body weight, 
ethnicity, etc. No formal statistical hypothesis testing will be performed.  
Dose and/or exposure-response analyses may be performed for select safety and efficacy 
endpoints, as appropriate. 
Dense PK Substudy: 
The PK parameters to be determined, if possible, after the first dose for free, adjusted bound, 
and total aflibercept may include, but are not limited to: 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  69 of 109 
 
 
 
• Cmax 
• Cmax/Dose 
• Time of Cmax (tmax) 
• Last time point (tlast) 
• Last concentration (Clast) 
• AUClast 
• Area under the curve from time zero to infinity (AUCinf) 
• AUCinf/Dose  
• Half-life (t1/2) 
• Trough concentration (Ctrough) 
After repeat dosing, PK parameters to be determined, if possible, may include, but are not 
limited to, Ctrough, time to reach steady-state, and accumulation ratio. PK parameters will be 
summarized by descriptive statistics by treatment group, and geographical region as 
appropriate.  
This descriptive statistical assessment may include the geometric means and ratios of the 
geometric means for selected PK parameters, as deemed appropriate. No formal statistical 
hypothesis testing will be performed. 
Relationship of free aflibercept concentrations and blood pressure will be explored for all 
participants (if data available). Dose and/or exposure-response analyses may be performed for 
select safety and efficacy endpoints, as appropriate. 
PK data may also be explored using a population PK approach and, in case, will be reported 
separately. 
9.4.7 
Other Analyses 
All exploratory endpoints will only be analyzed descriptively. Continuous variables will be 
analyzed by similar repeated measurement models as for the primary endpoint. Binary 
endpoints will be analyzed by Cochran-Mantel-Haenszel methodology.  
Two-sided 95% confidence intervals and p-values might be provided for descriptive purposes. 
Details will be provided in the SAP. 
9.5 
Interim Analyses 
No interim analyses are planned.  
An analysis of data up to Week 48 (including the primary efficacy analysis) will take place 
once all participants have completed Week 48 (or prematurely discontinued). Another 
analysis of data up to Week 60 (including a confirmatory analysis at this timepoint for 
regulatory submission to EMA and PMDA) will take place once all participants have 
completed Week 60 (or prematurely discontinued). Another analysis will be conducted after 
all participants have completed the masked part of study at Week 96 (or prematurely 
discontinued). In addition, exploratory analyses may be performed at earlier time points (after 
the completion of the confirmatory analyses at Week 48 and Week 60) as necessary, e.g. to 
address health authority requests and queries. A final exploratory analysis will be conducted 
after all participants who continued the study beyond Week 96 have completed the Week 156 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  70 of 109 
 
 
 
visit (or prematurely discontinued), and additional exploratory analyses may be performed at 
earlier time points during the extension phase as necessary. 
9.5.1 
Data Monitoring Committee (DMC) and Other Committees 
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. All 
members of the Steering Committee will be masked with regard to treatment assignments 
throughout the study. The composition of the committee, the functional roles, and 
responsibilities will be specified in its charter. 
Data Monitoring Committee 
An independent DMC will meet periodically to review the ongoing safety of participants in 
the study and to provide recommendations to continue or terminate the study depending upon 
these reviews. The operation of the DMC is governed by a charter that describes the group’s 
frequency of meeting, procedures (including but not limited to periodic safety monitoring), 
and requirements for reporting its observations to the sponsor. The DMC oversight will 
continue through the last participant’s completion of the end of masked study visit (Week 96) 
and until completion of the masked transition period (Week 108). 
During the course of the study, the Steering Committee and DMC will keep each other 
informed in order to assess all relevant safety information in a timely and efficient manner. 
Communications between Steering Committee and DMC will only include masked data. 
Anti-Platelet Trialists’ Collaboration (APTC) Adjudication Committee 
Potential ATEs will be evaluated by a masked adjudication committee according to criteria 
formerly applied and published by the APTC prior to database unmasking (Antithrombotic 
Trialists' Collaboration 1994, Antithrombotic Trialists' Collaboration 2002). ATEs as defined 
by the APTC criteria include nonfatal myocardial infarction, nonfatal ischemic stroke, 
nonfatal hemorrhagic stroke, or death resulting from vascular or unknown causes. The 
committee will include at least 2 cardiologists and the provision of data and activities of the 
committee will be governed by a charter. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  71 of 109 
 
 
 
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 laws and regulations. 
The protocol, protocol amendments, ICF, Investigator 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 participants. Any substantial modification of the protocol will be submitted to 
the competent authorities as substantial amendments for approval, in accordance with ICH 
Good Clinical Practice and national and international regulations. 
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 and 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 to the participant 
or his/her legally authorized representative and answer all questions regarding the study.  
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC 
or study center.  


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  72 of 109 
 
 
 
The medical record must include a statement that written informed consent was obtained 
before the participant 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. 
Participants 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 participant or the participant’s legally authorized 
representative. 
A new ICF is required if a participant is re-screened.  
A separate ICF will address the use of remaining samples for optional exploratory research. 
The investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate and 
may withdraw their consent at any time and for any reason during the storage period.  
10.1.3.1 
Informed Consent for Study Extension 
Participants who are asked and choose to remain in the study for a 1-year extension period 
after Week 96 are required to sign separate ICFs for the study extension period. 
10.1.4 
Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant 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 participant who will be required to give consent for their data to be used as 
described in the informed consent  
The participant 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 
Dissemination of Clinical Study Data 
Result summaries of Bayer’s sponsored clinical trials in drug development phases 2, 3, and 4 
and phase 1 studies in participants 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 
trials will be provided on the publicly funded website www.ClinicalTrials.gov and European 
Union (EU) Clinical Trials Register in line with the applicable regulations. 
Bayer commits to sharing upon request from qualified scientific and medical researchers 
participant-level clinical trial data, study-level clinical trial data, and protocols from clinical 
trials in participants for medicines and indications approved in the United States (US) and EU 
on or after 01 JAN 2014 as necessary for conducting legitimate research. 
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  73 of 109 
 
 
 
10.1.6 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or eCRF 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 electronically signing 
the eCRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
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 (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). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants 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.  
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.  
10.1.7 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
The site must implement processes to ensure availability of all required source 
documentation. A source document checklist (not part of this protocol) will be used at the site 
to identify the source data for key data points collected and the monitor will work with the site 
to complete this. It is the expectation of the sponsor that all data have source documentation 
available at the site.  
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 can be found in ICH GCP guidelines E6(R2) §1.51, 
1.52. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  74 of 109 
 
 
 
10.1.8 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The sponsor 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: 
• 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 recruitment of participants by the investigator 
• Discontinuation of further study intervention development 
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 participant 
and should assure appropriate participant therapy and/or follow-up. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  75 of 109 
 
 
 
10.2 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 10–1 will be performed by the central laboratory.  
Local laboratory results are only required in the event that central laboratory results are not 
available in time for either study intervention administration and/or response evaluation. If a 
local sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, and meet the criteria for an AE, such AEs must 
be recorded in the eCRF. 
Protocol-specific laboratory requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations. 
Table 10–1: Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count 
RBC count 
Hemoglobin 
Hematocrit 
RBC Indices 
 
WBC count  
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical 
Chemistry 
Sodium 
Potassium 
Chloride 
Carbon dioxide 
Calcium 
Creatinine 
Glucose (non-fasting) 
Albumin 
AST/SGOT 
ALT/SGPT 
Alkaline phosphatase 
Total and direct 
bilirubin 
Urea (or BUN) 
LDH 
Total protein, serum 
Total cholesterol 
Triglycerides 
LDL 
HDL 
Uric acid 
Creatinine 
CPK 
Routine 
Urinalysis 
• 
Specific gravity, color, clarity, crystals 
• 
pH, glucose (non-fasting), protein, blood, ketones, bilirubin, nitrite, 
leukocyte esterase by dipstick  
• 
WBC, RBC, hyaline and other casts, bacteria, epithelial cells, yeast 
• 
Creatinine 
• 
UPCR 
Other Screening 
Tests 
• 
Follicle stimulating hormone and estradiol (as needed in women of non-
childbearing potential only) 
• 
Highly sensitive serum hCG pregnancy test (as needed for WOCBP)a 
The results of each test must be entered into the eCRF. 
ALT=alanine aminotransferase, AST=aspartate aminotransferase, BUN=blood urea nitrogen, 
CPK=creatine phosphokinase, eCRF=electronic case report form, hCG=human chorionic 
gonadotropin, HDL=high density lipoprotein, LDH=lactate dehydrogenase, LDL=low density 
lipoprotein, RBC=red blood cell, SGOT=serum glutamic-oxaloacetic transaminase, SGPT=serum 
glutamic-pyruvic transaminase, UPCR=urine protein:creatinine ratio, WBC=white blood cell, 
WOCBP=women of childbearing potential 
a 
For WOCBP, a negative serum pregnancy test at screening is required for eligibility. 
Investigators must document their review of each laboratory safety report. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  76 of 109 
 
 
 
Laboratory/analyte results that could unmask the study will not be reported to investigative 
sites or other masked personnel until the study has been unmasked. However, no laboratory 
data are anticipated to cause unmasking. 
Pregnancy Testing 
For WOCBP, a negative serum 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. 






















CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  87 of 109 
 
 
 
10.4.7 
Medical Device AE, ADE, SAE, SADE Determination Flow Chart 
Note: Adverse event reporting for countries/regions other than the USA and EU must follow 
the regulatory and ethical requirements for that country. 
 
 
 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  88 of 109 
 
 
 
10.5 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information 
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 not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• 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), investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Post-menopausal female 
• 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. 
Contraception Guidance: 
Refer to Section 5.1, Inclusion Criteria, for details of contraception requirements for this 
study. 
 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  89 of 109 
 
 
 
Collection of Pregnancy Information: 
Male Participants With Partners Who Become Pregnant  
• The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study intervention. 
• 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 Participants Who Become Pregnant  
• The investigator will collect pregnancy information on any female participant 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 participant’s pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant 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) or still birth 
(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 8.3.4. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  90 of 109 
 
 
 
10.6 
Appendix 6: Genetics 
Genetic predisposition that might be associated with treatment response to aflibercept and/or 
disease progression will be investigated as a voluntary genomic substudy. 
• The participation in the genomic substudy is voluntary and has no influence on the 
participation in the main study.  
• A whole blood sample will be obtained from those participants, who have signed a 
separate ICF for genomic substudy. The sample may be used as source of germline 
DNA.  
• DNA sample will be utilized for genotyping of candidate genes suggested to play a 
role in retinal diseases and may include analysis of the entire genome for discovery 
of new variants. 
• Genomic analyses may include sequencing of the candidate genes and allele 
specific polymerase chain reaction (PCR) analyses, for example. The methods will 
be chosen according to current state of the art utilizing analytically validated 
assays.  
• Details on the collection and handling of samples will be provided in separate 
documents (e.g., sample handling sheets or laboratory manual), available at the 
Investigator Site File. 
• Results will be reported separately (e.g. in a biomarker evaluation report). 
 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  91 of 109 
 
 
 
10.7 
Appendix 7: Study Intervention Administration and Procedures 
10.7.1 
Preparation of Study Intervention 
Only designated unmasked individuals may prepare study intervention for administration. 
10.7.1.1 
Aflibercept HD and 2 mg  
Refer to Section 6.1 for details of study intervention presentation. 
The volume of injection will be 50 μL (0.05 mL) for the 2q8 group during the masked part of 
study through Week 96.  
The volume of injection will be
 μL 
 mL) for HDq12 and HDq16 groups during the 
 study;
 during the 
 period of the study from 
.  
The study intervention will be withdrawn using aseptic technique through an 18-gauge 
filtered needle attached to a 1-mL syringe. The needle will be discarded after withdrawal of 
the vial contents and shall not be used for IVT injection. The needle shall be replaced with a 
sterile 30-gauge needle for the IVT injection. The contents should be expelled until the 
plunger is aligned with the line that marks 0.05 mL (for 
 group during the 
part of 
study through Week 
) or 
 mL (for 
 and
 during the 
 study; 
and for the 
 
 during the 
 period of the study from Week 
) on the syringe. 
The plunger alignment should be double-checked for accuracy. 
Injections will follow the procedures described below. 
10.7.1.2 
Sham  
The sham procedure will use a syringe without a needle. No IVT or intraocular penetration 
will be performed and no drug will be administered intravitreally.  
For the sham procedure, the unmasked injector will ensure that all procedures besides the 
actual injection are identical to an intravitreal injection of study intervention and will take 
precaution to ensure that the participant remains masked during the procedure. 
10.7.2 
Injection Procedure 
The sequence of steps described below is recommended. This drug administration protocol is 
based upon recommendations from the Euretina Expert Consensus (9).  
Use of Topical Antibiotic Agents 
At the time of this study, the use of topical antibiotics as prophylaxis in intravitreal injections, 
both in the preparation and post-injection, varies considerably between different practices. 
There is no consensus on the use of topical antibiotics, the agent to be used, and the dose 
administered. Therefore, topical antibiotic prophylaxis is allowed in line with local practices 
and at the discretion of the investigator.  
10.7.2.1 
Preparation 
The investigator or designee will prepare the participant for the injection. 
Only designated unmasked individuals may administer study intervention. Individuals 
involved in performing participants’ assessments must remain masked to treatment 
assignment. 
1. Apply topical anesthetic. 
2. Apply povidone iodine to eyelid margins, eyelashes, and conjunctival surface. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  92 of 109 
 
 
 
3. Place 1 or 2 drops of 5% povidone iodine on the ocular surface at the intended injection 
site. 
4. Use sterilized forceps and calipers (speculum) to stabilize the globe and measure the 
injection site. 
5. Optional: Inject 0.5 mL of 2% xylocaine without epinephrine subconjunctivally at the 
intended injection site (the entry site of the needle for the intravitreal injection should be 
in the inferotemporal quadrant, 3.0 to 3.5 mm from the limbus in aphakic/pseudophakic 
participants, and 3.5 to 4.0 mm in the phakic participants). 
6. Drape. 
7. Apply additional drop of 5% povidone iodine to site of injection. 
10.7.2.2 
Study Intervention Administration 
Active Drug Procedure: 
1. Insert needle at marked injection point. 
2. Gently inject study intervention. 
3. As the needle is withdrawn, a sterile cotton tip applicator should be rolled over the entry 
site to minimize the risk of drug reflux. This should be held in place for a full 10 seconds. 
Sham Procedure: 
1. Prepare injection site as above. 
2. Use syringe without needle attached. 
3. Apply syringe hub to conjunctival surface, pressing gently to simulate force of actual 
injection. 
10.7.2.3 
Post-injection Procedures 
1. Indirect ophthalmoscopy in the study eye only as soon as possible, approximately 0 to 
15 minutes after injection. The exact timing is left to the discretion of the unmasked 
investigator. If the indirect ophthalmoscopy cannot be performed immediately after 
injection, the unmasked investigator needs to assess the visual function of the injected 
eye: light perception and ability to count fingers within 0 to 5 minutes after the injection. 
2. Measure IOP approximately 30 to 60 minutes after injection in the study eye only. The 
exact timing is left to the discretion of the unmasked investigator. 
Additional post-injection management procedures as recommended by the guidelines are as 
follows: 
3. Instruct the participant to self-administer 1-2 drops of a topical antibiotic to the injected 
eye, 3 times a day, for an additional 3 days. 
4. Post-injection reperfusion of the optic nerve: 
a. Visualize the optic nerve to verify reperfusion of the central retinal artery in the 
immediate post-injection period. 
b. Verify IVT location of therapeutic agent when possible. 
c. Verify that the retina is attached and that there is no new intraocular hemorrhage. 
5. Intraocular pressure: 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  93 of 109 
 
 
 
IOP may be lowered by pharmaceutical or surgical intervention, if required. If a Tonopen 
is used to check pressure, a clean Tonopen condom should be placed on the tip before 
taking each measurement. If an Icare tonometer is used, a clean probe should be used. If 
applanation tonometry is used, a disposable prism should be used or, in case this is not 
available, the non-disposable prism should be disinfected (e.g., swabbing tip with alcohol 
and allowing to dry before using it to measure IOP). 
a. Monitor IOP for at least 30 minutes after each injection. The exact timing is left to the 
discretion of the unmasked investigator. 
b. Check IOP while maintaining a clean field. 
c. Monitor IOP closely until it reaches a value that will not be expected to cause damage, 
e.g., below 25 mm Hg. 
d. Treatment should be initiated whenever IOP is increased to the extent that the central 
retinal artery remains closed and the participant has no light perception for more than 
1 to 2 minutes. 
e. Transient graying or obscuration of vision following injection is expected and should 
not be treated. 
f. Paracentesis should be used only in extreme circumstances when the degree of 
pressure elevation poses an imminent and irreversible threat to vision. In the rare 
situation when a paracentesis is warranted, IOP should be recorded both before and 
after the procedure. A 0.1- to 0.2-mL paracentesis may be performed at the temporal 
limbus using a 27- or 30-gauge needle or surgical knife, if judged to be necessary by 
the investigator. 
g. Record the last IOP measurement and related treatments in the source document and 
on the appropriate eCRF page. 
10.7.2.4 
Discharge 
No special precautions are required before discharge of a participant who has had an 
uneventful recovery from IVT injection, but participants and/or caregivers should be educated 
to avoid rubbing the eye and to recognize the signs and symptoms of endophthalmitis, retinal 
detachment, or intraocular hemorrhage. These signs and symptoms include eye pain or 
increased discomfort, increased redness of the eye (compared to immediately after injection), 
blurred or decreased vision, and increased ocular sensitivity to light. 
Participants should be informed that some blurring of vision is common after an injection, 
which is often described as seeing spots floating in the eye. Floaters usually resolve after a 
few days or weeks. 
Participants who experience AEs after injection that require additional monitoring should 
remain in the clinic until the condition is resolved, and should be treated according to the 
investigator’s medical judgment. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  94 of 109 
 
 
 
10.8 
Appendix 8: Abbreviations 
2q8 
aflibercept 2 mg administered every 8 weeks, after 3 initial injections at 
4-week intervals 
ADA 
anti-drug antibody(ies) 
ADE 
adverse device effect 
AE 
adverse event 
AMD 
age-related macular degeneration 
ANCOVA 
analysis of covariance 
AOBP 
automated office blood pressure 
APTC 
Anti-Platelet Trialists’ Collaboration 
ATE 
arterial thromboembolic events 
AUClast 
area under the curve to the last quantifiable concentration 
AUCinf 
area under the curve from time zero to infinity 
BCVA 
best corrected visual acuity 
Cmax 
maximum concentration 
CNV 
choroidal neovascularization 
CRF 
(paper) case report form 
CRT 
central retinal thickness 
CST 
central subfield retinal thickness 
Ctrough 
trough concentration 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DRM 
dose regimen modification 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
E-DRM 
dose regimen modification criteria for the extension period 
EMA 
European Medicines Agency 
EOS 
end of study 
EP-SAP 
EMA/PMDA statistical analysis plan 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EU 
European Union 
FA 
fluorescein angiography 
FAS 
full analysis set 
FBR 
future biomedical research 
FDA 
Food and Drug Administration 
FP 
fundus photography 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
G-SAP 
Global statistical analysis plan 
HD 
high dose (aflibercept) 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  95 of 109 
 
 
 
HDq12 
high dose aflibercept 8 mg administered every 12 weeks, after 3 initial 
injections at 4-week intervals 
HDq16 
high dose aflibercept 8 mg administered every 16 weeks, after 3 initial 
injections at 4-week intervals 
HRT 
hormonal replacement therapy 
ICF 
informed consent form 
ICGA 
indocyanine green angiography 
IEC 
Independent Ethics Committee 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IRF 
intraretinal fluid 
IUD 
intrauterine device 
IUS 
intrauterine hormone releasing system 
IV 
intravenous 
IVT 
intravitreal  
IXRS 
Interactive Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measurements 
NAb 
neutralizing antibody(ies) 
nAMD 
neovascular (wet) age-related macular degeneration 
NB 
new baseline 
NEI-VFQ-25 
National Eye Institute Visual Functioning Questionnaire-25 
OCT 
optical coherence tomography 
OCT-A 
optical coherence tomography angiography 
PCSV 
potentially clinically significant value 
PCV 
polypoidal choroidal vascularization 
PK 
pharmacokinetics 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPS 
per protocol set 
PTC 
product technical complaint 
q8 
every 8 weeks 
q12 
every 12 weeks 
q16 
every 16 weeks 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SD-OCT 
spectral domain optical coherence tomography 
SoA 
Schedule of Activities 
SRF 
subretinal fluid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  96 of 109 
 
 
 
TEAE 
treatment-emergent adverse event 
UPCR 
urine protein:creatinine ratio 
USADE 
unexpected serious adverse device effect 
VEGF 
vascular endothelial growth factor 
WOCBP 
women of childbearing potential 
YAG 
yttrium-aluminum-garnet 
 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  97 of 109 
 
 
 
10.9 
Appendix 9: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment 3 (13 SEP 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to investigate the long-term efficacy and safety of 
HD aflibercept beyond 2 years of treatment. Therefore, the study will be extended in an 
open-label part (after a masked transition period of 12 weeks) for approximately one 
additional year (60 weeks) in countries and sites selected by the sponsor. During this third 
year of treatment, 
 participants who consent to continue in the study, 
 those 
 assigned to the 
 
, will be treated with 
 The treatment 
intervals for all groups will be adjusted according to individual participant response as 
determined by dose regimen modification criteria for the extension period (E-DRM) in 
Year 3. 
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  98 of 109 
 
 
 
Section # 
and Name 
Description of 
Change 
Brief Rationale 
1.1 Synopsis 
1.2 Schema 
Figure 1-1, Figure 1-2 
1.3 Schedule of Activities (SoA) 
Table 1-3 
2.1 Study Rationale 
2.3 Benefit/Risk Assessment 
3. Objectives and Endpoints 
4.1 Overall Design 
4.2 Scientific Rationale for Study Design 
4.4 End of Study Definition 
5.1.1 Additional Inclusion Criteria for the 
Extension Period 
6.1 Study Intervention(s) Administered 
Table 6–1 Study Interventions 
6.2 Preparation/Handling/Storage/Accountability 
6.3.2.1 Masked Part (Screening to Week 96) 
and Masked Transition Period for Extension 
(Week 96 to Week 108) 
6.3.2.2 Open-label Part (After Week 108 to 
Week 156) 
6.6 Dose Regimen Modification/Rescue 
Regimen 
6.6.2 Year 2: Week 52 to Week 96 (End of 
Masked Part of Study) 
6.6.3 Year 3 (Masked Transition Period and 
Open-label Extension Part): Week 96 to 
Week 156 (End of Study) / E-DRM Criteria 
8.4 Treatment of Overdose 
9.4 Statistical Analyses 
9.4.4.1 Adverse Events 
9.5 Interim Analyses 
9.5.1 Data Monitoring Committee (DMC) and 
Other Committees 
10.1.3.1 Informed Consent for Study Extension 
10.7.1.1 Aflibercept HD and 2 mg 
10.8 Appendix 8: Abbreviations 
Added or updated 
language to describe 
the extension period of 
the study throughout 
the document 
To update or add the 
sections needed to 
accommodate the 
additional language 
required to 
implement an 
extension period into 
the study. 
Throughout 
Minor editorial 
changes for 
consistency of the 
updates described 
above, company 
template updates, 
spelling, and 
document formatting. 
Minor, therefore have 
not been 
summarized. 
E-DRM=dose regimen modification criteria for extension period 
 
Amendment 2 (26 APR 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  99 of 109 
 
 
 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to simplify and extend the confirmatory testing 
hierarchy: 
1. To remove the initial Bonferroni-based split of the overall significance level (which 
had been introduced originally to allow simultaneous testing of the 2 hypotheses 
(HDq12 vs. 2q8 and HDq16 vs. 2q8) of the primary endpoint at a significance level of 
0.0125 [one-sided] each) and to assign the full significance level of 0.025 (one-sided) 
to the first hypothesis (HDq12 vs. 2q8). 
The reason for this change is to adjust the testing sequence to the perceived clinical 
probability of success, i.e., since HDq12 is more likely to succeed than HDq16 (due to 
the higher dosing frequency after the loading phase). 
2. To remove the subsequent splitting of the remaining alpha levels between 
2 hypotheses and replace it by a simpler hierarchical testing procedure in both the 
global statistical analysis plan (G-SAP) and the European Medicines 
Agency/Pharmaceuticals and Medical Devices Agency (EMA/PMDA) statistical 
analysis plan (EP-SAP). This change allows sequential testing of hypotheses at the full 
significance level after successful rejection of the hypotheses which are ranked higher 
in the hierarchy. 
The reason for this change is to prioritize testing of hypotheses which are deemed to 
be clinically more relevant. 
3. To allow formal statistical testing for superiority of the change from baseline in best 
corrected visual acuity (BCVA) at Week 48 (and Week 60, for regulatory submissions 
to EMA/PMDA Analysis Plan only) that controls the overall family-wise type 1 error. 
The formal statistical testing for superiority is added at the end of the revised testing 
hierarchy. 
Of note, the updated confirmatory testing hierarchy still controls the overall family-wise 
type 1 error. The change was implemented after the end of enrollment but before the database 
lock and before any unmasking occurred. 
In addition, the definition of the Full Analysis Set (FAS) was updated to include all 
participants who received at least 1 dose of study intervention. 
This amendment also clarifies a discrepancy in the following exclusion criteria: 
• Section 5.2, Exclusion Criterion 2.l: Aphakia, or pseudophakia with absence of 
posterior capsule (unless it occurred as a result of a yttrium-aluminum-garnet 
[YAG] posterior capsulotomy performed more than 4 weeks (28 days) before 
screening), in the study eye. 
• Section 5.2, Exclusion Criterion 13.g: YAG capsulotomy in the study eye within 
30 days before the screening visit. 
Eligibility requires that none of the exclusion criteria are met, therefore, this amendment 
confirms that the strictest definition, as used in Section 5.2, Exclusion Criterion 13.g, needs to 
be applied, i.e., a patient is not eligible if YAG was applied in the study eye within 30 days 
before the screening visit. 
Additionally, this amendment includes updates of secondary-other and exploratory endpoints, 
clarifications with regard to the type and follow-up time of adverse events (AEs) during the 
post-injection period by the unmasked team, the contact information in case unmasking of a 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  100 of 109 
 
 
 
participant’s intervention assignment is warranted, the baseline to be used for the dose 
regimen modification (DRM), the definition of treatment-emergent adverse events (TEAEs), 
and the timing of indirect ophthalmoscopy and intraocular pressure (IOP) measurements 
performed after study intervention. 
Section # 
and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis and 
3 Objectives and 
Endpoints 
 
Secondary – Other 
Objective: 
To evaluate the 
pharmacokinetics (PK) 
and immunogenicity of 
aflibercept 
Modified secondary – other 
endpoint: 
• 
Systemic exposure to 
aflibercept as assessed by 
plasma concentrations of 
free, adjusted bound and 
total aflibercept from 
baseline through Week 48 
Removal of concentrations of 
“bound” aflibercept from the 
secondary – other and the 
exploratory endpoints related to PK 
as concentrations of “adjusted 
bound” aflibercept were considered 
sufficient. 
3 Objectives and 
Endpoints 
 
Exploratory Objective: 
Based on dense PK 
sampling, characterize 
the concentrations in 
plasma over time, and 
corresponding PK 
parameters for 
aflibercept 
Modified exploratory endpoint: 
• 
Concentrations of free, 
adjusted bound and total 
aflibercept over time, and PK 
parameters 
9.4.6 
Pharmacokinetics 
Endpoints 
 
Main Study and 
Dense PK Substudy 
Text was updated to reflect the 
removal of “bound” aflibercept 
from the secondary – other and 
the exploratory endpoints 
3 Objectives and 
Endpoints 
 
Exploratory Objective: 
To determine the effect 
of HD versus 2 mg 
aflibercept on 
functional and 
anatomic measures of 
response as well as on 
vision related quality of 
life 
Removed exploratory endpoint: 
• 
Change from baseline in 
BCVA at each visit in relation 
to fluid outcomes 
Correlation between OCT and 
vision has never been formally 
established; Change from baseline 
in BCVA at each visit in relation to 
fluid outcomes is to be assessed in 
a post-hoc analysis, as appropriate. 
Added exploratory endpoint: 
• 
Proportion of participants 
without leakage on 
fluorescein angiography (FA) 
at Week 48, Week 60, and 
Week 96 
To explore the effect of treatment 
on the inhibition of vascular 
leakage. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  101 of 109 
 
 
 
Section # 
and Name 
Description of Change 
Brief Rationale 
3 Objectives and 
Endpoints 
 
Exploratory Objective: 
To evaluate the 
duration of effect of HD 
after 3 initial doses at 
4 week intervals 
followed by dosing q12 
or q16 
Modified exploratory endpoints: 
• 
Proportion of participants 
with q16 or longer treatment 
interval through Week 48, 
Week 60, and Week 96 in 
HDq16 group 
• 
Proportion of participants 
with q12 or longer interval 
through Week 48, Week 60, 
and Week 96 in the HDq12 
and HDq16 groups 
• 
Proportion of participants 
with q12 or q16 or longer 
treatment interval as the last 
treatment interval at 
Week 48, Week 60, and 
Week 96 in HDq12 and 
HDq16 groups, respectively 
To also identify the proportion of 
participants who did not require any 
shortening of their treatment 
intervals throughout the study 
duration and to delete the 
inappropriate word “maintained“ 
from the endpoint to clarify the 
intention of the analysis referring to 
the last treatment interval. 
5.2.2.l Exclusion 
Criteria 
 
Medical Conditions – 
Per Eye 
Correction of restrictive period of 
YAG posterior capsulotomy in 
Section 5.2.2.l to more than 
30 days before screening. 
Clarification of discrepancy 
between Section 5.2.2.l and 
Section 5.2.13.g. 
6.3.2 Masking 
 
Unmasked Roles 
Text was amended to clarify that 
AEs relating to the injection 
procedure and AEs/SAEs/device 
deficiencies should be reported 
during the post-injection period 
until the next scheduled visit. 
To clarify which AEs should be 
reported by the unmasked 
investigator and during which 
period of time. 
6.3.2 Masking 
 
Emergency Unmasking 
Update of contact information. 
To clarify who should be contacted 
if the investigator decides that 
unmasking is warranted. 
6.6.1 Year 1: Baseline 
to Week 48 
Added paragraph: 
In case the Week 12 
measurement is not available, the 
Week 8 measurement should be 
used instead. If both, Week 12 
and Week 8 measurements are 
not available, the Week 4 
measurement should be used 
instead. 
Clarification of the baseline to be 
used for the DRM if the Week 12 
measurement is not available. 
1.3 Schedule of 
activities, Tables 1-1 
and 1-2, footnote ‘j’ 
 
8.1.1.2 Intraocular 
Pressure (IOP) 
Text was amended to clarify that 
on days when study intervention 
is administered, IOP should also 
be measured approximately 30 to 
60 minutes after administration of 
study intervention and that the 
exact timing is left to the 
discretion of the unmasked 
investigator. 
To clarify the timing of indirect 
ophthalmoscopy and intraocular 
pressure IOP measurements 
performed after study intervention 
administration. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  102 of 109 
 
 
 
Section # 
and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
activities, Tables 1-1 
and 1-2, footnote ‘l’ 
 
8.1.1.4 Indirect 
Ophthalmoscopy 
Text was amended to clarify that 
post-dose evaluation should be 
performed as soon as possible, 
approximately 0 to 15 minutes 
after injection and that the exact 
timing is left to the discretion of 
the unmasked investigator. For 
post-injection procedures if the 
indirect ophthalmoscopy cannot 
be performed immediately after 
injection, a reference to 
Section 10.7.2.3 was added. 
 
9.1 Statistical 
Hypotheses 
 
Null and Alternative 
Hypotheses 
Added bullet point: 
1. Change from baseline in BCVA 
at Week 48 (non-inferiority at a 
margin of 4 letters): 
To add a subheader for the primary 
family of hypotheses for more 
clarity and to distinguish between 
the different hypotheses tested. 
Null and alternative hypotheses 
renumbered. 
To match the order in the revised 
hierarchical testing procedure. 
Added text: 
The HDq12 and HDq16 treatment 
groups will also be tested for 
superiority against the control 
group of 2q8 with respect to the 
change from baseline in BCVA at 
Week 48 (and Week 60, only for 
EP-SAP). 
 
4. Change from baseline in BCVA 
at Week 48 (superiority):  
H60: μ1 ≤ μ0 vs. H61: μ1 > μ0 (i.e., 
HDq12 vs. 2q8) 
H80: μ2 ≤ μ0 vs. H81: μ2 > μ0 (i.e., 
HDq16 vs. 2q8) 
where μ0, μ1, μ2 are the mean 
change from baseline in BCVA at 
Week 48 for 2q8, HDq12, and 
HDq16, respectively. 
 
5. Only included in the EP-SAP 
for EMA and PMDA:  
Change from baseline in BCVA at 
Week 60 (superiority) 
H70: μ1 ≤ μ0 vs. H71: μ1 > μ0 (i.e., 
HDq12 vs. 2q8) 
H90: μ2 ≤ μ0 vs. H91: μ2 > μ0 
(i.e., HDq16 vs. 2q8) 
where μ0, μ1, μ2 are the mean 
change from baseline in BCVA at 
Week 60 for 2q8, HDq12, and 
HDq16, respectively. 
To add the description of the 
additional superiority hypotheses. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  103 of 109 
 
 
 
Section # 
and Name 
Description of Change 
Brief Rationale 
9.1 Statistical 
Hypotheses 
 
Control of Multiplicity;  
Figure 9-1- Adjustment 
for Multiplicity 
Text was amended and the 
2 figures replaced showing 
Global SAP (G-SAP) 
EMA/PMDA SAP(EP-SAP) 
by a table summarizing the testing 
order of the hierarchical testing 
procedure in the G-SAP and 
EP‑SAP. 
To replace the graphical 
representations of the adjustment 
for multiplicity by a hierarchical 
testing procedure, and including the 
superiority hypotheses at the end of 
the confirmatory testing hierarchy. 
9.2 Sample Size 
Determination 
Text was amended to clarify that 
sample size determination is still 
based on the non-inferiority tests 
but not on the superiority tests. 
Clarification required since both 
non-inferiority tests and superiority 
tests are now applied to the primary 
endpoint. 
Text was added to describe the 
power, based on the revised 
confirmatory testing hierarchy 
(according to Protocol version 3.0, 
Global Amendment 2). 
 
Clarification required of the power 
based on the revised testing 
strategy, i.e., the hierarchical 
confirmatory testing procedure 
without alpha split. 
Text was removed which referred 
to the initial alpha split and 
Figure 9-1 which are no longer 
applicable.  
Text no longer applicable due to 
revision of confirmatory testing 
hierarchy.  
9.3 Populations for 
Analyses 
The definition of the FAS was 
amended. 
To include randomized participants 
who received at least 1 dose of 
study intervention in the FAS. 
The definition of the PPS was 
amended. 
To clarify that patients should not 
have an important protocol 
deviation affecting the primary 
efficacy endpoint. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  104 of 109 
 
 
 
Section # 
and Name 
Description of Change 
Brief Rationale 
9.4.2 Primary Efficacy 
Endpoint 
Text was amended to clarify that 
the estimand of primary interest 
will mainly be based on a 
hypothetical strategy, that the 
population defined is the target 
population, and that the 
population-level summary is 
defined as the difference in the 
least squared (LS) rather than the 
mean change from baseline. 
Clarification required since both 
non-inferiority tests and superiority 
tests are now applied to the primary 
endpoint. 
It was also clarified that the 
analysis will be repeated on the 
PPS as a supplementary rather 
than a sensitivity analysis. 
 
Text was amended to clarify that 
the first 2 hypotheses in the 
primary analysis will be tested to 
assess non‑inferiority in the 
primary endpoint. 
 
MMRM updated to remove 
random effect bi, to add index k to 
Y and є; clarification of є updated.  
Random effect bi removed, to avoid 
over parametrization.  
Paragraphs were re-ordered and 
text added: 
Furthermore, the following 
2 hypotheses will be tested (within 
the pre-defined testing strategy, 
see Section 9.1), using the 
MMRM described above, to 
assess superiority in the primary 
endpoint: 
• 
HDq12 is superior to 2q8 
regarding the mean change 
in BCVA from baseline to 
Week 48. 
• 
HDq16 is superior to 2q8 
regarding the mean change 
in BCVA from baseline to 
Week 48. 
To replace the original sentence: 
“Two-sided confidence intervals will 
be provided to allow the 
assessment of superiority if non-
inferiority could be concluded.” by a 
formal test for superiority at the end 
of the testing strategies. 
 
Text was amended to indicate 
that a hierarchical testing 
procedure will be applied which 
also includes the confirmatory 
testing for superiority at the end of 
the confirmatory testing hierarchy. 
To refer to the updated hierarchical 
testing procedure and to remove 
the reference to the graphical 
representations of the adjustment 
for multiplicity, which are no longer 
applicable. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  105 of 109 
 
 
 
Section # 
and Name 
Description of Change 
Brief Rationale 
9.4.3 Secondary 
Efficacy Endpoints 
Added text: 
The HDq12 and HDq16 treatment 
groups will be tested for 
non‑inferiority and superiority 
against the control group of 2q8, 
according to the confirmatory 
testing strategy outlined in 
Section 9.1. 
To clarify the testing strategy on 
key secondary endpoint “change 
from baseline to Week 60 in 
BCVA”. 
 
Added text: 
The pooled high dose groups 
(HDq12 and HDq16) will be tested 
for superiority against the control 
group of 2q8, according to the 
confirmatory testing strategy 
outlined in Section 9.1. 
To clarify the testing strategy on 
key secondary endpoint “proportion 
of participants with no IRF and no 
SRF in central subfield at 
Week 16”. 
9.4.4.1 Adverse Events 
Text was amended to clarify that 
TEAEs are defined as AEs that 
occurred in the time frame from 
first injection to the last injection 
(active or sham) in the study plus 
30 days. 
Clarification of the definition of 
TEAEs by deleting references to 
the rescue regimen, which is 
inherent in the DRM/rescue 
regimen paradigm, and to delete 
sham from the first injection as no 
sham procedure is done at the first 
injection. 
9.4.6 
Pharmacokinetics 
Endpoints 
Text was amended to clarify that 
the PK parameters mentioned are 
to be determined if possible. 
To clarify that PK parameters are to 
be determined based on their 
availability. 
10.7.2.3 Post‑injection 
Procedures 
Text was amended to update the 
following procedures: 
1. Indirect ophthalmoscopy in the 
study eye only as soon as 
possible, approximately 0 to 15 
minutes after injection. The exact 
timing is left to the discretion of 
the unmasked investigator. If the 
indirect ophthalmoscopy cannot 
be performed immediately after 
injection, the unmasked 
investigator needs to assess the 
visual function of the injected eye: 
light perception and ability to 
count fingers within 0 to 5 minutes 
after the injection. 
2. Measure IOP approximately 30 
to 60 minutes after injection in the 
study eye only. The exact timing 
is left to the discretion of the 
unmasked investigator. 
... 
5a. Monitor IOP for at least 
30 minutes after each injection. 
The exact timing is left to the 
discretion of the unmasked 
investigator. 
To clarify the timing of indirect 
ophthalmoscopy and intraocular 
pressure IOP measurements 
performed after study intervention 
administration. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  106 of 109 
 
 
 
Section # 
and Name 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial changes for 
consistency of the updates 
described above, company 
template updates and document 
formatting. 
Minor, therefore have not been 
summarized. 
AE=adverse event, BCVA=best corrected visual acuity, DRM= dose regimen modification, 
EMA=European Medicines Agency, EP-SAP=EMA/PMDA statistical analysis plan, FAS=full 
analysis set, G-SAP=global statistical analysis plan, HD=high dose, IOP=intraocular pressure, 
IRF=intraretinal fluid, MMRM=mixed model for repeated measurements, OCT=optical coherence 
tomography; PK=pharmacokinetic; PMDA= Pharmaceuticals and Medical Devices Agency, 
PPS=per protocol set, q8=every 8 weeks, q12=every 12 weeks, q16=every 16 weeks, SAE= 
serious adverse event, SRF=subretinal fluid, TEAE=treatment-emergent adverse event, 
YAG=yttrium aluminum garnet 
 
DOCUMENT HISTORY 
Document 
Date 
Protocol Amendment 1 
14-February-2020 
Original Protocol 
09-December-2019 
Amendment 1 (14-February-2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to update the study design to simplify 
implementation of dose regimen modifications (DRMs) and rescue regimen. The updated 
design encompasses combining rescue regimen with DRM assessments in both Year 1 and 
Year 2, allowing dose regimen flexibility while maintaining participant safety. In Year 1, 
participants in the high dose (HD) groups will be eligible for dose interval shortening (to a 
rescue regimen with 8 mg aflibercept every 8 weeks) beginning at Week 16. In Year 2, all 
participants in HD groups will be eligible for dose interval adjustments (shortening or 
extension) based on DRM criteria from Week 52 onwards, with the dose interval adjustments 
(shortening or extension) becoming effective at or after Week 60 (after data collection for key 
secondary efficacy endpoint). To improve dosing flexibility, all participants in HD groups 
whose dosing intervals were shortened during Year 1 will be eligible for dose interval 
extension in Year 2 if they meet pre-specified criteria. 
Additionally, recent shifts in disease characteristics at presentation led to the adjustment 
(broadening) of the inclusion criterion for best corrected visual acuity (BCVA) to allow 
inclusion of participants with BCVA scores between 78 and 24 letters (20/32 to 20/320). 
Section #  
and Name 
Description of Change 
Brief Rationale 
1.2 Schema, 
Figure 1-2 Dosing 
Schedule 
Updated to reflect the updated DRM and rescue 
regimen assessments. 
To provide detail on combined 
rescue regimen and DRM 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  107 of 109 
 
 
 
Section #  
and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities (SoA), 
Table 1-1 and 
Table 1-2 
Rows for Rescue Treatment and DRM 
Assessment were combined, footnote ‘g’ was 
deleted, and footnote ‘h’ was amended to reflect 
combined DRM and rescue regimen 
assessments. 
assessments in Year 1 and 
Year 2. 
In Year 1, participants in HD 
groups will be eligible for dose 
interval shortening (rescue 
regimen with 8 mg aflibercept 
q8 or reduction to q12 dosing, if 
applicable) beginning at 
Week 16, according to 
pre-specified criteria.  
From Week 52, all participants 
in HD groups will be eligible 
for dose interval shortening (to 
a minimum of q8) or extension 
(by 4-week increments) 
according to pre-specified DRM 
criteria.  
All participants in HD groups 
whose dosing intervals were 
shortened during Year 1 will 
eligible for dose interval 
extension in Year 2 if they meet 
pre-specified criteria. 
4.1 Overall Design 
Text was amended to update information on 
potential dose interval changes during Year 1 
and Year 2. 
6.3.2 Masking 
Masked roles were updated to reflect the current 
DRM activities. 
6.5.3 Rescue 
Treatment 
The section was deleted. Relevant information 
has now been combined and included into 
Section 6.6 Dose Regimen Modification. 
6.6 Dose Regimen 
Modification 
The section was renamed to “Dose Regimen 
Modification/Rescue Regimen”. 
Section completely replaced with new text 
describing the combined DRM and rescue 
regimen criteria for Years 1 and 2. 
9.4.2 Primary 
Efficacy Endpoint 
Estimand definitions updated to reflect the 
updated DRM and rescue regimen assessments.  
Text that was previously in Section 6.6 was 
added for completeness: For primary analysis, 
participants will be analyzed within their original 
randomized group, regardless of any changes to 
dose interval. 
5.1 Inclusion 
Criteria, criterion 4 
Upper limit of BCVA ETDRS letter score for the 
study eye was updated from 73 to 78 
(corresponding to a Snellen equivalent of 
approximately 20/32). 
Broadened to better reflect 
patient population disease 
characteristics at presentation. 
3 Objectives and 
endpoints 
Two additional exploratory endpoints were 
added: 
• 
Change from baseline in BCVA averaged 
over the period from Week 36 to Week 48 
and from Week 48 to Week 60. 
• 
Change from baseline in BCVA at each visit 
in relation to fluid outcomes. 
As treatment before Week 48 
and Week 60 are less 
synchronized due to the 
modifications introduced for the 
DRMs, it is now important to 
assess these additional/earlier 
endpoints. 
6.5.2 Fellow Eye 
Treatment 
Added text: The costs of aflibercept 2 mg used 
for treatment of the fellow eye will be supported 
by the sponsor in compliance with local 
regulations. 
To clarify that, although 
aflibercept 2 mg for fellow eye 
treatment will not be provided 
by the sponsor through study 
medication supplies, costs for 
purchase of EYLEA® 2 mg will 
be reimbursed where allowed. 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  108 of 109 
 
 
 
Section #  
and Name 
Description of Change 
Brief Rationale 
6.5.2 Fellow Eye 
Treatment 
8.3.2 Method of 
Detecting AEs and 
SAEs 
New text: Once the fellow eye receives 
aflibercept 2 mg therapy during the study, AEs 
will be assessed as related/not related to 
aflibercept 2 mg treatment in the fellow eye in 
addition to being assessed as related/not related 
to the study drug (aflibercept 2 mg/aflibercept 
High Dose treatment in the study eye), IVT 
injection-procedure, and other protocol-specified 
procedures. 
To improve characterization of 
the safety profile of 
investigational aflibercept, 
separate documentation of 
potential relationship of AEs to 
commercial or investigational 
aflibercept. 
1.3 Schedule of 
activities, Table 1-1 
Addition of new footnote ‘f’ associated with 
Inclusion/Exclusion Eligibility at Visit 2: 
Inclusion/exclusion criteria will be evaluated at 
screening and baseline to confirm subject’s 
eligibility. The investigator is responsible for 
confirming that any changes between screening 
and baseline do not affect the participant’s 
eligibility. 
To clarify which data are to be 
used to confirm eligibility. 
1.3 Schedule of 
activities, Table 1-3 
On Day 1, the 4 and 8 hour PK sampling is to be 
within ±30 minutes and ±2 hours, respectively, 
of the scheduled time. 
To allow flexibility while still 
ensuring accuracy of PK 
sampling time-points. 
1.3 Schedule of 
activities, Table 1-1 
8.10 Immunogenicity 
Assessments 
PK sample time pre-dose changed from 
Screening (Visit 1) to Baseline (Visit 2). 
Deleted paragraph about evaluation of 
aflibercept serum concentrations at same time 
points as immunogenicity assessments. 
Alignment of PK and anti-drug 
antibody sampling times. 
Text in Section 8.10 is 
unnecessary due to 
correspondence of PK and 
anti-drug antibody sampling at 
baseline and Week 48. The PK 
profile is sufficiently 
characterized. 
1.3 Schedule of 
activities, Table 1-1, 
footnote ‘d’ 
8.7.1 Optional 
Genomic Substudy 
Participants from China will not be enrolled in 
the optional genomic substudy. 
Clarification that participants in 
China will not take part in the 
optional substudy. 
8.2.1 Physical 
Examination 
Addition of body weight at Visit 1. 
Body weight should be 
measured in all participants. 
Throughout 
Minor editorial changes for improved 
clarity/readability, company template updates, 
and document formatting. 
Minor, therefore have not been 
summarized. 
AE=adverse event, BCVA=best corrected visual acuity, DRM=dose regimen modification, 
ETDRS=Early Treatment Diabetic Retinopathy Study, HD=high dose, IVT=intravitreal, 
PK=pharmacokinetic, q8=every 8 weeks, q12=every 12 weeks, SAE=serious adverse event 
 


CONFIDENTIAL 
Clinical Study Protocol Global Amendment 4 
No. BAY 86-5321 / IMPACT 20968 
27 FEB 2023 
Page:  109 of 109 
 
 
 
11. 
References 
 
1  
Cao J, MacPherson TC, Iglesias BV, Liu Y, Tirko N, Yancopoulos GD, et al. 
Aflibercept action in a rabbit model of chronic retinal neovascularization: 
reversible inhibition of pathologic leakage with dose-dependent duration. 
Invest Ophthalmol Vis Sci. 2018:59:1033-44. 
2  
Regeneron Pharmaceuticals, Inc. Press release from 11 February 2022, 
available from: https://investor.regeneron.com/news-releases/news-release-
details/regeneron-presents-encouraging-phase-2-results-high-dose 
3  
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. 
4  
Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD. 
Development of the 25-item National Eye Institute Visual Function 
Questionnaire (VFQ-25). Arch Ophthalmol. 2001;119, 1050-8. 
5  
CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, 
Fine SL, et al. Ranibizumab and bevacizumab for neovascular age-related 
macular degeneration. N Engl J Med. 2011 May 19;364(20):1897-908. 
6  
Ho AC, Busbee BG, Regillo CD, Wieland MR, Van Everen SA, Li Z, et al. 
Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in 
patients with subfoveal neovascular age-related macular degeneration. 
Ophthalmology. 2014 Nov;121(11):2181-92. 
7  
Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, et al. 
HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked 
Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. 
Ophthalmology. 2019 Apr 12. pii: S0161-6420(18)33018-5.  
8  
Basic principles on global clinical trials. PMDA Guidance, 2007. 
https://www.pmda.go.jp/files/000153265.pdf. 
9  
Grzybowski A, Told R, Sacu S, Bandello F, Moisseiev E, Loewenstein A, 
Schmidt-Erfurth U, on behalf of the Euretina Board. 2018 Update on 
intravitreal injections: Euretina expert consensus recommendations. 
Ophthalmologica. 2018;239:181-93. 

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
Randomized, Double-Masked, Active-Controlled, Phase 3 Study of 
the Efficacy and Safety of High Dose Aflibercept in Patients With 
Neovascular Age-Related Macular Degeneration 
NCT Number: 
NCT04562155 
Document Date: 
22 AUG 2022 
 




Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 2 of 103
 
 
Table of Contents 
Title page ............................................................................................................................... 1 
Table of Tables ..................................................................................................................... 4 
Abbreviations ........................................................................................................................ 5 
1. 
Introduction ................................................................................................................... 7 
2. 
Study Objectives ............................................................................................................ 8 
3. 
Study Design ................................................................................................................ 10 
4. 
General Statistical Considerations ............................................................................ 12 
4.1 
General Principles ...................................................................................................... 12 
4.1.1 
Determination of Sample Size ................................................................................ 12 
4.2 
Handling of Dropouts ................................................................................................ 13 
4.3 
Handling of Missing Data .......................................................................................... 14 
4.3.1 
Additional Descriptive Analyses in the Presence of Missing Data ........................ 14 
4.3.2 
General Rules ......................................................................................................... 14 
4.4 
Interim Analyses and Data Monitoring ..................................................................... 14 
4.5 
Data Rules .................................................................................................................. 15 
4.5.1 
Determination of Baseline Values .......................................................................... 15 
4.5.2 
Unscheduled Assessments ...................................................................................... 15 
4.5.3 
End of Study / Early Discontinuation Visit ............................................................ 15 
4.5.4 
Imaging data assessed by the reading center .......................................................... 16 
4.5.5 
Definition of Fellow Eye Treatment ....................................................................... 20 
4.5.6 
Definition of Prohibited Medications ..................................................................... 21 
4.6 
Masked Review .......................................................................................................... 21 
4.7 
Outputs/Procedures related to COVID-19 ................................................................. 22 
4.8 
Outputs/Procedures related to the Ukraine/Russia crisis ........................................... 22 
5. 
Analysis Sets ................................................................................................................ 22 
5.1 
Assignment of Analysis Sets ..................................................................................... 23 
5.2 
Definition of Subgroups ............................................................................................. 24 
6. 
Statistical Methodology .............................................................................................. 25 
6.1 
Population Characteristics ......................................................................................... 25 
6.1.1 
Demographics and Disease Characteristics ............................................................ 25 
6.1.2 
Medical History ...................................................................................................... 26 
6.1.3 
Disposition of Study Participants ........................................................................... 26 
6.1.4 
Exposure and Compliance to Study Intervention ................................................... 27 
6.1.5 
Prior and Concomitant Medication......................................................................... 29 
6.2 
Efficacy ...................................................................................................................... 29 
6.2.1 
Confirmatory Hypothesis Testing .......................................................................... 30 
6.2.2 
Primary Efficacy Endpoint ..................................................................................... 31 
6.2.3 
Secondary Efficacy Endpoints................................................................................ 36 
6.2.4 
Exploratory Efficacy Endpoints ............................................................................. 43 
6.2.5 
Subgroup Analyses ................................................................................................. 47 
6.3 
Pharmacokinetics/Pharmacodynamics ....................................................................... 47 
6.3.1 
Main Study ............................................................................................................. 47 
6.3.2 
Dense PK Substudy ................................................................................................ 48 
6.4 
Safety ......................................................................................................................... 49 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 3 of 103
 
 
6.4.1 
Adverse Events and Serious Adverse Events ......................................................... 49 
6.4.2 
Immunogenicity ...................................................................................................... 51 
6.4.3 
Surgeries ................................................................................................................. 51 
6.4.4 
Clinical Laboratory Variables ................................................................................ 51 
6.4.5 
Electrocardiogram .................................................................................................. 53 
6.4.6 
Vital Signs .............................................................................................................. 53 
6.4.7 
Other Safety Measures............................................................................................ 53 
7. 
Document History and Changes in the Planned Statistical Analysis ..................... 54 
8. 
References .................................................................................................................... 63 
9. 
Appendix ...................................................................................................................... 63 
9.1 
Handling of Questionnaires ....................................................................................... 63 
9.1.1 
NEI-VFQ-25 Sub-scale Scores and Total Score .................................................... 63 
9.2 
Development of Anti-drug Antibodies ...................................................................... 65 
9.3 
Pre-defined Laboratory Abnormalities ...................................................................... 67 
9.4 
Definition of safety subgroups ................................................................................... 67 
9.4.1 
Hypertension ........................................................................................................... 67 
9.4.2 
Intraocular inflammation ........................................................................................ 68 
9.4.3 
Nasal mucosal events.............................................................................................. 69 
9.4.4 
Medical history of cerebrovascular disease (e.g. CVA / Stroke) ........................... 70 
9.4.5 
Medical history of ischaemic heart disease (e.g., myocardial infarction) .............. 76 
9.4.6 
Medical history of renal impairment ...................................................................... 78 
9.4.7 
Medical history of hepatic impairment ................................................................... 79 
9.5 
Strategies for occurrence of intercurrent events ........................................................ 90 
9.6 
Participating Regions and Countries .......................................................................... 97 
9.7 
Additional Pre-Specified Exploratory Efficacy Variables and Analyses .................. 98 
9.7.1 
Analysis Populations .............................................................................................. 98 
9.7.2 
Additional Pre-Specified Exploratory Efficacy Variable(s) ................................... 98 
9.7.3 
Additional Pre-Specified Exploratory Efficacy Analyses ...................................... 98 
 
 
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 4 of 103
 
 
Table of Tables 
Table 2–1: Objectives and Endpoints......................................................................................... 8 
Table 6–1: Testing Order of Hierarchical Testing Procedure in G-SAP and EP‑SAP ............ 31 
Table 6–2: Pre-defined laboratory abnormalities ..................................................................... 52 
Table 7–1: Document history ................................................................................................... 55 
Table 9–1: Recoding of NEI-VFQ 25 items ............................................................................ 64 
Table 9–2: Sub-scales of the NEI-VFQ 25 score ..................................................................... 64 
Table 9–3: Classification of the respective antibody status ..................................................... 65 
Table 9–4: Pre-defined laboratory abnormalities ..................................................................... 67 
Table 9–5: PTs for selection of “Hypertension” ...................................................................... 68 
Table 9–6: PTs for selection of “Intraocular Inflammation” ................................................... 69 
Table 9–7: PTs for selection of “Nasal mucosal events” ......................................................... 69 
Table 9–8: PTs for selection of medical history of “Cerebrovascular Disease” ...................... 70 
Table 9–9: PTs for selection of medical history of “Ischaemic Heart Disease” ...................... 76 
Table 9–10: PTs for selection of medical history of “Requiring dialysis” .............................. 79 
Table 9–11: PTs for selection of medical history of “Hepatic Impairment” ........................... 79 
Table 9–12: Strategies for occurrence of intercurrent events for analysis at week 48 for BCVA 
and other continuous endpoint variables ............................................................... 90 
Table 9–13: Strategies for occurrence of intercurrent events for analysis of proportions of 
participants with no IRF and no SRF in central subfield and other binary endpoint 
variables ................................................................................................................. 94 
Table 9–14: Participating Regions and Countries .................................................................... 97 
Table 9–15: Additional Pre-Specified Exploratory Efficacy Analyses – Alternative Tipping 
Point Analyses ..................................................................................................... 100 
 
 
 
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 5 of 103
 
 
Abbreviations 
2q8 
aflibercept 2 mg administered every 8 weeks, after 3 initial injections at 4-week 
intervals 
AAS 
ADA Analysis Set 
ADA 
Anti-drug Antibodies 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
APTC 
Anti-Platelet Trialists Collaboration 
AUCinf 
Area under the curve from time zero to infinity 
AUClast 
Area under the curve to the last quantifiable concentration 
BCVA 
Best corrected visual acuity 
BLOQ 
Below limit of quantification 
BMI 
Body mass index 
CI 
Confidence interval 
Cmax 
Maximum concentration 
CNV 
Choroidal neovascularization 
CRF 
Case Report Form 
CSF 
Cerebrospinal fluid 
CSR 
Clinical Study Report 
CST 
Central subfield retinal thickness 
Ctrough 
Trough concentration 
DB 
Database 
DPKS 
Dense Pharmacokinetic analysis set 
DRSS 
diabetic retinopathy severity scale 
DMC 
Data Monitoring Committee 
DRM 
Dose regimen modification 
ECG 
Electrocardiogram 
ED 
Early Discontinuation 
EMA 
European Medicines Agency 
EOS 
end of study 
EP-SAP 
EMA/PMDA Statistical Analysis Plan 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
fluorescein angiography 
FAS 
Full Analysis Set 
FCS 
Fully Conditional Specification 
FDA 
U.S. Food and Drug Administration 
FP 
fundus photography 
GA 
Geographic atrophy 
G-SAP 
Global Statistical Analysis Plan 
HD 
High dose (aflibercept 8 mg) 
HDq12 
high dose aflibercept 8 mg administered every 12 weeks, after 3 initial injections at 
4-week intervals 
HDq16 
high dose aflibercept 8 mg administered every 16 weeks, after 3 initial injections at 
4-week intervals 
HLT 
MedDRA High level term 
ICE 
Intercurrent event 
ICGA 
Indocyanine green angiography 
IOP 
Intraocular pressure 
IRF 
Intraretinal fluid 
IVT 
Intravitreal 
IXRS 
Interactive Response System 
LL 
Lower limit 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
LOCF 
Last observation carried forward 
LOQ 
Limit of quantification 
LS 
Least squared 
LSmeans 
Least-square means 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 6 of 103
 
 
MAR 
Missing at random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MMRM 
Mixed model for repeated measurements 
MNAR 
Missing not at random 
NAb 
Neutralizing antibody data 
nAMD 
Neovascular (wet) age-related macular degeneration 
NAbAS 
NAb Analysis Set 
NEI-VFQ-25 
National Eye Institute Visual Functioning Questionnaire-25 
OC 
Observed case 
OCT-A 
optical coherence tomography angiography 
PCSV 
Potentially clinically significant value 
PCV 
Polypoidal choroidal vascularization 
PD 
Protocol deviation 
PK 
Pharmacokinetics 
PKS 
Pharmacokinetic analysis set 
PMDA 
Pharmaceuticals and Medical Devices Agency (Japan) 
PPS 
Per protocol set 
PT 
Preferred Term 
q12 
every 12 weeks 
q16 
every 16 weeks 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SD-OCT 
Spectral domain optical coherence tomography 
SOC 
Primary system organ class 
SRF 
Subretinal fluid 
subRPE 
Subretinal pigment epithelium 
t1/2 
Half-life 
tlast 
Last time point 
tmax 
Time of Cmax 
TEAE 
Treatment-emergent adverse event 
TFLs 
Tables, figures and listings 
UA 
Unscheduled Assessment 
ULN 
Upper limit of normal 
VEGF 
Anti-vascular endothelial growth factor 
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 7 of 103
 
 
1. 
Introduction 
Neovascular (wet) age-related macular degeneration (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. In elderly patients affected by nAMD, vision loss frequently has 
an even greater impact, as it substantially reduces the visual compensation of functional 
impairment by other age-related comorbidities, such as arthritis and osteoporosis. 
Although many patients benefit from treatment with currently available anti-vascular 
endothelial growth factor (VEGF) agents, a sizable proportion of patients still need 
intravitreal (IVT) injections as frequently as every 4 to 8 weeks, specifically in the first year 
of treatment. A continued need for treatment in intervals as short as 4 to 8 weeks poses 
significant treatment burden to patients, physicians, and to healthcare systems. In addition, 
long-term data in patients with nAMD suggest that visual benefits achieved in the first year of 
treatment may be lost if regular dosing is not maintained. 
EYLEA (also known as aflibercept 2 mg) is a VEGF antagonist approved as of 07 OCT 2019 
in over 109 countries for the treatment of nAMD at a dosage level of 2 mg (administered at a 
concentration of 40 mg/mL injected IVT) administered every 8 (q8) weeks.  
This study will investigate the efficacy and safety of a high dose aflibercept 8 mg (HD; 
provided at a concentration of 114.3 mg/mL) with the intent of achieving non-inferior best 
corrected visual acuity (BCVA), while extending the dosing interval and potentially 
improving visual and/or anatomic outcomes for HD versus the currently approved aflibercept 
2 mg dose regimen. 
This statistical analysis plan (SAP) describes all details of the required statistical analyses to 
be conducted at Week 48, Week 60 and Week 96 (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 
3.0 (dated 26 APR 2022), which includes Amendment 2. All references to study protocol 
hereafter refer to that version of the protocol. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 8 of 103
 
 
2. 
Study Objectives 
Table 2–1: Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To determine if treatment with 
aflibercept 8 mg (HD) at intervals 
of 12 or 16 weeks provides non-
inferior BCVA change compared 
to aflibercept 2 mg every 
8 weeks in participants with 
nAMD 
Primary Endpoint  
• 
Change from baseline in BCVA measured by the Early 
Treatment Diabetic Retinopathy Study (ETDRS) letter 
score at Week 48 
Secondary - Efficacy 
 
To determine the effect of HD 
versus 2 mg aflibercept on other 
visual and anatomic measures of 
response 
Key Secondary Efficacy Endpoints 
• 
Change from baseline in BCVA measured by the 
ETDRS letter score at Week 60 (for regulatory 
submissions to European Medicines 
Agency/Pharmaceuticals and Medical Devices Agency 
[EMA/PMDA] Analysis Plan only, see Section 6.2 
• 
Proportion of participants with no intraretinal fluid (IRF) 
and no subretinal fluid (SRF) in central subfield at 
Week 16 
Additional Secondary Efficacy Endpoints 
• 
Proportion of participants gaining at least 15 letters in 
BCVA from baseline at Week 48 
• 
Proportion of participants achieving an ETDRS letter 
score of at least 69 (approximate 20/40 Snellen 
equivalent) at Week 48 
• 
Change in choroidal neovascularization (CNV) size 
from baseline to Week 48 
• 
Change in total lesion area from baseline to Week 48 
• 
Proportion of participants with no IRF and no SRF in 
the central subfield at Week 48  
• 
Change from baseline in central subfield retinal 
thickness (CST) at Week 48  
To assess the efficacy of HD 
compared to 2 mg aflibercept on 
vision-related quality of life 
• 
Change from baseline in National Eye Institute Visual 
Functioning Questionnaire-25 (NEI-VFQ-25) total 
score at Week 48 
Secondary - Safety 
 
To evaluate the safety of 
aflibercept 
• 
Treatment-emergent adverse events (AEs) and 
serious AEs (SAEs) through Week 48, 60, and 96 
Secondary - Other 
 
To evaluate the 
pharmacokinetics (PK) and 
immunogenicity of aflibercept 
• 
Systemic exposure to aflibercept as assessed by 
plasma concentrations of free, bound, adjusted bound 
and total aflibercept from baseline through Week 48 
• 
Assessment of immunogenicity to aflibercept through 
end of study (Week 96) 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 9 of 103
 
 
Table 2–1: Objectives and Endpoints 
Objectives 
Endpoints 
Exploratory 
 
To determine the effect of HD 
versus 2 mg aflibercept on 
functional and anatomic 
measures of response as well as 
on vision-related quality of life 
• 
Change from baseline in BCVA measured by the 
ETDRS letter score at Week 96 
• 
Change from baseline in BCVA averaged over the 
period from Week 36 to Week 48 and from Week 48 to 
Week 60 
• 
Proportion of participants gaining at least 15 letters in 
BCVA from baseline at Week 60 and Week 96 
• 
Proportion of participants achieving an ETDRS letter 
score of at least 69 (approximate 20/40 Snellen 
equivalent) at Week 60 and Week 96  
• 
Proportions of participants gaining and losing at least 5 
or at least 10 letters in BCVA from baseline at 
Week 48, Week 60, and Week 96 
• 
Proportion of participants losing at least 15 letters in 
BCVA from baseline at Week 48, Week 60, and 
Week 96 
• 
Change in CNV size from baseline to Week 60 and 
Week 96 
• 
Change in total lesion area from baseline to Week 60 
and Week 96 
• 
Change from baseline in CST at Week 60 and 
Week 96  
• 
Proportion of participants with no IRF and no SRF in 
the central subfield at Week 96  
• 
Proportion of participants without retinal fluid (total 
fluid, IRF, and/or SRF) and subretinal pigment 
epithelium (subRPE) fluid in central subfield at 
Week 48, Week 60, and Week 96 
• 
Time to fluid-free retina over 48 weeks, 60 weeks, and 
96 weeks (total fluid, IRF, and/or SRF in the central 
subfield) 
• 
Proportion of participants with sustained fluid-free 
retina over 48 weeks, 60 weeks, and 96 weeks (total 
fluid, IRF, and/or SRF in the central subfield)  
• 
Change from baseline in NEI-VFQ-25 total score at 
Week 60 and Week 96 
• 
Proportion of participants without leakage on 
fluorescein angiography (FA) at Week 48, Week 60, 
and Week 96 
To evaluate the duration of effect 
of HD after 3 initial doses at 
4-week intervals followed by 
dosing q12 or q16 
• 
Proportion of participants with q16 or longer treatment 
interval through Week 48, Week 60, and Week 96 in 
HDq16 group 
• 
Proportion of participants with q12 or longer interval 
through Week 48, Week 60, and Week 96 in the 
HDq12 and HDq16 groups  
• 
Proportion of participants with q12 or q16 or longer 
treatment interval as the last treatment interval at 
Week 48, Week 60, and Week 96 in HDq12 and 
HDq16 groups, respectively 
Based on dense PK sampling, 
characterize the concentrations 
in plasma over time, and 
corresponding PK parameters 
• 
Concentrations of free, bound, adjusted bound and 
total aflibercept over time, and PK parameters 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 10 of 103
 
 
Table 2–1: Objectives and Endpoints 
Objectives 
Endpoints 
for aflibercept  
For all participants, explore the 
relationship between PK and 
selected systemic and ocular 
response variables 
• 
Relationship of free aflibercept concentrations and 
blood pressure 
• 
Dose and/or exposure-response analyses for select 
safety and efficacy endpoints, as appropriate 
Other Pre-specified Objectives  These objectives will be reported outside of the CSR. 
To study molecular drivers of 
nAMD or related diseases, 
clinical efficacy of aflibercept, 
and affected molecular pathways 
• 
Evaluation of clinical efficacy parameters by repertoire 
or frequency of genetic alterations (genomics 
substudy) 
• 
Treatment related changes in circulating biomarkers 
(future biomedical research [FBR]) 
Additional pre-specified exploratory efficacy endpoints and analyses are added to this SAP 
for submission to the US FDA (based on the G-SAP that constitutes the primary analysis for 
the study). See Appendix 9.7 for details. 
 
3. 
Study Design 
This is a randomized, double-masked (participant and investigator masked), active-controlled, 
multi-center study with 3 parallel groups. 
The study consists of a screening/baseline period, a treatment period with duration of 
92 weeks, and an end of study visit at Week 96 (and a safety follow-up visit at Week 100 for 
French participants only). No study intervention will be administered at the end of study visit 
at Week 96 (or Week 100). 
Approximately 960 eligible participants with nAMD will be randomly assigned to receive 
IVT injections of HD or 2 mg in a 1:1:1 ratio to 3 parallel treatment groups (320 in each 
group): 
• 2q8: aflibercept 2 mg administered every 8 weeks, after 3 initial injections at 
4-week intervals.  
• HDq12: aflibercept 8 mg administered every 12 weeks, after 3 initial injections at 
4-week intervals. 
• HDq16: aflibercept 8 mg administered every 16 weeks, after 3 initial injections at 
4-week intervals. 
Participants will be centrally assigned to randomized study intervention using an Interactive 
Response System (IXRS). 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 in the study protocol. 
Participants will be stratified based on baseline BCVA (<60 vs. ≥60) and geographical region 
(Japan vs. Rest of World), to ensure balanced distribution of the treatment groups within each 
stratum. A Dense PK Substudy is planned to be conducted in 24 participants (refer to Section 
6.3.2). 
Only one eye can be treated within the study. Sham procedures will be done on visits when an 
active injection is not planned. No sham procedures will be done at the non-treatment visits 5 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 11 of 103
 
 
(Day 60-64) and 6 (Week 12). At all subsequent visits, all participants will receive either 
active study treatment injection or sham procedure (for masking purposes), depending on 
their assigned treatment schedule (including any changes to the interval based on the dose 
regimen modification (DRM) assessments). 
For masking purposes, assessments for DRM will be performed in all participants at all visits 
(through the IXRS) starting from Week 16.  
Based on these assessments, participants in the HD groups may have their treatment intervals 
shortened or extended. The minimum interval between injections will be 8 weeks, which is 
considered a rescue regimen for participants randomized to HD aflibercept who are unable to 
tolerate a dosing interval greater than every 8 weeks. Participants in the aflibercept 2 mg 
group will remain on fixed q8 dosing throughout the study (i.e., will not have modifications of 
their treatment intervals regardless of the outcomes of the DRM assessments). 
Beginning at Week 16, participants in the HD groups may have the dosing interval shortened 
based on meeting pre-specified DRM criteria. 
Starting at Week 52, all participants randomized to HDq12 or HDq16 will be eligible for 
adjustments of their treatment intervals (shortening or extension) based on pre-specified DRM 
criteria, with the dose interval adjustments (shortening or extension) becoming effective at or 
after Week 60. All participants will be followed every 4 weeks through Week 96 (Week 100 
for French participants only). 
Due to differing requirements for the submission to regulatory authorities, 2 different testing 
strategies will be applied, which will be detailed in this SAP document: a Global plan (G-
SAP) and an European Medicines Agency [EMA] and Pharmaceuticals and Medical Devices 
Agency [PMDA] plan (EP-SAP). The G-SAP will constitute the main analysis for the study. 
The EP-SAP has been specifically planned for submission to the EMA/PMDA regulatory 
authorities. 
An analysis of data up to Week 48 (including the primary efficacy analysis according to the 
G-SAP) will take place once all participants have completed Week 48 (or prematurely 
discontinued). A further analysis of data up to Week 60 (including a confirmatory analysis at 
this time point according to the EP-SAP) will take place once all participants have completed 
Week 60 (or prematurely discontinued). Furthermore, a descriptive analysis of all data will be 
conducted after all participants have completed the study at Week 96 (or prematurely 
discontinued). This SAP covers all three planned analyses. 
The databases and analyses at Week 48 and Week 60 will only include study intervention 
information up to the visit prior to Week 48 and Week 60, respectively. For these visits 
(Week 48 and Week 60, respectively), only data assessed prior to the study intervention will 
be part of the database/analyses. Further details are provided in a separate document “Data 
Cut-Off Specifications”. 
Masking of the study site personnel will continue until the end of the study. 
Masking/unmasking of the study team is described in the study protocol and will further be 
detailed in the blinding maintenance plan. 
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 12 of 103
 
 
4. 
General Statistical Considerations 
4.1 
General Principles 
Continuous data will be summarized in terms of the number of observations, mean, standard 
deviation (SD), median, quartiles, minimum, and maximum. The minimum and maximum 
will be reported to the same number of decimal places as the raw data recorded in the 
database (DB). All other statistics (mean, median, quartiles, arithmetic SD, confidence 
intervals [CI]) will have one additional decimal place more than the raw data recorded in the 
database.  
Categorical data will be summarized in terms of the number of participants 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. Percentages will be 
calculated using n (the number of observations with non-missing values) as the denominator, 
except for outputs where the denominator is already specified differently. Change from 
baseline will be calculated as the visit value of interest minus the baseline value.  
All p-values should have 4 decimal digits; in case of p-values less than 0.0001, the 
documentation should be <.0001. 
The statistical evaluation will be performed by using the software package SAS release 9.4 or 
higher (SAS Institute Inc., Cary, NC, USA).  
4.1.1 
Determination of Sample Size 
The sample size calculation is based on the primary endpoint analysis, “change from baseline 
in BCVA measured by Early Treatment Diabetic Retinopathy Study (ETDRS) letter score to 
Week 48” in 2 comparisons to assess non-inferiority: HDq12 versus 2q8, and HDq16 versus 
2q8. 
The sample size has been calculated under the following assumptions: 
• The changes in BCVA letter score from baseline are normally distributed. 
• The true difference in the mean change in BCVA between HDq12 and 2q8, and between 
HDq16 and 2q8 is 0 letters. 
• The SD of the residuals is 
 (derived from the residuals of an analysis of covariance 
(ANCOVA) analysis of the VIEW1/VIEW2 studies). 
Under the hierarchical testing strategy, a sample size of 288 evaluable participants per group 
provides 94% power for rejecting the initial null hypothesis (HDq12 vs 2q8) for the primary 
endpoint assessing non-inferiority with a 1-sided t-test at significance level of 0.025. The 
power to reject both primary null hypotheses (HDq12 vs 2q8 and HDq16 vs 2q8) is 88%. 
Under the prior testing strategy that was planned originally (before Protocol version 3.0, 
Global Amendment 2), a sample size of 288 evaluable participants per group provides 90% 
power for rejecting each of the null hypotheses for the primary endpoints assessing non-
inferiority (HDq12 vs 2q8 and HDq16 vs 2q8) with a 1-sided t-test at significance level of 
1.25% (=2.5%/2 Bonferroni correction). 
Approximately 10% of the participants are assumed to drop out before Week 48 (time point 
of the primary endpoints). Therefore, approximately 320 participants are to be randomized in 
each group, leading to a total sample size of approximately 960 participants. 
CCI


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 13 of 103
 
 
Approximately 1600 participants will be screened to achieve 960 randomly assigned to study 
intervention and total of 864 evaluable participants for an estimated number of 288 evaluable 
participants per intervention group. 
Justification of Japanese sample size 
Out of the total sample size of approximately 960 participants, at least 96 (10%) are to be 
enrolled in Japan in order to provide consistent results with a certain probability.  
For superiority trials, the PMDA guidance (1) proposes to determine the number of Japanese 
participants so that DJapan / Dall > π will occur with a probability of 80 % or higher, whereas 
Dall is the treatment difference in the entire study population across regions, and DJapan is the 
treatment difference within the Japanese sub-population. Furthermore, π = 0.5 is generally 
recommended.  
As the present study is a non-inferiority trial, this consistency criterion is adapted as follows: 
(DJapan + non-inferiority margin) / (Dall + non-inferiority margin) > π.  
With the sample size of at least 96 Japanese participants and π = 0.5:  
• the probability to show a consistent result in at least one of the 2 hypothesis tests for the 
primary endpoints assessing non-inferiority (HDq12 vs. 2q8 and HDq16 vs. 2q8)) 
described in Section 6.2.2 is 81%.  
• the probability to show a consistent result in one particular hypothesis test for the primary 
endpoints is 71%. 
4.2 
Handling of Dropouts 
Dropouts will be defined as participants who prematurely discontinue from the study and 
study intervention at the same time for any reason. This includes also participants who are lost 
to follow-up. Possible reasons for premature discontinuation from the study can be found in 
the protocol, Section 7.2. Additionally, participants might prematurely discontinue from the 
study and study intervention due to the COVID-19 pandemic. It may be also necessary for a 
participant to permanently discontinue study intervention, while remaining in the study to be 
evaluated for safety evaluation as described in the protocol, Section 7.1.  
In the case of such premature discontinuation of the study intervention, all assessments, as 
described in the protocol for the end of study/early discontinuation (ED) visit, should be 
completed (ED assessments). If the discontinuation from the study and from the study 
intervention is happening at the same time, an ED visit should be completed (see 
Section 4.5.3) while for participants who prematurely discontinued study intervention at the 
timing of one of their regular study intervention visits (i.e. Visits 3-26) but remained in the 
study afterwards, all ED assessments that were not planned at the respective visit, should be 
entered as unscheduled assessments and need to be re-mapped to the regular visit, since some 
assessments are not scheduled to be conducted at each visit. 
Data assessed after the time period as described in Table 9–12 below, but prior to study 
completion or discontinuation will not be used in the main confirmatory analysis of primary 
and key secondary endpoints. 
Handling of missing data due to dropouts is described in Section 6.2 for efficacy variables. 
No action for missing data due to dropouts is taken for other variables. Participants who 
dropped out will not be excluded from any summaries except where clearly stated.  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 14 of 103
 
 
4.3 
Handling of Missing Data 
All missing or partial data will be presented in the participant data listing as they are recorded 
on the Case Report Form (CRF). 
4.3.1 
Additional Descriptive Analyses in the Presence of Missing Data 
The number of participants 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.  
4.3.2 
General Rules 
Where appropriate, the following rules will be implemented so as not to exclude participants 
from statistical analyses due to missing or incomplete data: 
• Efficacy Variables 
Statistical methods for missing data due to dropouts in efficacy variables is described in 
Section 6.2. 
• Concomitant medication and adverse events 
For AEs and medications the complete start and stop date must be available to determine 
if the AE or medication is occurring during the study intervention period. When only 
partial dates are available, the following rules will be used: 
If only month and year of the start date are available and the end date is after the date of 
first study intervention, impute with the first day of the month or with the date of the first 
study intervention (i.e. first injection in the study eye), whichever occurs later. 
If only the year of the start date is available and the end date is after the date of first study 
intervention, impute with month and day of first study intervention or with the first day of 
the year, whichever occurs later. 
Imputed dates will only be used for summary tables, listings will contain the original 
(partial) entries. 
4.4 
Interim Analyses and Data Monitoring 
No interim analyses in the sense of a group-sequential or adaptive design are planned.  
An analysis of data up to Week 48 (including the primary efficacy analysis) will take place 
once all participants have completed Week 48 (or prematurely discontinued). A further 
analysis of data up to Week 60 (including a confirmatory analysis at this time point for 
regulatory submission to EMA and PMDA) will take place once all participants have 
completed Week 60 (or prematurely discontinued). A final analysis of all data will be 
conducted after all participants have completed the study at Week 96 (or prematurely 
discontinued). 
An independent Data Monitoring Committee (DMC) will meet periodically to review the 
ongoing masked and unmasked safety data of participants in the study and to provide 
recommendations to continue or terminate the study depending upon these reviews. The 
operation of the DMC is governed by a charter that describes the group’s frequency of 
meeting, procedures (including but not limited to periodic safety monitoring), and 
requirements for reporting its observations to the sponsor. No early stopping for 
overwhelming efficacy is foreseen (consequently no alpha level adjustment will be done with 
regards to DMC analyses). 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 15 of 103
 
 
A Steering Committee will have close communication with the DMC, but only masked data 
will be shared or discussed. The study protocol provides more details on this.  
Furthermore, potential arterial thromboembolic events (ATEs) will be evaluated by a masked 
adjudication committee prior to database unmasking. ATEs as defined by the Anti-Platelet 
Trialists’ Collaboration (APTC) criteria include nonfatal myocardial infarction, nonfatal 
ischaemic stroke, nonfatal haemorrhagic stroke, or death resulting from vascular or unknown 
causes. 
4.5 
Data Rules 
4.5.1 
Determination of Baseline Values 
Baseline values are defined as the last valid non-missing measurement at or prior to 
randomization (including scheduled and unscheduled assessments). This may be the 
measurement at screening (Visit 1) or the measurement at baseline (Visit 2) depending on the 
planned timing of procedures for each study visit. The study protocol provides more details 
on the timing of study procedures. 
For systolic and diastolic blood pressure the baseline value is defined as the average of all 
measurements at or prior to randomization (for participants who failed the initial screening, 
measurements taken at the initial screening visit will not be included). 
4.5.2 
Unscheduled Assessments 
Any measurements taken at unscheduled visits will be shown in subject 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.  
4.5.3 
End of Study / Early Discontinuation Visit 
Participants may discontinue prematurely from study intervention. At the same time or later 
participants may discontinue prematurely from study. In case of premature discontinuation of 
the study and/or study intervention, all assessments should be completed, as described in the 
protocol for the end of study (EOS)/ED visit.  
For participants who discontinue prematurely from the study and/or study intervention, visit-
based information recorded in the EOS/ED visit folder might be re-mapped to the regular 
study visit, if the EOS/ED visit was performed within the relevant regular visit window and 
the corresponding regular study visit was not perfomed (see detailed rules below). Visit-based 
information recorded in the EOS/ED visit folder which cannot be re-mapped to the regular 
study visit will be mapped to “ED Visit” and handled like unscheduled assessments, described 
in the section above.  
For participants who completed the study and study intervention, no re-mapping is necessary, 
but visit-based information recorded in the EOS/ED visit folder will be mapped to “Visit 27 / 
Week 96” and displayed in summary tables as such.  
For some variables this can result in data for visits at which this variable was not scheduled to 
be collected. This data will nevertheless be included into the LOCF analyses. In descriptive 
by visit summary tables and also in repeated measurement analysis, only the pre-planned 
scheduled visits should be shown/included. 
Mapping of selected assessments to regular study visits  
The following assessments will be mapped:  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 16 of 103
 
 
• BCVA (ETDRS) and Refraction (24) 
• IOP 
• Slit Lamp Examination 
• Indirect Ophthalmoscopy 
• SD-OCT 
• Vital signs 
• Pregnancy test 
The following rule will be used:  
• If EOS/ED visit performed within visit window of a regular study visit (as specified in 
the “Schedule of Activities” in the protocol), then re-mapping to regular study visit  
For example, if a participant discontinued prematurely (study and/or study intervention) at the 
timing of Visit 3 / Week 4 (i.e. EOS/ED visit date = study day 29±5 days), then any of the 
assessments listed above recorded in the EOS/ED visit folder will be re-mapped to regular 
study Visit 3, unless a regular study Visit 3 was already perfomed.  
No remapping to Visit 5 will be done (i.e. PK collection visit only).  
4.5.4 
Imaging data assessed by the reading center 
If imaging data have been assessed by the reading center, but were also captured in the eCRF, 
only the data assessed by the reading center will be used for the analysis. 
In summary tables the following parameters will be evaluated and classified as follows: 
From spectral domain optical coherence tomography (SD-OCT) assessment:  
• Intraretinal fluid (IRF) in central subfield (Reading center variable: IRF presence 
[IRF], Testname in OE domain: IRTFLVIS): 
o IRF=No (if any of them is ticked): 
▪ Absent 
▪ Definite, outside center subfield only  
▪ Questionable 
o IRF=Yes (if any of them is ticked): 
▪ Definite, only non-cystoid, center subfield involved 
▪ Definite, cystoid, center subfield involved 
o IRF=Undetermined (if any of them is ticked): 
▪ Cannot Grade 
▪ Not Applicable 
• Subretinal fluid (SRF) in central subfield (Reading center variable: SRF presence 
[SRF], Testname in OE domain: SRFVIS): 
o SRF=No (if any of them is ticked): 
▪ Absent 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 17 of 103
 
 
▪ Definite, outside center subfield only  
▪ Questionable 
o SRF=Yes: 
▪ Definite, center subfield involved 
o SRF=Undetermined (if any of them is ticked): 
▪ Cannot Grade 
▪ Not Applicable 
• Subretinal pigment epithelium (subRPE) fluid in central subfield (Reading center 
variable: SubRPE fluid [SRPEFP], Testname in OE domain: SRPEFP): 
o SubRPE fluid =No (if any of them is ticked): 
▪ Absent 
▪ Definite, outside center subfield only  
▪ Questionable 
o SubRPE fluid =Yes: 
▪ Definite, center subfield involved 
o SubRPE fluid = Undetermined (if any of them is ticked): 
▪ Cannot Grade 
▪ Not Applicable 
• IRF in foveal center (Reading center variable: IRF presence at center point [IRFPCP], 
Testname in OE domain: PRIRFCP): 
o IRF in foveal center = No (if any of them is ticked): 
▪ IRF presence = Absent  
▪ IRF presence = Questionable  
▪ IRF presence = Definite, outside center subfield only  
▪ IRF presence = Definite, only non-cystoid, center subfield involved  
AND IRF presence at center point = Absent  
▪ IRF presence = Definite, only non-cystoid, center subfield involved  
AND IRF presence at center point = Questionable  
▪ IRF presence = Definite, cystoid, center subfield involved  
AND IRF presence at center point = Absent  
▪ IRF presence = Definite, cystoid, center subfield involved  
AND IRF presence at center point = Questionable  
o IRF in foveal center=Yes (if any of them is ticked): 
▪ IRF presence = Definite, only non-cystoid, center subfield involved  
AND IRF presence at center point = Definite 
▪ IRF presence = Definite, cystoid, center subfield involved  
AND IRF presence at center point = Definite 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 18 of 103
 
 
o IRF in foveal center=Undetermined (if any of them is ticked): 
▪ IRF presence = Cannot Grade 
▪ IRF presence = Not Applicable 
▪ IRF presence = Definite, only non-cystoid, center subfield involved  
AND IRF presence at center point = Cannot Grade 
▪ IRF presence = Definite, only non-cystoid, center subfield involved  
AND IRF presence at center point = Not Applicable 
▪ IRF presence = Definite, cystoid, center subfield involved  
AND IRF presence at center point = Cannot Grade 
▪ IRF presence = Definite, cystoid, center subfield involved  
AND IRF presence at center point = Not Applicable 
• SRF in foveal center (Reading center variable: SRF presence at center point 
[SRFPCP], Testname in OE domain: SRFPCP ): 
o SRF in foveal center=No (if any of them is ticked): 
▪ SRF presence = Absent  
▪ SRF presence = Questionable  
▪ SRF presence = Definite, outside center subfield only  
▪ SRF presence = Definite, center subfield involved  
AND SRF presence at center point = Absent  
▪ SRF presence = Definite, center subfield involved  
AND SRF presence at center point = Questionable  
o SRF in foveal center=Yes: 
▪ SRF presence = Definite, center subfield involved  
AND SRF presence at center point = Definite 
o SRF in foveal center=Undetermined (if any of them is ticked): 
▪ SRF presence = Cannot Grade 
▪ SRF presence = Not Applicable 
▪ SRF presence = Definite, center subfield involved  
AND SRF presence at center point = Cannot Grade 
▪ SRF presence = Definite, center subfield involved  
AND SRF presence at center point = Not Applicable 
• Central subfield retinal thickness (CST) (Reading center variable: SECTORC, 
Testname in OE domain: RETHKSEC, note: it is recorded in mm but needs to be 
summarized in µm) 
From fluorescein angiography (FA)/ fundus photography (FP) assessment: 
• Geographic atrophy (GA) (Reading center variable: GA, Testname in OE domain: 
GAVIS): 
o GA=No (if any of them is ticked): 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 19 of 103
 
 
▪ Absent 
▪ Questionable 
o GA=Yes: 
▪ Definite 
o GA=Not available (if any of them is ticked): 
▪ Cannot Grade 
▪ Not Applicable 
• Choroidal neovascularization (CNV) size (Reading center variable: CNVCLSZ [Total 
CNV area – AreaSize], Testname in OE domain: CNVSIZE, note: it is recorded in 
mm2) 
• CNV type (Reading center variable: CNVTYPE, Testname in OE domain: 
CNVTYPE): 
o CNVTYPE= Type 1 – occult or PCV: 
▪ Type 1 
o CNVTYPE= Type 2 – classic CNV: 
▪ Type 2 
o CNVTYPE= Type 1 and Type 2 – both classic and occult are present: 
▪ Type 1 and Type 2 
o CNVTYPE= Type 3 – RAP: 
▪ Type 3 
o CNVTYPE= Cannot grade: 
▪ Cannot grade 
o CNVTYPE= Not applicable – no CNV present: 
▪ Not applicable 
• CNV classification (Reading center variable: CNVCLASS, Testname in OE domain: 
CNVCLASS) 
o CNVCLASS: 
▪ CNV less than 50% of lesion 
▪ Predominantly classic 
▪ Minimally classic 
▪ Occult only 
▪ RAP 
▪ PCV 
▪ Cannot grade 
▪ Not applicable 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 20 of 103
 
 
• Total lesion area (Reading center variable: TLEAREA [Total lesion area within 
ETDRS grid – AreaSize], Testname in OE domain: TLESAREA, note: it is recorded 
in mm2) 
• Leakage on fluorescein angiography (based on reading center variables LEAAREA 
[Leakage Area], LEASIZE [Area Size - Total Leakage Area], RPERIPTE [Presence of 
RPE Rip Tear (Macular)], Testnames in OE domain: LEAKAREA, LEAKSIZE, 
RPERIPTE) 
o Leakage = No (when the following is fulfilled): 
▪ LEAAREA = “Not Applicable” and RPERIPTE is not ”Definite” 
o Leakage = Yes (when the following is fulfilled): 
▪ LEAAREA is not “Not Applicable” and is not “Cannot grade” and 
LEASIZE > 0 
o Leakage = Undetermined (when any of the following is fulfilled): 
▪ LEAAREA = “Not Applicable” and RPERIPTE=” Definite” 
▪ LEAAREA = “Cannot grade” 
From indocyanine green angiography (ICGA) assessment: 
• Polypoidal choroidal vascularization (PCV) (Reading center variable: PCV, Testname 
in OE domain: PCV) 
o PCV=No (if any of them is ticked): 
▪ Absent 
▪ Questionable 
o PCV=Yes: 
▪ Definite 
o PCV=Not available (if any of them is ticked): 
▪ Cannot Grade 
▪ Not Applicable 
The subgroup of participants with PCV is defined as participants with “Definite” PCV in the 
ICGA assessment (Reading center variable: PCV, Testname in OE domain: PCV) or “PCV” 
as CNV classification in the FA/FP assessment (Reading center variable: CNVCLASS, 
Testname in OE domain: CNVCLASS).  
4.5.5 
Definition of Fellow Eye Treatment 
Fellow eye treatment will be identified from the prior and concomitant medication page by 
• selecting for any of the following medications:  
o Aflibercept (trade name: Eylea) 
o Bevacizumab (trade name: Avastin) 
o Brolucizumab (trade name: Beovu) 
o Ranibizumab (trade name: Lucentis) 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 21 of 103
 
 
o Faricimab (trade name: Vabysmo) 
o Conbercept (trade name Lumitin) 
o Pegaptanib sodium (trade name: Macugen) 
• and selecting for the laterality of the fellow eye. 
Medication that was administered prior to the first dose of study treatment will be considered 
prior fellow eye treatment, whereas medication that was administered at the first dose of study 
treatment or later will be considered concomitant fellow eye treatment (i.e. bilateral 
treatment).  
4.5.6 
Definition of Prohibited Medications 
Prohibited medications as identified from the prior and concomitant medication page are 
• any of the following anti-VEGF medications 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) 
• as well as those following medications 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. 
4.6 
Masked Review 
Upon each database release (Week 48, Week 60 and Week 96), listings of masked 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, where for Week 48 database release it will be decided which participants will be 
excluded from the per protocol set. The validity for the different analysis sets for the analysis 
at Week 48, Week 60 and Week 96, respectively, and especially the decision at Week 48 
database release regarding the exclusion of participants from the per protocol analysis will be 
determined. Note, the PPS should not change throughout the analysis at Week 48, Week 60 
and Week 96, respectively, since exclusion of subjects is mainly based on screening/baseline 
data which will not change over time.  
For determining the validity for the different analysis sets, all participants of these meetings 
are masked to the treatment assignment and to the detailed results. The results of these 
meetings may comprise decisions and details relevant for statistical evaluation. Any changes 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 22 of 103
 
 
to the statistical analysis prompted by the results of the Data Review Meetings will be 
documented in an amendment to this SAP. 
After unmasking of the frozen/locked clinical eCRF DB 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 and also to identify those 
PDs that can only be assessed after unmasking. Those evaluations for the analyses at Week 48 
and Week 60 will be done by an unmasked statistician, while the main study team will remain 
masked until the final analysis at Week 96 as described in the blinding maintenance plan. 
4.7 
Outputs/Procedures related to COVID-19 
This study started after the onset of the COVID-19 pandemic. A separate listing will display 
all participants affected by the COVID-19 related study disruption by unique participant 
identifier and by investigational site, and a description of how the participant’s study 
participation was altered. Other listings will display all participants with protocol deviations 
associated with the COVID-19 pandemic and with COVID-19 adverse events. Furthermore, 
tables for participant 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: Participants affected by COVID-19 pandemic related 
study disruption for all enrolled participants 
• Number of participants by country / region for all participants affected by COVID-19 
pandemic related study disruption 
• Number of participants affected by COVID-19 pandemic related study disruption. 
Additional analyses may be added due to regulatory requirements or requests. 
4.8 
Outputs/Procedures related to the Ukraine/Russia crisis 
This study started prior to the onset of the 2022 crisis between Russia and Ukraine and 
includes study sites located in Ukraine and in Russia. A separate listing will display all 
participants affected by the crisis related findings and deviations by unique participant 
identifier and by investigational site, and a description of the finding or deviation. 
Additional analyses may be added due to regulatory requirements or requests. 
 
5. 
Analysis Sets 
Primary and the key secondary efficacy variables will be evaluated on both the Full Analysis 
Set (FAS) and the Per Protocol Set (PPS), all other efficacy variables will be evaluated on the 
FAS only. Safety variables will be analyzed using the Safety Analysis Set (SAF). Sparse 
pharmacokinetic data will be analyzed using the Pharmacokinetic analysis set (PKS), while 
dense pharmacokinetic data will be analyzed using the Dense Pharmacokinetic Analysis Set 
(DPKS). Anti-drug antibody (ADA) data will be analyzed using the ADA Analysis Set (AAS) 
and neutralizing antibody (NAb) data will be analyzed using the NAb Analysis Set (NAbAS). 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 23 of 103
 
 
5.1 
Assignment of Analysis Sets 
Final decisions regarding the assignment of participants to analysis sets will be made during 
the Data Review Meetings prior to unmasking at Week 48, Week 60 and Week 96 and the list 
of important deviations and validity findings leading to exclusion from analysis sets as well as 
assignment to analysis sets will be documented in the Data Review Meeting minutes (see 
Section 4.6). 
Full analysis set (FAS) 
The FAS will include all participants who have been randomly assigned to study intervention 
and who received at least 1 dose of study intervention. Participants will be analyzed within 
their original randomized group (regardless of any changes to dose interval; as randomized). 
Per protocol set (PPS) 
As defined in the protocol, 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 
• had any IRF or SRF affecting the central subfield at baseline according to the 
definitions described in Section 4.5.4. 
Other relevant deviations from the protocol affecting efficacy will be considered as 
intercurrent events in the context of the Estimands strategy described in Section 9.5. 
The final determination on the exclusion of participants from the PPS will be made during the 
Data Review Meeting (on masked data) held in accordance with ICH E9 prior to database 
freeze on Week 48 data. 
Analysis of the PPS will be performed according to the treatment the participant actually 
received (as treated). 
Safety analysis set (SAF) 
The SAF will include all participants who were randomly assigned to study intervention and 
who received at least 1 dose of study intervention. Analysis of the SAF will be performed 
according to the treatment the participant actually received (as treated). 
PK analysis sets 
The PKS will include all participants who received any study intervention and who had at 
least 1 non-missing drug concentration measurement following the first dose of study 
intervention. Analysis of the PKS will be performed according to the treatment the participant 
actually received (as treated). 
The DPKS will include all participants who did not meet any of the additional exclusion 
criteria for the Dense PK Substudy, who gave their written consent to participate in the Dense 
PK Substudy and who had a at least 1 non-missing drug concentration measurement (dense 
PK result) following the first dose of study intervention. Analysis of the DPKS will be 
performed according to the treatment the participant actually received (as treated). 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 24 of 103
 
 
Immunogenicity analysis sets 
The AAS will include all participants who received study intervention and had at least 1 non-
missing result in the ADA assay following the first study dose. 
The NAbAS will include all participants who received any study intervention that are 
included in the ADA analysis set and that tested negative at all ADA sampling times or tested 
positive at one or more post-dose ADA sampling times and had at least one non-missing post-
dose NAb result (either imputed or analysis result).  
Analysis of both immunogenicity analysis sets will be performed according to the treatment 
the participant actually received (as treated). 
As randomized versus as treated  
Since the only systematic deviation from the randomized treatment could occur due to a 
systematic error in the IXRS system set up, it is assumed that, in general, participants are 
treated as randomized (i.e. the randomized treatment group will be considered the actual 
treatment group, unless the participant has not been treated at all after randomization). 
Isolated incorrect treatments at particular timepoints will not constitute a change in the “as 
treated” assignment, but will be considered as intercurrent events (refer to Section 9.5). 
Participants whose “as treated” assignment differs from their “as randomized” assignment 
will be listed. 
5.2 
Definition of Subgroups 
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 
• Geographic region: Japan, Rest of the world 
• Ethnicity: Not Hispanic or Latino, Hispanic or Latino 
• Race (only subgroups with sufficient sample size): White, Asian 
• Baseline BCVA: ≤ 73 letters, > 73 letters 
• Baseline PCV: yes, no (as defined in Section 4.5.4) 
All subgroup analyses will be descriptive only, i.e. any statistical testing / calculation of p-
values were done for exploratory purpose. 
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 
• Geographic region: Japan, Rest of the world  
• Ethnicity: Not Hispanic or Latino, Hispanic or Latino 
• Race (only subgroups with sufficient sample size): White, Asian 
• Medical history of hypertension: No, Yes 
• Medical history of cerebrovascular disease: No, Yes  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 25 of 103
 
 
• Medical history of ischaemic heart disease: No, Yes 
• Medical history of renal impairment: Normal, Mild, Moderate, Severe 
• Medical history of hepatic impairment: No, Yes 
These subgroups are defined in more detail in Appendix 9.4. 
 
6. 
Statistical Methodology 
All summaries will be presented by study intervention. All variables shown in summaries will 
also be included in subject data listings.  
The analysis of the primary and key secondary efficacy endpoints will be done for FAS and 
also for PPS. Pharmacokinetic analysis will be presented for PKS and DPKS. Safety analyses 
will be presented for SAF and immunogenicity analyses also for AAS or NAbAS. 
6.1 
Population Characteristics 
6.1.1 
Demographics and Disease Characteristics 
Demographics and baseline assessments of vital signs to be summarized for FAS, DPKS and 
PPS will include: 
• Age (as entered in CRF)  
• Age categorized (< 65 years, ≥ 65 to < 75 years, ≥ 75 years to < 80 years, ≥ 80 years to < 
85 years, ≥ 85 years) 
• Sex  
• Race (incl. further subgroupings for Asians) and ethnicity 
• Weight (kg) 
• Height (cm) 
• Body mass index (BMI in 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 
• Diastolic blood pressure 
• Heart rate 
• Body temperature (°C) 
• Fellow eye with history of wet AMD (YES/NO) 
• Prior fellow eye treatment (as defined in Section 4.5.6) (YES/NO) 
o Aflibercept  
o Bevacizumab  
o Brolucizumab  
o Ranibizumab  
o Faricimab  
o Conbercept  
o Pegaptanib sodium 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 26 of 103
 
 
• Hypertension: yes, no 
• Medical history of cerebrovascular disease: yes, no 
• Medical history of ischaemic heart disease: yes, no 
• Medical history of renal impairment: normal, mild, moderate, severe 
• Medical history of hepatic impairment: yes, no 
Baseline assessments of disease characteristics to be summarized for FAS, DPKS and PPS 
will include: 
• Baseline BCVA (ETDRS letters score) 
• Categorized baseline BCVA: ≤ 73 letters, > 73 letters 
• Categorized baseline BCVA: < 60, ≥ 60 letters 
• Baseline intraocular pressure (IOP in mmHg) 
• Baseline GA (YES/NO/not available as defined in Section 4.5.4) 
• Baseline PCV (YES/NO/not available as defined in Section 4.5.4) 
• Baseline CST (in µm as defined in Section 4.5.4) 
• Baseline CNV size (in mm2 as defined in Section 4.5.4) 
• Baseline total lesion area (in mm2 as defined in Section 4.5.4) 
• CNV type (as defined in Section 4.5.4) 
• CNV classification (as defined in Section 4.5.4) 
• Baseline National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25, total 
score) 
Demographic data and baseline characteristics variables will be summarized using descriptive 
statistics for all three analysis sets (i.e. FAS, DPKS and PPS). Disease characteristics will be 
presented in a separate table. Only data of the study eye will be shown although most 
examinations are done bilateral.  
6.1.2 
Medical History 
Medical history will be coded according to the version of Medical Dictionary for Regulatory 
Activities (MedDRA) available at database lock. Medical history is evaluated by a frequency 
table, showing number of participants with medical history findings by primary system organ 
class (SOC) and preferred term (PT). 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 
will be summarize, respectively. All summaries will be presented for the SAF. Additionally, a 
listing including medical history records will be provided. 
6.1.3 
Disposition of Study Participants 
The following categories for disposition of participants will be summarized descriptively: 
The total number of participants who signed informed consent, were randomized, treated, 
completed study intervention and completed study for the respective analysis (Week 48, 
Week 60 and Week 96). The summary will include all participants who gave informed 
consent. Participants prematurely discontinuing the study/ study intervention will be 
summarized by reason for discontinuation.  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 27 of 103
 
 
The total number and percentage of participants who qualified as FAS, SAF, PPS, PKS, 
DPKS, AAS and NAbAS (as defined in Section 5.1) including the reasons for exclusion from 
the respective analysis set will be included in a summary table. Participants who were 
excluded from PPS will also be listed. 
The disposition of participants 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 
participants with informed consent and in each analysis set. 
The disposition of participants and the number of 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 participants with important protocol deviations by country and study site will 
be presented for all participants with signed informed consent. Number of screen failures will 
be included. A second summary will show the number and percentage of participants in each 
protocol deviation category for the FAS. Important protocol deviations will be listed for FAS. 
6.1.4 
Exposure and Compliance to Study Intervention 
Compliance and exposure to the study intervention will be analyzed for SAF and PPS. 
Descriptive statistics will be used for analysis. For the analyses at Week 48 only study 
intervention data prior to Week 48 will be used and for the analyses at Week 60 only study 
intervention data prior to Week 60 will be used (as described in a separate document “Data 
Cut-Off Specifications”). 
6.1.4.1 
Compliance 
Compliance with study intervention during the first 48 weeks (60 weeks, 96 weeks, 
respectively) or up to premature discontinuation, respectively, will be calculated per 
participant as follows: 
Compliance = (Number of actual study interventions received during period [before Week 48/ 
Week 60/ Week 96 or up to premature discontinuation, respectively])/ (Number of planned 
study interventions during period [before Week 48/ Week 60/ Week 96 or up to premature 
discontinuation, respectively]) x 100%. 
For example, if a participant will prematurely discontinue the study after Week 20 but before 
or at the Week 24, the denominator will be 5 (i.e. the number of planned injections until 
before Week 24). For the calculation of compliance all injections (regardless if sham or active 
or from scheduled or unscheduled study interventions) will be used. 
Compliance will be summarized for all periods and a listing will be prepared.  
6.1.4.2 
Exposure 
For each participant, 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 active injections  
• Total number of sham injections 
• Total amount of active study treatment (mg) 
• Duration of study intervention calculated in weeks as: [(date of last study intervention 
prior to Week 48/ Week 60/ Week 96) – (date of first study intervention) +28]/7; 28 days 
are added because of the minimum 4-week dosing interval in the study 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 28 of 103
 
 
Based on assigned intervals as determined through IVRS, in accordance with DRM criteria 
(assessed at Week 16, Week 20 and at visits with active injections planned): 
• Proportion of participants with q16 or longer treatment interval through Week 48, Week 
60, and Week 96 in HDq16 group (i.e. all participants on q16 interval for whom it was not 
planned to have their interval shortened to q12 or q8 interval [according to DRM criteria] 
prior to Week 48, prior to Week 60, and prior to Week 96 [i.e. including only DRM 
criteria through Week 44, through Week 56, and through Week 92]) – exploratory 
endpoint 
• Proportion of participants with q12 or longer interval through Week 48, Week 60, and 
Week 96 in the HDq12 and HDq16 groups (i.e. all participants on q12 or q16 interval for 
whom it was not planned to have their interval shortened to q8 interval [according to 
DRM criteria] prior to Week 48, prior to Week 60, and prior to Week 96 [i.e. including 
only DRM criteria through Week 44, through Week 56, and through Week 92]) – 
exploratory endpoint 
• Proportion of participants with q12 or q16 or longer treatment interval as the last intended 
treatment interval at Week 48, Week 60, and Week 96 in HDq12 and HDq16 groups, 
respectively (based on DRM criteria assessed at the last visit with active injection before 
Week 48, Week 60, and Week 96 [i.e. including DRM criteria until Week 44, through 
Week 56, and through Week 92]) – exploratory endpoint 
• Proportion of participants shortening treatment interval to q8 at Week 16 in HDq12 and 
HDq16 groups, respectively (i.e. immediately / never tolerated intervals longer than q8) 
• Proportion of participants shortening treatment interval to q8 at Week 20 in HDq12 and 
HDq16 groups, respectively (i.e. immediately / never tolerated intervals longer than q8) 
• Proportion of participants shortening treatment interval at anytime through Week 48, 
Week 60, and Week 96 in HDq12 and HDq16 groups, respectively 
o Proportion of participants shortening treatment interval to q8 at anytime 
through Week 48, Week 60, and Week 96 in HDq12 and HDq16 groups, 
respectively  
o Proportion of participants shortening treatment interval to q12 at anytime 
through Week 48, Week 60, and Week 96 in HDq12 and HDq16 groups, 
respectively 
• Proportion of participants never extending treatment interval through Week 60, and 
Week 96 in HDq12 and HDq16 groups, respectively  
• Proportion of participants extending treatment interval at anytime through Week 60, and 
Week 96 in HDq12 and HDq16 groups, respectively 
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 48 (excluding intervention data at Week 48) – summary to be 
displayed at Week 48 and Week 60 analysis, 
• from Baseline to Week 48 (excluding intervention data at Week 48, only participants 
considered as completer for Week 48) – summary to be displayed at Week 48 and 
Week 60 analysis, 
• from Baseline to Week 60 (excluding intervention data at Week 60), 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 29 of 103
 
 
• from Baseline to Week 60 (excluding intervention data at Week 60, only participants 
considered as completer for Week 60), 
• from Baseline to end of study (Week 96), 
• from Week 48 to end of study (Week 96). 
For each participant who received concomitant fellow eye treatment (as defined in 
Section 4.5.6), the following variables will be shown for SAF only: 
• Total number of injections in fellow eye 
• Participants without concomitant fellow eye treatment 
• Participants with concomitant fellow eye treatment 
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) 
Listings will show the participants’ exposure duration, the number of sham and active 
injections. All participants who met DRM criteria will be listed separately.  
6.1.5 
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 World Health Organization 
Drug Dictionary (WHO Drug Dictionary) available at database lock. 
Prior and concomitant medication will be presented for the number and percentage of 
participants who took at least one prior and (new) concomitant medication and by ATC class 
(level 1) and subclass (level 2) for the SAF. Participants with prior and concomitant 
medication will be summarized for all medications. All medication will be included in a 
listing including reason for use, start and end dates and dosage information for the SAF. The 
following definitions will be used: 
• 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 4.5.6) will be collected as concomitant 
medication. 
All prior and concomitant medication will be listed.  
6.2 
Efficacy 
Due to differing requirements for the submission to regulatory authorities, 2 different testing 
strategies for the analysis at Week 48 and the analysis at Week 60 will be applied and 
described in detail in this section. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 30 of 103
 
 
Furthermore, a descriptive analysis of all data will be conducted after all participants have 
completed the study at Week 96 (or prematurely discontinued).  
All efficacy analyses will be evaluated based on the FAS, which is considered the primary 
analysis set for all efficacy endpoints. As a supplementary analysis the primary endpoint and 
the key secondary endpoint “dryness at Week 16” will also be evaluated based on the PPS. 
The key secondary endpoint “BCVA change at Week 60” will also be evaluated based on the 
PPS. 
All efficacy analyses will be using the injection visits (i.e., multiples of 4 weeks) and not the 
calendar time as unit. 
The main confirmatory analysis of the primary and key secondary endpoints will only contain 
data up to the time period which has been described in Table 9–12 and Table 9–13 below. 
6.2.1 
Confirmatory Hypothesis Testing 
For the G-SAP, statistical hypotheses of the primary endpoint (BCVA at Week 48) and the 
key secondary endpoint (dryness at Week 16) will be assessed together, after all participants 
completed Week 48 (or discontinued prematurely) using the below described methods. 
For the EP-SAP, statistical hypotheses of primary endpoint (BCVA at Week 48) and the key 
secondary endpoints (BCVA at Week 60, dryness at Week 16) will be assessed together, after 
all participants completed Week 60 (or prematurely discontinued) using the below described 
methods. For this EP-SAP a repetition of the analysis of the primary endpoint (BCVA at 
Week 48) and the key secondary endpoint (dryness at Week 16) as well as all additional 
secondary and exploratory endpoints at Week 48 will not be done, but reference will be made 
to the analyses performed after all participants completed Week 48 (or discontinued 
prematurely) using the below described methods (i.e. Week 48 database). 
The overall family-wise type 1 error will be controlled at 0.025 (one-sided tests) for testing 
the primary and key secondary endpoints. Adjustment for multiple comparisons in the 
primary and key secondary endpoints will be made with a hierarchical testing procedure (see 
Table 6–1). This approach allows the confirmatory testing of a hypothesis at the full alpha 
level of 0.025 after successful rejection of the hypotheses which are ranked higher in the 
hierarchy. 
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 31 of 103
 
 
Table 6–1: Testing Order of Hierarchical Testing Procedure in G-SAP and EP‑SAP 
G-SAP 
EP-SAP 
H10: non-inferiority of HDq12 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at Week 
48” 
H10: non-inferiority of HDq12 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at Week 
48” 
H20: non-inferiority of HDq12 vs. 2q8 in key 
secondary endpoint “Change from baseline in 
BCVA at Week 60” 
H30: non-inferiority of HDq16 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at Week 
48” 
H30: non-inferiority of HDq16 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at Week 
48” 
H40: non-inferiority of HDq16 vs. 2q8 in key 
secondary endpoint “Change from baseline in 
BCVA at Week 60” 
H50: superiority of pooled high dose vs. 2q8 in key 
secondary endpoint “Proportion of participants with 
no IRF and no SRF in central subfield at Week 16” 
H50: superiority of pooled high dose vs. 2q8 in key 
secondary endpoint “Proportion of participants with 
no IRF and no SRF in central subfield at Week 16” 
H60: superiority of HDq12 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at Week 
48” 
H60: superiority of HDq12 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at Week 
48” 
H70: superiority of HDq12 vs. 2q8 in key secondary 
endpoint “Change from baseline in BCVA at Week 
60” 
H80: superiority of HDq16 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at Week 
48” 
H80: superiority of HDq16 vs. 2q8 in primary 
endpoint “Change from baseline in BCVA at Week 
48” 
H90: superiority of HDq16 vs. 2q8 in key secondary 
endpoint “Change from baseline in BCVA at Week 
60” 
2q8=aflibercept 2 mg administered every 8 weeks, after 3 initial injections at 4 week intervals, 
BCVA=best corrected visual acuity, EMA=European Medicines Agency, EP-SAP=EMA/PMDA 
statistical analysis plan, G-SAP=global statistical analysis plan, HDq12=aflibercept 8 mg 
administered every 12 weeks, after 3 initial injections at 4 week intervals, HDq16=aflibercept 8 mg 
administered every 16 weeks, after 3 initial injections at 4 week intervals, IRF= intraretinal fluid, 
IVT=intravitreal, PMDA=Pharmaceuticals and Medical Devices Agency, 
SRF=subretinal fluid 
 
6.2.2 
Primary Efficacy Endpoint 
The primary endpoint is the change in BCVA (as measured by ETDRS letter score) from 
baseline at Week 48. 
All main analyses described below for the primary efficacy variable will be analyzed for the 
FAS and the PPS, where the analysis for the FAS is considered as the primary one. 
The estimand of primary interest will mainly be based on a hypothetical strategy. It describes 
the change from baseline for all participants that started treatment assuming all participants 
have stayed on treatment until Week 48. 
The estimand is specified through the following definitions of population, variable, treatment 
condition, intercurrent events, and population-level summary: 
Target population:  
Defined by the inclusion/exclusion criteria.  
Variable:  
Absolute change from baseline to Week 48 in BCVA. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 32 of 103
 
 
Treatment condition:  
HD aflibercept administered HDq12 with option for 
DRM/rescue regimen, or HDq16 with option for DRM/rescue 
regimen, versus aflibercept 2 mg administered 2q8. 
Intercurrent events (ICE):  Premature discontinuation from treatment (handled by 
hypothetical strategy). Details for other potential ICEs are given 
in the Table 9–12 in Appendix 9.5. Shortening/extension of the 
dosing interval (DRM/rescue regimen) will not be considered an 
ICE, but as part of the randomized treatment regimen. 
Population-level summary:  Difference in least squares (LS) mean change from baseline to 
Week 48 in BCVA between HDq12 and 2q8 (HDq16 and 2q8, 
respectively). 
The following 2 hypotheses will be tested in the primary analysis, to assess non-inferiority in 
the primary endpoint:  
• HDq12 is non-inferior to 2q8 regarding the mean change in BCVA from baseline to 
Week 48 using a non-inferiority margin of 4 letters:  
H10:  μ1 ≤ μ0 – 4 vs. H11:  μ1 > μ0 – 4,  
where μ0, μ1, are the mean change from baseline in BCVA at Week 48 for 2q8 and 
HDq12, respectively. 
• HDq16 is non-inferior to 2q8 regarding the mean change in BCVA from baseline to 
Week 48 using a non-inferiority margin of 4 letters: 
H30:  μ2 ≤ μ0 – 4 vs. H31:  μ2 > μ0 – 4,  
where μ0, μ2 are the mean change from baseline in BCVA at Week 48 for 2q8, and 
HDq16, respectively. 
A justification of the non-inferiority margin and a description of the DRM are given in the 
protocol. 
6.2.2.1 
Primary Analysis 
For the analysis of the primary efficacy variable, a mixed model for repeated measurements 
(MMRM) will be used with baseline BCVA measurement as a covariate and treatment group 
(HDq16 vs. 2q8 and HDq12 vs. 2q8), visit and the stratification variables (geographic region 
[Japan vs. Rest of World] and baseline BCVA [<60 vs. ≥60]) as fixed factors as well as terms 
for the interaction between baseline BCVA and visit and for the interaction between treatment 
and visit. A Kenward-Roger approximation will be used for the denominator degrees of 
freedom. Further, an unstructured covariance structure will be used to model the within-
subject error, assuming different covariance parameters per treatment 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 and compound symmetry. 
𝑌𝑖𝑗𝑘= 𝛽0 + 𝑥𝑖× 𝛽𝑏𝑎𝑠𝑒+ 𝛽𝑟𝑒𝑔
(𝑙) + 𝛽𝑏𝑎𝑠𝑒_𝑐𝑎𝑡
(𝑚)
+ 𝛽𝑡𝑟𝑒𝑎𝑡
(𝑘)
+ 𝛽𝑣𝑖𝑠𝑖𝑡
(𝑗) + 𝑥𝑖× 𝛽𝑏𝑎𝑠𝑒∗𝑣𝑖𝑠𝑖𝑡
(𝑗)
+ 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝑘,𝑗)
+ 𝜖𝑖𝑗𝑘 
with 
• 𝑌𝑖𝑗𝑘 being the change from baseline to visit j for the ith participant receiving 
treatment k 
• 𝛽0 being the intercept 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 33 of 103
 
 
• 𝑥𝑖 being the baseline BCVA measurement of participant i 
• 𝛽𝑏𝑎𝑠𝑒 the fixed effect of the baseline BCVA measurement 
• 𝛽𝑟𝑒𝑔
(𝑙)  the fixed effect of region l (as recorded on the eCRF) 
• 𝛽𝑏𝑎𝑠𝑒−𝑐𝑎𝑡
(𝑚)
 the fixed effect of categorized baseline BCVA measurement m (as 
recorded on the eCRF) 
• 𝛽𝑡𝑟𝑒𝑎𝑡
(𝑘)  the fixed effect of treatment k 
• 𝛽𝑣𝑖𝑠𝑖𝑡
(𝑗)  the fixed effect of visit j 
• 𝛽𝑏𝑎𝑠𝑒∗𝑣𝑖𝑠𝑖𝑡
(𝑗)
 the interaction between baseline BCVA and visit j 
• 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝑘,𝑗)
 the interaction between treatment k and visit j 
• 𝜖𝑖𝑗𝑘 the residual error with 𝜖𝑖𝑗𝑘~𝑁(0, 𝜎𝑘
2) and 𝑐𝑜𝑟𝑟(𝜖𝑖𝑗𝑘,𝜖𝑖𝑗′𝑘) = 𝜌(𝑘)_{𝑗, 𝑗′}.  
In terms of the model parameters the population-level summary of the estimands (i.e. the 
treatment effect at Week 48) can then be expressed as 
𝐷𝐻𝐷𝑞12 = [𝛽𝑡𝑟𝑒𝑎𝑡
(𝐻𝐷𝑞12) + 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝐻𝐷𝑞12,𝑤48)] − [𝛽𝑡𝑟𝑒𝑎𝑡
(2𝑞8) + 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(2𝑞8,𝑤48) ] 
and 
𝐷𝐻𝐷𝑞16 = [𝛽𝑡𝑟𝑒𝑎𝑡
(𝐻𝐷𝑞16) + 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(𝐻𝐷𝑞16,𝑤48)] − [𝛽𝑡𝑟𝑒𝑎𝑡
(2𝑞8) + 𝛽𝑡𝑟𝑒𝑎𝑡∗𝑣𝑖𝑠𝑖𝑡
(2𝑞8,𝑤48) ]. 
 
In line with the definition of estimands (see above), the primary analysis will be performed on 
the FAS and participants 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 supplementary analysis. 
Furthermore, the following 2 hypotheses will be tested (within the pre-defined testing 
strategy, see Section 6.2.1), using the MMRM described above, to assess also superiority in 
the primary endpoint, only if non-inferiority could be concluded before: 
• HDq12 is superior to 2q8 regarding the mean change in BCVA from baseline to Week 
48: 
H60:  μ1 ≤ μ0  vs. H61:  μ1 > μ0 (i.e., HDq12 vs. 2q8),  
where μ0, μ1, are the mean change from baseline in BCVA at Week 48 for 2q8 and 
HDq12, respectively. 
• HDq16 is superior to 2q8 regarding the mean change in BCVA from baseline to Week 
48: 
H80:  μ2 ≤ μ0  vs. H81:  μ2 > μ0 (i.e., HDq16 vs. 2q8),  
where μ0, μ2 are the mean change from baseline in BCVA at Week 48 for 2q8, and 
HDq16, respectively. 
To control the overall family-wise type I error rate of 0.025, a hierarchical testing procedure 
will be applied (Section 6.2.1) that also includes the confirmatory testing of the key secondary 
endpoints described in Section 6.2.3.1 and the confirmatory testing of change from baseline in 
BCVA at Week 48 (and Week 60, only for EP-SAP) for superiority at the end of the 
confirmatory testing hierarchy. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 34 of 103
 
 
Summary tables will include number of participants, least-square mean (LSmean) change, 
(unadjusted) mean change and SD and baseline means of each treatment group. For non-
inferiority testing the one-sided adjusted 𝛼 (as described in Section 6.2.1) for the 
population‑level estimates comparing HDq16 vs. 2q8 (DHDq16) and HDq12 vs. 2q8 (DHDq12), 
respectively, the estimates expressed as LSmean change, the test statistics, the degrees of 
freedom and corresponding p-values will be presented. Two-sided 95% confidence intervals 
will be provided as well. 
The MMRM assumes missing at random (MAR) for participants who discontinue the study 
prematurely, i.e. missingness only depends on observed data. Alternative assumptions (not 
MAR) will be included in the sensitivity analyses. 
Descriptive summary tables will be provided by treatment group 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 LOCF (sensitivity analysis strategy for continuous endpoints) in the FAS 
population 
6.2.2.2 
Sensitivity Analyses 
Last observation carried forward (LOCF) will be conducted for participants who have at least 
one post-baseline value but have any further missing post-baseline BCVA values until 
Week 48 and ANCOVA will be applied for the change from baseline in BCVA at Week 48. 
Another approach assuming MAR will be implemented by using multiple imputation. 
6.2.2.2.1 ANCOVA using LOCF 
The sensitivity analysis of the primary efficacy endpoint using an 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 
baseline BCVA measurement as a covariate and treatment group (HDq16 vs. 2q8 and HDq12 
vs. 2q8) and the stratification variables (geographic region [Japan vs. Rest of World] and 
baseline BCVA [<60 vs. ≥60]) as fixed factors. A separate variance term will be estimated for 
the three treatment groups. 
The observation at Week 48 of participant i receiving treatment t can be written as follows: 
𝑌𝑖𝑡𝑟𝑏= 𝜇𝑡+ 𝛾𝑟+ 𝜂𝑏+ 𝑥𝑖𝛽+ 𝜖𝑖𝑡𝑟𝑏 
with 
• 𝑌𝑖𝑡𝑟𝑏 being the change from baseline to Week 48 for the ith participant, 
• 𝜇𝑡 being the treatment effect, 
• 𝛾𝑟 being the geographic region effect (as recorded on the eCRF), 
• 𝜂𝑏 being the categorical baseline BCVA (<60 vs. ≥60; as recorded on the eCRF), 
• 𝑥𝑖 being the baseline BCVA of participant i, 
• 𝜖𝑖𝑡𝑟𝑏 the residual error with 𝜖𝑖𝑡𝑟𝑏~𝑁(0, 𝜎𝑡
2 ) being the residual error for treatment 
arm t. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 35 of 103
 
 
In terms of the model parameters the population-level summary of the estimands (i.e. the 
treatment effect at Week 48) can then be expressed as 
𝐷𝐻𝐷𝑞12 = [𝛽𝑡𝑟𝑒𝑎𝑡
(𝐻𝐷𝑞12)] − [𝛽𝑡𝑟𝑒𝑎𝑡
(2𝑞8)] 
and 
𝐷𝐻𝐷𝑞16 = [𝛽𝑡𝑟𝑒𝑎𝑡
(𝐻𝐷𝑞16)] − [𝛽𝑡𝑟𝑒𝑎𝑡
(2𝑞8)]. 
For this analysis missing Week 48 BCVA data will be imputed by using LOCF. That means 
that the last non-missing post-baseline BCVA measurement will be carried forward up to 
Week 48. 
Summary tables will include number of participants, least-square mean (LSmean) change, 
(unadjusted) mean change and SD and baseline means of each treatment group. For non-
inferiority testing the one-sided 𝛼 of 2.5% for the population‑level estimates comparing 
HDq16 vs. 2q8 and HDq12 vs. 2q8, the estimates expressed as LSmean change, the test 
statistics, the degrees of freedom and corresponding p-values will be presented. Two-sided 
95% confidence intervals will be provided as well. 
This sensitivity analysis will be analyzed for the FAS. 
6.2.2.2.2 Multiple Imputation 
The sensitivity analysis of the primary efficacy endpoint using an ANCOVA after applying 
multiple imputation follows the same estimand strategy as the primary analysis. Multiple 
imputation (MI) methods involve three steps: 
I. Imputation 
Imputation is the generation of multiple copies of the original dataset by replacing missing 
values by using an appropriate stochastic model. The missing data will be imputed using the 
Fully Conditional Specification (FCS) method. The FCS method is based on an iterative 
algorithm; at each iteration and for each variable of the prediction model, there is a prediction 
step and an imputation step. The models used for prediction and imputation will be linear 
regression models. A total of 10 imputations will be performed using a seed of 12345.  
The imputation model will include treatment groups, geographic region (Japan, Rest of 
World) and categorical baseline BCVA (<60, ≥60), baseline BCVA, and the BCVA at each 
previous post-baseline visit.  
Final imputed values will be rounded to integer values and cut-offs will be applied to imputed 
values outside of the normal range of 0 to 100. 
II. Analysis 
The analysis step is performed for each of the imputed datasets. Since all imputed datasets are 
complete there is no need to bother with any missing data. 
The statistical method for analysis will be ANCOVA and is specified in Section 6.2.2.2.1. 
III. Pooling 
Pooling is the combination of the different parameter estimates across the multiple imputed 
datasets based on Rubin’s rules (Rubin, 1987 (6)) to produce a unique point estimate and 
standard error taking into account the uncertainty of the imputation process. 
This sensitivity analysis will be analyzed for the FAS. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 36 of 103
 
 
6.2.2.2.3 Tipping-point analysis 
In order to check the assumption that the missing data is not MAR, also a tipping point 
analysis will be conducted based on the multiple imputation analysis in Section 6.2.2.2.2. The 
objective of the tipping point analyses is to identify assumptions about the missing data under 
which the conclusions from the main analysis change, ie, under which non-inferiority cannot 
be shown anymore. These tipping point analyses will only be performed if the multiple 
imputation analysis results can show non-inferiority of the high dose groups compared to the 
low dose group. 
If the non-inferiority could be shown additional tipping point analyses will be repeated after 
reducing the imputed BCVA values in the high dose arms by ascending natural number of 
letters (1, 2, 3… etc.), with the goal to find for each high dose treatment group the “tipping 
point” that will significantly reverse the analysis result. The smallest delta, for which non-
inferiority cannot be shown anymore, will be the “tipping point”. 
For each value of delta, summary tables will include number of participants, least-square 
mean (LSmean) change, (unadjusted) mean change and SD and baseline means of each 
treatment group as well as the estimates expressed as LS mean change including the two-
sided CIs for α of 5%, the test statistics, the degrees of freedom and corresponding p-values. 
This sensitivity analysis will be analyzed for the FAS. 
6.2.3 
Secondary Efficacy Endpoints 
6.2.3.1 
Key Secondary Endpoints 
The key secondary efficacy endpoints are described below. 
6.2.3.1.1 Change from Baseline in BCVA Measured by the ETDRS Letter Score 
at Week 60 
This key secondary efficacy endpoint (for regulatory submissions to EMA/PMDA according 
to the EP-SAP only) has a similar underlying estimand that follows the same strategies as for 
the primary efficacy endpoint 
The following 2 non-inferiority hypotheses will be tested for this key secondary endpoint:  
• HDq12 is non-inferior to 2q8 regarding the mean change in BCVA from baseline to 
Week 60 using a non-inferiority margin of 4 letters:  
H20:  μ1 ≤ μ0 – 4 vs. H21:  μ1 > μ0 – 4,  
where μ0, μ1, are the mean change from baseline in BCVA at Week 60 for 2q8 and 
HDq12, respectively. 
• HDq16 is non-inferior to 2q8 regarding the mean change in BCVA from baseline to 
Week 60 using a non-inferiority margin of 4 letters: 
H40:  μ2 ≤ μ0 – 4 vs. H41:  μ2 > μ0 – 4,  
where μ0, μ2 are the mean change from baseline in BCVA at Week 60 for 2q8, and 
HDq16, respectively. 
The analysis of key secondary endpoints will be required for the submission to the 
EMA/PMDA regulatory authorities (EP-SAP, see Section 6.2.1). The change from baseline in 
BCVA at Week 60 will be analyzed with the same methodology and main and sensitivity 
summaries as for the primary endpoint assessing non-inferiority described in Section 6.2.2 in 
this SAP.  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 37 of 103
 
 
Also for the key secondary endpoint of change from baseline in BCVA at Week 60, the 
following 2 hypotheses will be tested, using the MMRM described above, to assess 
superiority, only if non-inferiority could be concluded before:  
• HDq12 is superior to 2q8 regarding the mean change in BCVA from baseline to Week 
60: 
H70:  μ1 ≤ μ0 vs. H71:  μ1 > μ0 (i.e., HDq12 vs. 2q8), 
where μ0, μ1, are the mean change from baseline in BCVA at Week 60 for 2q8 and 
HDq12, respectively. 
• HDq16 is superior to 2q8 regarding the mean change in BCVA from baseline to Week 
60: 
H90:  μ2 ≤ μ0 vs. H91:  μ2 > μ0 (i.e., HDq16 vs. 2q8), 
where μ0, μ2, are the mean change from baseline in BCVA at Week 60 for 2q8 and 
HDq16, respectively. 
6.2.3.1.2 Proportion of Participants with no IRF and no SRF in Central Subfield 
at Week 16 
The underlying estimand for the primary analysis of the binary key secondary endpoint using 
a Cochran-Mantel-Haenszel test with LOCF, mainly follows the hypothetical strategy. It 
describes the proportion of all participants with no IRF and no SRF in central subfield at 
Week 16 that started treatment assuming all participants have stayed on treatment until 
Week 16. 
The estimand is specified through the following definitions of population, variable, treatment 
condition, intercurrent events, and population-level summary: 
Target population:  
Defined by the inclusion/exclusion criteria. 
Variable:  
Absence of IRF and SRF in Central Subfield at Week 16. 
Treatment condition:  
HD aflibercept versus aflibercept 2 mg. 
Intercurrent events:  
Premature discontinuation from treatment (handled by 
hypothetical strategy). Details for other potential ICEs are given 
in the Table 9–13 in Appendix 9.5. 
Population-level summary:  Difference in proportion of participants with no IRF and no SRF 
in Central Subfield at Week 16 between pooled high dose groups 
(HDq12 and HDq16) and 2q8. 
The existence of IRF or SRF are abnormal findings of the SD-OCT and will be classified 
based on data assessed by a reading center as described in Section 4.5.4. 
For the calculation of the endpoint dryness, absence of IRF and SRF (or “Dryness at Week 
16” ) in Central Subfield is achieved, when the definitions for IRF=NO and SRF=NO are 
achieved at Week 16. 
The opposite “Not dry” will be achieved when the definitions for either 
• IRF=YES or 
• SRF=YES or  
• IRF=YES and SRF=YES  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 38 of 103
 
 
are achieved at Week 16 (including cases when [IRF=YES and SRF=missing/undetermined] 
or [IRF=missing/undetermined and SRF=YES]). 
In case of IRF and SRF as Missing or Undetermined or [IRF=NO and 
SRF=missing/undetermined] or [IRF=missing/undetermined and SRF=NO] the whole 
endpoint will be missing/undetermined. These cases will not be included in the denominator 
when calculating proportions. 
The following superiority hypothesis will be tested for this key secondary endpoint on the 
FAS and repeated as supplementary analysis on the PPS: 
• H50:  pHD ≤ p2q8 vs. H51:  pHD > p2q8 (i.e., pooled high dose vs. 2q8), 
• where p2q8, pHD are the proportion of participants with no IRF and no SRF in central 
subfield at Week 16 for 2q8, and the pooled high dose groups (HDq12 and HDq16), 
respectively. HDq12 and HDq16 high dose groups have same dosing regimen up to 
Week 16. 
This endpoint will be analyzed by a Cochran-Mantel-Haenszel test stratified by geographic 
region (Japan vs. Rest of World) and baseline BCVA (<60 vs. ≥60). 
The number of prematurely discontinued participants before Week 16 is assumed to be rather 
small. LOCF will be applied for participants not having a Week 16 SD-OCT performed 
(carrying forward the last non-missing [not missing/undetermined] post-baseline 
measurement).  
Additionally, 95% two-sided CIs for the Mantel-Haenszel weighted treatment difference 
between pooled high dose groups and 2q8 will be calculated using normal approximation. The 
following methodology (Koch et al, 1990 (4)) is used: 
𝑑= (∑
𝑤ℎ𝑘(𝑝̂ℎ𝑘𝑡−𝑝̂ℎ𝑘𝑐)
ℎ𝑘
)/ ∑
𝑤ℎ𝑘
ℎ𝑘
), where 𝑤ℎ𝑘= 𝑛ℎ𝑘𝑡𝑛ℎ𝑘𝑐/(𝑛ℎ𝑘𝑡+ 𝑛ℎ𝑘𝑐). 
Then var
̂ (d̂) = (∑
whk
2 (p̂hkc(1 −p̂hkc)/(nhkc −1) +
hk
p̂hkt(1 −p̂hkt)/(nhkt −
1)))/(∑
whk
hk
)2. 
With this, the 95% CI can be given as: 𝑑̂ ± 𝑧𝛼2
⁄ √𝑣𝑎𝑟(𝑑̂)
̂  (𝑧𝛼2
⁄ being the lower 𝛼2
⁄  
quantile of the standard normal distribution). 
In the formulae, 
• h: number of strata for the geographic region, which ranges from 1 to 2 (Japan, Rest of 
World; as recorded on the eCRF), 
• k: number of strata for the baseline BCVA, which ranges from 1 to 2 (<60, ≥60; as 
recorded on the eCRF), 
• 𝑝ℎ𝑘𝑡: proportion of participants with no IRF and no SRF in central subfield at Week 16 in 
the pooled high dose treatment group in stratum1 h and stratum2 k, 
•  𝑝ℎ𝑘𝑐: proportion of participants with no IRF and no SRF in central subfield at Week 16 in 
the 2q8 treatment group in stratum1 h and stratum2 k, 
• 𝑛ℎ𝑘𝑡: number of participants in the pooled high dose treatment group in stratum1 h and 
stratum2 k, 
• 𝑛ℎ𝑘𝑐: number of participants in the 2q8 dose treatment group in stratum1 h and stratum2 k. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 39 of 103
 
 
The number and percentage of participants with no IRF and no SRF in central subfield at 
Week 16 for each treatment group and the pooled HD group, the p-value of the one-sided 
Cochran-Mantel-Haenszel test and the weighted treatment difference including the two-sided 
95%-CI as percentage (multiplied by 100) will be included in a summary table.  
The analysis described above will be repeated on the PPS as supplementary analysis. 
Descriptive summary tables will be provided by treatment group and visit for: 
• All observed cases until the occurrence of an ICE with imputation of missing values 
with LOCF (primary estimand strategy for binary endpoints) in the FAS population 
• All observed cases until the occurrence of an ICE with imputation of missing values 
with LOCF (primary estimand strategy for binary endpoints) in the PPS population 
• All observed cases until the occurrence of an ICE in the FAS population 
Descriptive summary tables will be provided by treatment group and visit for IRF in central 
subfield and SRF in central subfield (LOCF as well as OC for the FAS population).  
In addition, descriptive summary tables will be provided by treatment group and visit for IRF 
in foveal center, SRF in foveal center and corresponding dryness status (LOCF as well as OC 
for the FAS population).  
6.2.3.1.2.1 Sensitivity Analyses 
A sensitivity analysis will be performed for the proportion of participants with no IRF and no 
SRF in central subfield at Week 16 for the FAS. In case of any participants prematurely 
discontinuing before Week 16 or having any occurrence of another ICE, a Cochran-Mantel-
Haenszel test will be calculated based on observed case (OC) only. The number and 
percentage of participants with no IRF and no SRF in central subfield at Week 16 for each 
treatment group and the pooled HD group, the p-value of the one-sided Cochran-Mantel-
Haenszel test and the weighted treatment difference including the two-sided 95%-CI will be 
included in a summary table. 
6.2.3.2 
Additional Secondary Efficacy Endpoints 
The additional secondary efficacy endpoints are 
• Proportion of participants gaining at least 15 letters in BCVA from baseline at Week 48 
• Proportion of participants achieving an ETDRS letter score of at least 69 (approximate 
20/40 Snellen equivalent) at Week 48 
• Change in CNV size from baseline to Week 48 
• Change in total lesion area from baseline to Week 48 
• Proportion of participants with no IRF and no SRF in the central subfield at Week 48  
• Change from baseline in CST at Week 48 
• Change from baseline in NEI-VFQ-25 total score at Week 48 
All analyses will be done for the FAS. 
All additional secondary efficacy endpoints will only be analyzed descriptively. Continuous 
variables will be analyzed by similar repeated measurement models as for the primary 
endpoint. Binary endpoints will be analyzed by Cochran-Mantel-Haenszel methodology.  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 40 of 103
 
 
6.2.3.2.1 Proportion of Participants Gaining at least 15 Letters in BCVA from 
Baseline at Week 48 
The proportion of participants gaining at least 15 letters in BCVA from baseline at Week 48 
will be summarized descriptively by treatment group 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 with imputation of missing values 
with LOCF (sensitivity analysis strategy for continuous endpoints) in the FAS 
population 
Missing cases will not be included in the denominator when calculating proportions. 
Additionally, the Cochran-Mantel-Haenszel test stratified by geographic region (Japan vs. 
Rest of World) and baseline BCVA (<60 vs. ≥60) will be applied for the comparison of the 
treatment groups HDq12 vs. 2q8 and HDq16 vs. 2q8. Two-sided 95% CIs and p-values will 
be provided for descriptive purposes. The main analysis will be done for the LOCF 
imputation of missing BCVA measurements in the FAS as described in Section 6.2.3.1.2 and 
an additional sensitivity analysis will be done for the OC only case in the FAS. 
6.2.3.2.2 Proportion of Participants Achieving an ETDRS Letter Score of at 
least 69 (Approximate 20/40 Snellen Equivalent) at Week 48 
The proportion of participants achieving an ETDRS letter score of at least 69 (approximate 
20/40 Snellen equivalent) at Week 48 will be summarized descriptively by treatment group 
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 with imputation of missing values 
with LOCF (sensitivity analysis strategy for continuous endpoints) in the FAS 
population 
Missing cases will not be included in the denominator when calculating proportions. 
Additionally, the Cochran-Mantel-Haenszel test stratified by geographic region (Japan vs. 
Rest of World) and baseline BCVA (<60 vs. ≥60) will be applied for the comparison of the 
treatment groups HDq12 vs. 2q8 and HDq16 vs. 2q8. Two-sided 95% CIs and p-values will 
be provided for descriptive purposes. The main analysis will be done for the LOCF 
imputation of missing BCVA measurements in the FAS as described in Section 6.2.3.1.2 and 
an additional sensitivity analysis will be done for the OC only case in the FAS. 
6.2.3.2.3 Change in CNV Size from Baseline to Week 48 
CNV size will be evaluated using FA/FP (see Section 4.5.4) and will be collected at 
screening, week 12 (visit 6), week 24 (visit 9), week 36 (visit 12), week 48 (visit 15), week 60 
(visit 18) and week 96 (visit 27). The change in CNV size from baseline to Week 48 will be 
summarized descriptively by treatment group for: 
• All observed cases until the occurrence of an ICE (primary analysis strategy for 
continuous endpoints) in the FAS population 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 41 of 103
 
 
• All observed cases until the occurrence of an ICE with imputation of missing values 
with LOCF (sensitivity analysis strategy for continuous endpoints) in the FAS 
population 
Additionally, a MMRM will be used with baseline CNV size as a covariate and treatment 
group (HDq16 vs. 2q8 and HD12 vs. 2q8), visit and the stratification variables (geographic 
region (Japan vs. Rest of World) and baseline BCVA (<60 vs. ≥60)) as fixed factors as well 
as terms for the interaction between baseline CNV size and the visit and for the interaction 
between treatment and visit. This model is similar to the model described in Section 6.2.2.1 
and will be provided for FAS. Two-sided 95% CIs for LSmeans, coefficient estimates and p-
values will be provided for descriptive purposes. As additional sensitivity analysis an 
ANCOVA will be calculated as described in Section 6.2.2.2.1 using the LOCF method for 
imputation of missing values for participants discontinuing before Week 48. 
Visit-based information recorded in the EOS/ED visit folder which will not be re-mapped to a 
regular study visit will nevertheless be included into the LOCF analysis. 
6.2.3.2.4 Change in Total Lesion Area from Baseline to Week 48 
Lesion characteristics will be evaluated using FA/FP (see Section 4.5.4) and will be collected 
at screening, week 12 (visit 6), week 24 (visit 9), week 36 (visit 12), week 48 (visit 15), week 
60 (visit 18) and week 96 (visit 27). The change in total lesion area from baseline to Week 48 
will be summarized descriptively by treatment group 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 with imputation of missing values 
with LOCF (sensitivity analysis strategy for continuous endpoints) in the FAS 
population 
Additionally, a MMRM will be used with baseline total lesion area as a covariate and 
treatment group (HDq16 vs. 2q8 and HD12 vs. 2q8), visit and the stratification variables 
(geographic region (Japan vs. Rest of World) and baseline BCVA (<60 vs. ≥60)) as fixed 
factors as well as terms for the interaction between baseline total lesion area and the visit and 
for the interaction between treatment and visit. This model is similar to the model described in 
Section 6.2.2.1 and will be provided for FAS. Two-sided 95% CIs for LSmeans, coefficient 
estimates and p-values will be provided for descriptive purposes. As additional sensitivity 
analysis an ANCOVA will be calculated as described in Section 6.2.2.2.1 using the LOCF 
method for imputation of missing values for participants discontinuing before Week 48. 
Visit-based information recorded in the EOS/ED visit folder which will not be re-mapped to a 
regular study visit will nevertheless be included into the LOCF analysis. 
6.2.3.2.5 Proportion of Participants with no IRF and no SRF in the Central 
Subfield at Week 48 
The proportion of participants with no IRF and no SRF (according to the definitions in 
Section 4.5.4 and Section 6.2.3.1.2) in the central subfield at Week 48 will be summarized 
descriptively by treatment group for: 
• All observed cases until the occurrence of an ICE with imputation of missing values 
with LOCF (primary estimand strategy for binary endpoints) in the FAS population 
• All observed cases until the occurrence of an ICE in the FAS population 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 42 of 103
 
 
Missing cases will not be included in the denominator when calculating proportions. 
Additionally, the Cochran-Mantel-Haenszel test stratified by geographic region (Japan vs. 
Rest of World) and baseline BCVA (<60 vs. ≥60) will be applied for the comparison of the 
treatment groups HDq12 vs. 2q8 and HDq16 vs. 2q8. Two-sided 95% CIs and p-values will 
be provided for descriptive purposes. The main analysis will be done for the LOCF 
imputation for participants with missing SD-OCT assessment in the FAS as described in 
Section 6.2.3.1.2 and an additional sensitivity analysis will be done for the OC only case in 
the FAS. 
6.2.3.2.6 Change from Baseline in CST at Week 48 
CST will be evaluated using SD-OCT (see Section 4.5.4) and will be collected at each visit. 
The change from baseline in CST at Week 48 will be summarized descriptively by treatment 
group 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 with imputation of missing values 
with LOCF (sensitivity analysis strategy for continuous endpoints) in the FAS 
population 
Additionally, a MMRM will be used with baseline CST as a covariate and treatment group 
(HDq16 vs. 2q8 and HD12 vs. 2q8), visit and the stratification variables (geographic region 
(Japan vs. Rest of World) and baseline BCVA (<60 vs. ≥60)) as fixed factors as well as terms 
for the interaction between baseline CST and the visit and for the interaction between 
treatment and visit. This model is similar to the model described in Section 6.2.2.1 and will be 
provided for FAS. Two-sided 95% CIs for LSmeans, coefficient estimates and p-values will 
be provided for descriptive purposes. As additional sensitivity analysis an ANCOVA will be 
calculated as described in Section 6.2.2.2.1 using the LOCF method for imputation of missing 
values for participants discontinuing before Week 48. 
6.2.3.2.7 Change from Baseline in NEI-VFQ-25 Total Score at Week 48 
The change from baseline in NEI-VFQ-25 total score (for calculation details see 
Section 9.1.1) at Week 48 will be summarized descriptively by treatment group 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 with imputation of missing values 
with LOCF (sensitivity analysis strategy for continuous endpoints) in the FAS 
population 
Additionally, a MMRM will be calculated with baseline NEI-VFQ-25 total score as a 
covariate and treatment group (HDq16 vs. 2q8 and HD12 vs. 2q8), visit and the stratification 
variables (geographic region (Japan vs. Rest of World) and baseline BCVA (<60 vs. ≥60)) as 
fixed factors as well as terms for the interaction between baseline NEI-VFQ-25 total score 
and the visit and for the interaction between treatment and visit. This model is similar to the 
model described in Section 6.2.2.1 and will be provided for FAS. Two-sided 95% CIs for 
LSmeans, coefficient estimates and p-values will be provided for descriptive purposes. As 
additional sensitivity analysis an ANCOVA will be calculated as described in Section 
6.2.2.2.1 using the LOCF method for imputation of missing values for participants 
discontinuing before Week 48. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 43 of 103
 
 
Visit-based information recorded in the EOS/ED visit folder which will not be re-mapped to a 
regular study visit will nevertheless be included into the LOCF analysis. 
6.2.4 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints will be analyzed descriptively for the FAS and will 
include the following: 
• Change from baseline in BCVA measured by the ETDRS letter score at Week 96 
• Change from baseline in BCVA averaged over the period from Week 36 to Week 48 and 
from Week 48 to Week 60 
• Proportion of participants gaining at least 15 letters in BCVA from baseline at Week 60 
and Week 96 
• Proportion of participants achieving an ETDRS letter score of at least 69 (approximate 
20/40 Snellen equivalent) at Week 60 and Week 96  
• Proportions of participants gaining and losing at least 5 or at least 10 letters in BCVA 
from baseline at Week 48, Week 60, and Week 96 
• Proportion of participants losing at least 15 letters in BCVA from baseline at Week 48, 
Week 60, and Week 96 
• Change in CNV size from baseline to Week 60 and Week 96 
• Change in total lesion area from baseline to Week 60 and Week 96 
• Change from baseline in CST at Week 60 and Week 96  
• Proportion of participants with no IRF and no SRF in the central subfield at Week 60 and 
Week 96  
• Proportion of participants without retinal fluid (total fluid, IRF, and/or SRF) and subRPE 
fluid in central subfield at Week 48, Week 60, and Week 96 
• Time to fluid-free retina over 48 weeks, 60 weeks, and 96 weeks (total fluid, IRF, and/or 
SRF in the central subfield) 
• Proportion of participants with sustained fluid-free retina over 48 weeks, 60 weeks, and 
96 weeks (total fluid, IRF, and/or SRF in the central subfield)  
• Change from baseline in NEI-VFQ-25 total score at Week 60 and Week 96 
• Proportion of participants without leakage on FA at Week 48, Week 60, and Week 96 
6.2.4.1 
Change from Baseline in BCVA Measured by the ETDRS Letter Score 
at Week 96 
The change from baseline in BCVA measured by the ETDRS letter score at Week 96 will be 
summarized descriptively by treatment group 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 with imputation of missing values 
with LOCF (sensitivity analysis strategy for continuous endpoints) in the FAS 
population 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 44 of 103
 
 
6.2.4.2 
Change from Baseline in BCVA Averaged over the Period from 
Week 36 to Week 48 and from Week 48 to Week 60 
BCVA will be averaged over all non-missing visits between Week 36 to Week 48 (Week 36, 
Week 40, Week 44, Week 48) and between Week 48 to Week 60 (Week 48, Week 52, 
Week 56, Week 60), respectively. Then the change from baseline BCVA will be calculated 
for both averages. The change from baseline in BCVA to the average periods will be analyzed 
descriptively and displayed by treatment group 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 with imputation of missing values 
during the periods from Week 36 to Week 48 and from Week 48 to Week 60 with 
LOCF (sensitivity analysis strategy for continuous endpoints) in the FAS population 
6.2.4.3 
Proportion of Participants Gaining at least 15 Letters in BCVA from 
Baseline at Week 60 and Week 96 
The proportion of participants gaining at least 15 letters in BCVA from baseline at Week 60 
and Week 96 will be analyzed descriptively by treatment group. Missing cases will not be 
included in the denominator when calculating proportions. 
6.2.4.4 
Proportion of Participants Achieving an ETDRS Letter Score of at 
least 69 (Approximate 20/40 Snellen Equivalent) at Week 60 and 
Week 96 
The proportion of participants achieving an ETDRS letter score of at least 69 (approximate 
20/40 Snellen equivalent) at Week 60 and Week 96 will be analyzed descriptively by 
treatment group. Missing cases will not be included in the denominator when calculating 
proportions. 
6.2.4.5 
Proportions of Participants Gaining and Losing at least 5 or at least 10 
Letters in BCVA from Baseline at Week 48, Week 60, and Week 96 
For each week (Week 48, Week 60 and Week 96) five proportions will be calculated 
• Proportion of participants gaining more than 0 letters in BCVA from baseline (any gain) 
• Proportion of participants gaining at least 5 letters in BCVA from baseline 
• Proportion of participants losing at least 5 letters in BCVA from baseline 
• Proportion of participants gaining at least 10 letters in BCVA from baseline 
• Proportion of participants losing at least 10 letters in BCVA from baseline 
Missing cases will not be included in the denominator when calculating proportions. The 
proportions will be analyzed descriptively and displayed by treatment group 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 with imputation of missing values 
with LOCF (sensitivity analysis strategy for continuous endpoints) in the FAS 
population 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 45 of 103
 
 
6.2.4.6 
Proportion of Participants Losing at least 15 Letters in BCVA from 
Baseline at Week 48, Week 60, and Week 96 
The proportion of participants gaining or losing at least 15 letters in BCVA from baseline will 
be analyzed descriptively and displayed by treatment group 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 with imputation of missing values 
with LOCF (sensitivity analysis strategy for continuous endpoints) in the FAS 
population 
Missing cases will not be included in the denominator when calculating proportions. 
6.2.4.7 
Change in CNV Size from Baseline to Week 60 and Week 96 
The change in CNV size from baseline to Week 60 and Week 96 will be analyzed 
descriptively by treatment group. Visit-based information recorded in the EOS/ED visit folder 
which will not be re-mapped to a regular study visit will nevertheless be included into the 
LOCF analysis. 
6.2.4.8 
Change in Total Lesion Area from Baseline to Week 60 and Week 96 
The change in total lesion area from baseline to Week 60 and Week 96 will be analyzed 
descriptively by treatment group. Visit-based information recorded in the EOS/ED visit folder 
which will not be re-mapped to a regular study visit will nevertheless be included into the 
LOCF analysis. 
6.2.4.9 
Change from Baseline in CST at Week 60 and Week 96 
The change from baseline in CST at Week 60 and Week 96 will be analyzed descriptively by 
treatment group. 
6.2.4.10 
Proportion of Participants with no IRF and no SRF in the Central 
Subfield at Week 60 and Week 96 
The proportion of participants with no IRF and no SRF (according to the definitions in 
Section 4.5.4 and Section 6.2.3.1.2) in the central subfield at Week 60 and Week 96 will be 
analyzed descriptively by treatment group. Missing/undetermined cases will not be included 
in the denominator when calculating proportions. 
6.2.4.11 
Proportion of Participants without Retinal Fluid (Total Fluid, IRF, 
and/or SRF) and subRPE Fluid in Central Subfield at Week 48, 
Week 60, and Week 96 
IRF, SRF and subRPE will be classified as defined in Section 4.5.4. 
The proportion of participants without retinal fluid (no IRF and no SRF), with retinal fluid 
(IRF and/or SRF) or IRF and SRF missing/undetermined will be analyzed descriptively in the 
subgroups of participants with and without subRPE fluid in central subfield at Week 48, 
Week 60, and Week 96 and displayed by treatment group for: 
• All observed cases until the occurrence of an ICE with imputation of missing values 
with LOCF (primary estimand strategy for binary endpoints) in the FAS population 
• All observed cases until the occurrence of an ICE in the FAS population 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 46 of 103
 
 
Missing/undetermined cases will not be included in the denominator when calculating 
proportions. 
6.2.4.12 
Time to Fluid-Free Retina over 48 Weeks, 60 Weeks, and 96 Weeks 
(Total Fluid, IRF, and/or SRF in the Central Subfield) 
Total fluid-free retina (no IRF and no SRF in central subfield) is defined as the absence of 
total fluid, i.e. no IRF and no SRF in the central subfield as found in the SD-OCT, regardless 
of whether any retinal fluid was found again after that. 
Time to total fluid-free retina (no IRF and no SRF in central subfield) will be analyzed by 
Kaplan-Meier analysis and shown in Kaplan-Meier plots and descriptive summaries. Time to 
total fluid-free retina is defined as the duration from randomization to the timepoint when 
total fluid was absent for the first time whereas intercurrent events are handled according to 
Table 9–13. The analysis will be using the study visits (i.e. multiples of 4 weeks) and not the 
calendar time as unit. Participants without total fluid-free retina will be censored at the time of 
their last SD-OCT assessment.  
Each of the HD groups will be compared with the 2q8 group using a stratified log-rank test 
and a stratified Cox proportional hazards model, including baseline BCVA (<60 vs. ≥60) and 
geographical region (Japan vs. Rest of World) as strata.  
Time to IRF-free retina (no IRF in central subfield) and time to SRF-free retina (no SRF in 
central subfield) will be analysed in the similar way.  
6.2.4.13 
Proportion of Participants with Sustained Fluid-Free Retina over 
48 Weeks, 60 Weeks, and 96 Weeks (Total Fluid, IRF, and/or SRF in 
the Central Subfield) 
Sustained total fluid-free retina (no IRF and no SRF in central subfield) is defined as the 
absence of total fluid for at least 2 consecutive visits and all subsequent visits, i.e. no IRF and 
no SRF in the central subfield as found in the SD-OCT.  
The proportion of participants with sustained total fluid-free retina (no IRF and no SRF in 
central subfield) over 48 weeks, 60 weeks and 96 weeks will be analyzed descriptively by 
treatment group for: 
• All observed cases until the occurrence of an ICE in the FAS population 
Missing cases will not be included in the denominator when calculating proportions.  
Additionally, time to sustained total fluid-free retina (no IRF and no SRF in central subfield) 
over 48 weeks, 60 weeks and 96 weeks will be analyzed by Kaplan-Meier analysis and shown 
in Kaplan-Meier plots and descriptive summaries. Time to total sustained fluid-free retina is 
defined as the duration from randomization to the timepoint when total fluid was absent for 
the first time at 2 consecutive visits and for all subsequent study visits whereas intercurrent 
events are handled according to Table 9–13. The analysis will be using the study visits (i.e. 
multiples of 4 weeks) and not the calendar time as unit. Participants without sustained total 
fluid-free retina will be censored at the time of their last SD-OCT assessment.  
Each of the HD groups will be compared with the 2q8 group using a stratified log-rank test 
and a stratified Cox proportional hazards model, including baseline BCVA (<60 vs. ≥60) and 
geographical region (Japan vs. Rest of World) as strata.  
Time to sustained IRF-free retina (no IRF in central subfield) and time to sustained SRF-free 
retina (no SRF in central subfield) will be analysed in the similar way.  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 47 of 103
 
 
6.2.4.14 
Change from Baseline in NEI-VFQ-25 Total Score at Week 60 and 
Week 96 
The change from baseline in NEI-VFQ-25 total score at Week 60 and Week 96 will be 
analyzed descriptively by treatment group. Visit-based information recorded in the EOS/ED 
visit folder which will not be re-mapped to a regular study visit will nevertheless be included 
into the LOCF analysis. 
6.2.4.15 
Proportion of Participants Without Leakage on FA at Week 48, 
Week 60, and Week 96 
The proportion of participants without leakage on FA (as defined in Section 4.5.4) will be 
analyzed descriptively and displayed by treatment group for: 
• All observed cases until the occurrence of an ICE with imputation of missing values 
with LOCF (primary estimand strategy for binary endpoints) in the FAS population 
• All observed cases until the occurrence of an ICE in the FAS population.  
Missing cases will not be included in the denominator when calculating proportions. Visit-
based information recorded in the EOS/ED visit folder which will not be re-mapped to a 
regular study visit will nevertheless be included into the LOCF analysis. 
6.2.5 
Subgroup Analyses 
Statistical analyses for primary and key secondary efficacy endpoints will be conducted for 
the FAS by each subgroup defined in Section 5.2 for efficacy analyses. For the subgroup 
analysis by geographic region the corresponding variable will be removed from the statistical 
models. The subgroup analyses are only descriptive and 95% CIs will be presented in tables. 
Subgroups for continuous endpoints are done using the MMRM without imputation of 
missing values and subgroups for categorical endpoints are done using Cochran-Mantel-
Haenszel test with imputation by LOCF. 
6.3 
Pharmacokinetics/Pharmacodynamics 
All analysis done for sparse PK samples will be done by treatment group on the PKS. 
Analysis of the data from the dense PK substudy will be analyzed by treatment group for the 
DPKS. Pharmacodynamic parameters are not evaluated in this study. 
6.3.1 
Main Study 
PK samples for sparse PK are collected during Year 1 only at baseline (Visit 2), Week 4 
(Visit 3), Visit 5, Week 12 (Visit 6), Week 28 (Visit 10) and Week 48 (Visit 15) for all 
participants (optional for participants in China). The individual concentrations of free, 
adjusted bound, and total aflibercept over time will be summarized and listed by descriptive 
statistics by visit. As far as possible, the increase of concentrations will be described.  
Individual concentrations of adjusted bound aflibercept will be calculated as 0.717 x 
individual concentrations of bound aflibercept. 
Individual concentrations of total aflibercept will be calculated as the sum of individual 
concentrations of free and adjusted bound aflibercept. 
The following LLOQs were used by the laboratory: 
• For free aflibercept assay: LLOQ = 15.6ng/mL 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 48 of 103
 
 
• For bound aflibercept assay: LLOQ = 31.3ng/mL 
Drug concentrations will be further grouped by the following baseline factors: 
• age categories as defined in 5.2,  
• medical history of renal impairment as determined by baseline serum creatinine values 
as defined in 9.4.6,  
• hepatic impairment based on medical history as defined in 9.4.7,  
• BMI categories as defined in 6.1.1,  
• ethnicity as defined in 5.2,  
• race as defined in 5.2 
and evaluated by means of descriptive statistics.Dose and/or exposure-response analyses may 
be performed for select safety and efficacy endpoints, as appropriate.  
No formal statistical hypothesis testing will be performed.  
6.3.2 
Dense PK Substudy 
The Dense PK Substudy is planned to include approximately 24 participants (at least 12 
Japanese participants from Japan sites and at least 12 non-Asian participants from Europe or 
U.S. sites). For each region a minimum of 6 participants should be randomized to the HDq12 
group or the HDq16 group combined. The stratification factors for randomization in the study 
(geographic region [Japan vs. Rest of World], and baseline BCVA [<60 vs. ≥60]) will also 
apply for the Dense PK Substudy as part of the overall population. 
All participants in the Dense PK Substudy will participate in the main study for 96 weeks but 
will have additional visits for the substudy as outlined in the protocol. Samples for Dense PK 
will be collected at a screening visit, at baseline visit pre-injection and then 4 h (within 
±30 minutes) and 8 h (within ±2 hours) after injection, as well as on post-baseline day 2, 3, 5, 
8, 15 and 22 (all within ±2 hours of the clock time of dosing at baseline).  
The PK parameters to be determined, if possible, after the first dose for free, adjusted bound, 
and total aflibercept may include, but are not limited to: 
• Maximum concentration (Cmax) 
• Cmax/Dose 
• Time of Cmax (tmax) 
• Last time point (tlast) 
• Last concentration (Clast) 
• Area under the curve to the last quantifiable concentration (AUClast) 
• Area under the curve from time zero to infinity (AUCinf) 
• AUCinf/Dose  
• Half-life (t1/2) 
• Trough concentration (Ctrough) 
After repeat dosing, PK parameters to be determined, if possible, may include, but are not 
limited to Ctrough, time to reach steady-state, and accumulation ratio. PK parameters will be 
summarized by descriptive statistics by treatment group, and geographical region as 
appropriate. This descriptive statistical assessment will include number of observations, the 
geometric mean, 95% CI of the geometric mean, geometric coefficient of variation, arithmetic 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 49 of 103
 
 
mean, SD, CV%, median, Q1,Q3, minimum and maximum values. No formal statistical 
hypothesis testing will be performed. If there are any values below limit of quantification 
(BLOQ) they will be substituted by 1/2 of the lower limit of quantification (LLOQ) for the 
calculation of geometric statistics and 0 for arithmetic statistics.  
Dose and/or exposure-response analyses may be performed for select safety endpoints, as 
appropriate. 
6.4 
Safety 
The analysis of safety variables will be conducted descriptively on the SAF population for the 
data up to Week 48, up to Week 60 and up to Week 96 (Week 100 for French participants 
only).  
6.4.1 
Adverse Events and Serious Adverse Events 
An AE is any untoward medical occurrence in a clinical study participant, associated with the 
use of study intervention, whether or not considered related to the study intervention. All 
reported AEs will be coded using the version of MedDRA available at database lock. Coding 
will be to lowest level terms according to Bayer global standards. 
AEs will be collected from the time of informed consent signature and at each visit until the 
end of the study. If the participant withdraws from the study during the screening, AEs will be 
collected up until the participant withdraws. If the participant is withdrawn after receiving the 
first dose 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 started after the 
participant has signed the informed consent, but prior to the first injection at baseline 
(Visit 2, date of the participant’s first dose of study intervention). 
• Post-treatment AE: Post-treatment AEs are defined as AEs that started more than 30 
days after the last injection (active or sham) in the study. For the participants who 
have not discontinued study treatment prematurely (i.e. are “ongoing”) at the Week 48 
analysis and at the Week 60 analysis, respectively, no AEs will be considered post-
treatment, even if they started more than 30 days after the latest injection. 
• Treatment-emergent adverse event (TEAE): TEAEs are defined as AEs that started 
in the time frame from first injection to the last injection (active or sham) in the study 
plus 30 days. For the participants who have not discontinued study treatment 
prematurely (i.e. are “ongoing”) at the Week 48 analysis and at the Week 60 analysis, 
respectively, all AEs that started at first injection or later will be considered treatment-
emergent. 
The data cut-off rules for Week 48 and Week 60 AE reporting are described in a separate 
document “Data Cut-Off Specifications”). 
The proportions of participants 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 commercial aflibercept (2 mg), relationship of AE 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 50 of 103
 
 
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 participants reporting AEs will include 
the PTs and the SOCs. 
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 alphabetical order. 
For overall characterization of the AE profile for aflibercept in this study, an AE summary 
will include AEs within each SOC listed in alphabetical order with columns for treatment 
group, including a column “All HD” for the pooled HD group. 
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 commercial aflibercept (2 mg) will be summarized separately. 
A listing will be constructed that includes the participant identification, the treatment group, 
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 and SOC, will be displayed by treatment arm (see Section 9.4 for definition of 
terms). 
A frequency table of adjudicated treatment-emergent APTC events terms, cross-tabulated 
with related MedDRA PT and SOC, will be displayed by treatment arms. The adjudication of 
AE is described in the “APTC adjudication committee charter”. 
A frequency table of TEAEs of hypertension terms, cross-tabulated with related MedDRA 
PT and SOC, will be displayed by treatment arm (see Section 9.4 for definition of terms). 
A frequency table of TEAEs of nasal mucosal finding terms, cross-tabulated with related 
MedDRA PT and SOC, will be displayed by treatment arm (see Section 9.4 for definition of 
terms). 
6.4.1.1 
Subgroup Analyses  
Subgroup analyses for TEAEs will be performed for the safety analysis subgroups described 
in Section 5.2, for each of the following types of TEAE: 
Number of participants with 
• ocular TEAEs in the study eye 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 51 of 103
 
 
• non-ocular TEAEs 
• Serious ocular TEAEs in the study eye 
• Serious non-ocular TEAEs 
6.4.2 
Immunogenicity 
Antibodies to aflibercept will be evaluated in serum samples collected from all participants 
(optional for participants in China) at baseline (Visit 2), at Week 48 (Visit 15) and at Week 96 
(EOS) or ED visit. 
The number and proportion of participants developing a treatment-emergent ADA response 
will be summarized for the AAS by treatment group, by visit and overall (for definitions, see 
Appendix 9.2). ADA titers will be summarized descriptively by treatment arm and visit. 
ADA titer will additionally be summarized with number and percentage of sujects for 
categories: 
- 
Low (titer <1,000) 
- 
Moderate (1,000 ≤ titer ≤ 10,000) 
- 
High (titer >10,000). 
The number and proportion of participants positive in the NAb assay will be summarized for 
the NAbAS by treatment group and visit and overall. 
Samples that tested negative for ADA are not assayed in the NAb assay and the 
corresponding NAb result are imputed as negative and included as such in the NAb analysis 
set. Participants in the NAbAS with multiple post-dose ADA results which consist of both 
imputed NAb-negative result(s) for ADA negative samples and only missing NAb results for 
all ADA-positive result(s), are set to NAb negative. Participants in the NAbAS that have at 
least one post-dose positive NAb analysis result are set to NAb positive even if other NAb 
results are missing. Plots of drug concentrations will be examined and the influence of ADAs 
and NAbs on individual PK profiles evaluated.  
6.4.3 
Surgeries 
All surgeries after informed consent are collected on the CRF. All surgeries and diagnostic 
procedures will be displayed in listings. 
6.4.4 
Clinical Laboratory Variables 
Chemistry, hematology and urinalysis will be collected at screening (Visit 1), Week 48 
(Visit 15) and at Week 96 (EOS) or ED. Only pregnancy testing is done at each visit. The 
tests detailed in Table 6–2 will be performed by the central laboratory. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 52 of 103
 
 
Table 6–2: Pre-defined laboratory abnormalities 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count 
RBC count 
Hemoglobin 
Hematocrit 
RBC Indices 
WBC count  
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical Chemistry Sodium 
Potassium 
Chloride 
Carbon dioxide 
Calcium 
Creatinine 
Glucose (non-fasting) 
Albumin 
AST/SGOT 
ALT/SGPT 
Alkaline phosphatase 
Total and direct bilirubin 
Urea (or BUN) 
LDH 
Total protein, serum 
Total cholesterol 
Triglycerides 
LDL 
HDL 
Uric acid 
CPK 
Routine Urinalysis 
• 
Specific gravity, color, clarity, crystals 
• 
pH, glucose (non-fasting), protein, blood, ketones, bilirubin, nitrite, 
leukocyte esterase by dipstick 
• 
WBC, RBC, hyaline and other casts, bacteria, epithelial cells, yeast 
• 
Creatinine 
• 
UPCR 
Other Screening 
Tests 
• 
Follicle stimulating hormone and estradiol (as needed in women of non-
childbearing potential only) 
• 
Highly sensitive serum hCG pregnancy test (as needed for WOCBP)a 
ALT=alanine aminotransferase, AST=aspartate aminotransferase, BUN=blood urea nitrogen, 
CPK=creatine phosphokinase, eCRF=electronic Case Report Form, hCG=human chorionic 
gonadotropin, HDL=high density lipoprotein, LDH=lactate dehydrogenase, LDL=low density 
lipoprotein, RBC=red blood cell, SGOT=serum glutamic-oxaloacetic transaminase, SGPT=serum 
glutamic-pyruvic transaminase, UPCR=urine protein: creatinine ratio, WBC=white blood cell, 
WOCBP=women of childbearing potential 
a 
For WOCBP, a negative serum pregnancy test at screening is required for eligibility. 
Laboratory test results will be summarized by baseline and change from baseline at each 
scheduled assessment using descriptive statistics. 
If there are any values below LOQ they will be substituted by 1/2 LLOQ for the calculation of 
statistics. 
Number and percentage of participants with a treatment-emergent potentially clinically 
significant value (PCSV, any value fulfilling pre-defined criteria for abnormal laboratory 
parameters as described in Table 9–4 in the Appendix 9.3) at any time point will be 
summarized for selected clinical laboratory test for all participants. 
Shift tables based on baseline normal/abnormal will be used to present the results for 
laboratory tests. 
Laboratory values out of normal range will be summarized in tables and also flagged in 
laboratory value listings. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 53 of 103
 
 
6.4.5 
Electrocardiogram 
A standard digital 12-lead Electrocardiogram (ECG) will be performed at screening (Visit 1), 
Week 48 (Visit 15) and at Week 96 (EOS) or ED. ECG variables will include the heart rate 
recorded from the ventricular rate and the PR interval, QRS duration, RR interval, QT interval 
and overall interpretation of ECG (normal/abnormal) . QTc with Bazett and Fridericia 
correction will be used. 
All ECG variables as described above will be analyzed for the SAF by appropriate descriptive 
methods and change from baseline or frequency tables and/or cross-tabulation of baseline vs. 
post-baseline status for categorical variables (overall interpretation of ECG normal/abnormal) 
by visit and treatment arms. 
6.4.6 
Vital Signs 
Vital signs will be collected pre-injection, and before any blood draws at each visit during the 
study. When possible, timing of all blood pressure assessments should be within ±2 hours of 
clock time of dosing at the baseline visit. Variables of analysis for 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 scheduled visit by treatment 
group for the SAF. 
Additionally, summaries will be provided for participants with at least one systolic blood 
pressure treatment emergent PCSV of 
• ≤ 95 mmHg and decrease from baseline ≥ 20 mmHg 
• ≥160 mmHg and increase from baseline ≥ 20 mmHg 
As well as for participants with diastolic blood pressure treatment emergent PCSV of 
• ≤ 45 mmHg and decrease from baseline ≥ 10 mmHg 
• ≥110 mmHg and increase from baseline ≥ 10 mmHg. 
Heart rate and blood pressure assessments will also be displayed as figures with mean change 
from baseline for SAF. 
6.4.7 
Other Safety Measures 
Variables of analysis for ocular safety measures include: 
• Proportion of participants with increased IOP 
o ≥ 10 mmHg increase in IOP measurement from baseline to any pre-dose 
measurement 
o > 21 mmHg for any pre-dose measurement at any time during the study 
o ≥ 25 mmHg for any pre-dose measurement at any time during the study 
o ≥ 35 mmHg for any pre-dose or post-dose measurement at any time during the 
study, 
where the post-dose IOP measurement will be the final measurement before the participant 
leaves the site. 
Summary statistics will also be displayed by visit for: 
• change from baseline for pre-dose IOP values 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 54 of 103
 
 
• Proportion of participants with Anterior Chamber Cells (only pre-dose assessment for 
study eye) 
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 participants with Anterior Chamber Flare (only pre-dose assessment for 
study eye) 
o 0: no protein 
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. 
• Proportion of participants with Vitreous cells (only pre-dose assessment for study eye) 
o 0: clear (0-1 cells) 
o Trace: few opacities (2-20 cells) 
o 1+: scattered opacities (21-50 cells) 
o 2+: moderate opacities (51-100 cells) 
o 3+: many opacities (101-250 cells) 
o 4+: dense opacities (>251 cells). 
Frequency tables will be provided for each of the above categories at each visit where data is 
available. Shift tables will be provided for the gradings (only pre-dose assessment for study 
eye). 
• Proportion of participants with PCV (YES/NO/not available) 
• Proportion of participants with GA development (YES/NO/not available) 
Frequency tables will be provided for each of the above categories at each visit where data is 
available. 
 
7. 
Document History and Changes in the Planned Statistical Analysis 
This Statistical Analysis Plan is based on the integrated clinical study protocol version 3.0 
(dated 26 APR 2022), which includes Amendment 2. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 55 of 103
 
 
Table 7–1: Document history 
SAP 
Version 
Date 
Change 
Rationale 
V 0.8 
14/AUG/2020 
Stable draft  
V 1.0 
27/SEP/2021 
- 
Safety follow-up at Week 100 for French 
participants added (sections 3, 4.5.4, 6.4) 
- 
Section 4.5.5 regarding imaging data added 
- 
Additional COVID-related outputs added 
(section 4.7) 
- 
Only one per protocol set kept (section 5.1) 
- 
Analysis timepoints for exposure analysis 
updated (section 6.1.4.2) 
- 
Section 6.2.1.3 for adjusted confidence limits 
added 
- 
Section 6.2.2.2.2.1 Tipping point analysis 
added 
- 
Further information for analysis regarding 
different intercurrent events added (sections 
6.2.2.1, 6.2.3.1.2, 6.2.3.2.1 – 6.2.3.2.7, 6.2.4.1, 
6.2.4.2, 6.2.4.5, 6.2.4.6, 6.2.4.11, 6.2.4.14) 
- 
Estimand description for sensitivity analysis of 
primary endpoint added (section 6.2.2.2.1) 
- 
Estimand description for binary key secondary 
endpoint added (section 6.2.3.1.2) 
- 
PK plots added (section 6.3.1) 
- 
Analysis timepoints for safety analysis updated 
(section 6.4.1) 
- 
AE relationship summaries added (section 
6.4.1) 
- 
Surgery summaries removed (section 6.4.3) 
- 
Lab section updated according to required 
summaries (section 6.4.4) 
- 
Heart rate and blood pressure pots added 
(section 6.4.6) 
- 
IOP summaries updated (section 6.4.7) 
- 
ADA definitions updated (appendix 9.2) 
- 
Pre-defined abnormalities removed for 
parameter that are not collected (appendix 9.3) 
- 
Table 9-12 with Strategies for occurrence of 
intercurrent events for analysis of continous 
variables added 
- 
Table 9-13 with Strategies for occurrence of 
intercurrent events for analysis of binary 
variables added 
- 
Table 9-14 with regions and countries added 
- 
Minor wording updates and clarifications added 
More details added; 
Updates made to align 
with Regeneron and 
after Bayer review of 
TLF shells 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 56 of 103
 
 
V2.0 
13 JUL 2022 
- 
Section 2, Table 1: Exploratory endpoint 
“Change from baseline in BCVA at each visit in 
relation to fluid outcomes” removed (as well as 
corresponding analysis in section 6.2.4)  
- 
Section 2, Table 1: Exploratory endpoint 
“Proportion of participants without leakage on 
fluorescein angiography (FA) at Week 48, 
Week 60, and Week 96” added (as well as 
corresponding analysis in section 6.2.4.15 and 
definition in section 4.5.5)  
- 
Section 2, Table 1: Exploratory endpoints 
updated to “Proportion of participants with q16 
or longer treatment interval through Week 48, 
Week 60, and Week 96 in HDq16 group”, 
“Proportion of participants with q12 or longer 
interval through Week 48, Week 60, and Week 
96 in the HDq12 and HDq16 groups”, and 
“Proportion of participants with q12 or q16 or 
longer treatment interval as the last treatment 
interval at Week 48, Week 60, and Week 96 in 
HDq12 and HDq16 groups, respectively” (as 
well as corresponding analysis in section 
6.1.4.2) 
- 
Section 3: Clarification added that the two 
statistical analysis strategies (G-SAP and EP-
SAP) will be described in one SAP document 
instead of two separate SAP documents 
- 
Section 4.1.1 Sample Size Determination: Text 
was added to describe the power, based on 
the revised confirmatory testing hierarchy.  
- 
Section 5.1: FAS definition updated to include 
“and who received at least 1 dose of study 
intervention” 
- 
Section 6.2.1 Statistical Hypotheses - Control 
of Multiplicity: Replaced the 2 figures showing: 
Global SAP (G-SAP), EMA/PMDA SAP(EP-
SAP) and related explanations by a strictly 
sequential confirmatory testing hierarchy, and 
including the superiority hypotheses at the end 
of the confirmatory testing hierarchy, all related 
sections updated consistently  
- 
Section 6.2.1.3 for adjusted confidence 
intervals removed and related sections 
updated consistently 
- 
Section 6.2.2: Minor updates in wording and 
re-numbering of hypotheses according to 
section 6.2.1 
- 
Section 6.2.2.1 Primary Efficacy Endpoint: 
MMRM updated to remove random effect bi to 
avoid over parametrization, to add index k to Y 
and є; clarification of є updated. 
- 
Section 6.2.2.1 PPS analysis renamed from 
sensitivity to supplementary analysis and 
added to this section 
- 
Section 6.2.2.2 Sensitivity Analysis: PPS 
moved into section 6.2.2.1 
- 
Section 6.2.2.2.1 updated for consistency with 
Primary Efficacy Endpoint section 
- 
Section 6.2.3.1.: Re-numbering of hypotheses 
To reflect the changes 
introduced in the clinical 
study protocol v3.0 
(amendment 2)  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 57 of 103
 
 
Table 7–1: Document history 
SAP 
Version 
Date 
Change 
Rationale 
according to section 6.2.1 
- 
Section 6.2.3.1.2 updated for consistency with 
Primary Efficacy Endpoint section, PPS 
analysis renamed from sensitivity to 
supplementary analysis and added to this 
section 
- 
Section 6.2.3.1.2.1 PPS moved into section 
6.2.3.1.2 
- 
Section 6.3.1 PK analysis main study: bound 
concentrations removed and further minor text 
updates 
- 
Section 6.3.2 Dense PK analysis: minor text 
updates 
- 
Section 6.4.1: Frequency tables, cross-
tabulated with related MedDRA PT, added for 
intraocular inflammation, hypertension and 
nasal mucosal finding  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 58 of 103
 
 
Table 7–1: Document history 
SAP 
Version 
Date 
Change 
Rationale 
- 
Section 4.5.1: Definition of baseline for blood 
pressure clarified (to describe that average 
over all visits at or prior to randomization will 
be calculated) 
- 
Section 4.6: Clarifying text added that only one 
PPS will be defined for all analyses 
- 
Section 5.1: PPS definition updated to remove 
“received at least one dose of study treatment” 
(because this condition was added to the FAS) 
and to include “had a baseline BCVA value 
available” and “had at least one post-baseline 
BCVA value available”. NAbAS definition 
updated to add that the participants must also 
be in the ADA analysis set, test negative at all 
ADA sampline times or test positive at one or 
more post-dose ADA sampling times, and must 
have at least one post-dose NAb result. 
- 
Section 6.2.4.5: Proportion of participants with 
any gain in BCVA added  
- 
Section 6.4.7: Proportion of participants with 
increased IOP changed from “≥10 mmHg 
increase in IOP measurement from pre-dose to 
post-dose” to “≥10 mmHg increase in IOP 
measurement from baseline to pre-dose”; 
Proportion of participants with increased IOP 
changed from “≥21 mmHg for any pre-dose 
and post-dose measurement at any time during 
the study” to “>21 mmHg for any pre-dose 
measurement at any time during the study”; 
Remove post-dose summaries for IOP “≥10 
mmHg, “>21 mmHg and “≥25 mmHg  
- 
Sections 6.2.4.12 and 6.2.4.13: Addition of 
separate analysis on IRF and SRF for “time to 
fluid-free retina” and “time to sustained fluid-
free retina”. Addition of stratified log-rank test 
and addition of Cox proportional hazards 
model to compare each HD group with the 2q8 
group using the study visits, not calendar days, 
as units.  
- 
Section 6.2.4.13: Definition of sustained fluid-
free retina clarified and analysis of time to 
sustained fluid-free retina added. 
- 
Section 6.3.1: Subgroup analysis by body 
weight changed to by BMI categories.  
- 
Section 9.4: Subsections and their PTs 
updated using MedDRA version 25.0. 
 
To align with PHOTON 
study  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 59 of 103
 
 
Table 7–1: Document history 
SAP 
Version 
Date 
Change 
Rationale 
- 
Section 5 / Section 6 / Section 6.2: Remove 
PPS analysis for additional secondary efficacy 
variables  
- 
Section 6.1.2: General summary for all medical 
history events removed, MH listings for drop-
out participants removed 
- 
Section 6.2.2 / Section 6.2.3 (and subsections) 
/ Section 6.2.4 (and subsections): Remove 
summary tables for observed cases ignoring 
the occurrence of ICEs for all efficacy 
endpoints; Remove MI analysis for all binary 
additional secondary and exploratory efficacy 
variables 
- 
Section 6.2.3.1.2.1: Remove logistic 
regressions for dryness endpoint  
- 
Section 6.2.5: Remove subgroup analysis for 
all additional secondary endpoints; Removed 
forrest plots  
- 
Remove analysis of Bilateral Treatment 
Experience with Aflibercept Treatment (prior 
Section 6.4.1.2)  
- 
Section 6.3.1: Removal of summaries for PK 
concentration and BP relationship, Removal of 
summaries for PK concentration by ADA 
subgroups. Removal of PK listings by 
subgroup. 
- 
Section 6.3.2: Removal of summaries for PK 
concentration and BP relationship 
- 
Section 6.4.2: Removed immunogenecity 
subgroup for analysis of TEAEs. 
- 
Sections 6.2.2.2.1 and 9.5: Definition of the 
Sensitibity Estimand and “Strategy” column 
removed from “Sensitivity Estimand” section in 
Table 16 as it follows the same strategy as the 
primary estimand but using a different analysis 
approach. 
To remove analyses that 
are not necessary for 
the clinical study report  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 60 of 103
 
 
Table 7–1: Document history 
SAP 
Version 
Date 
Change 
Rationale 
- 
Section 4.5.3: Clarification added for re-
mapping of early discontinuation visit data  
- 
Section 4.5.4: Clarification added how to 
classify and summarize imaging data assesses 
by the reading center  
- 
Section 4.5.5: Definition of fellow eye treatment 
added and subsequent sections updated 
accordingly 
- 
Section 4.5.6: Definition of prohibited 
medication added 
- 
Section 4.8: Listing added for participants 
affected by Ukraine/Russia crisis related 
findings and deviations 
- 
Section 6.2.2.1: Proposal added for 
convergence issues with unstructured 
covariance matrix. Additional text to clarify that 
different covariance parameters are assumed 
per treatment group. This information was 
already illustrated in the equation. 
- 
Section 6.2.2.2.1 / 6.2.2.2.2.1 / 6.2.3.1.2.1: 
Clarification added that unadjusted two-sided 
95% CIs will be presented as well for the 
primary and key secondary efficacy endpoints  
- 
Section 6.2.2.2.2: Clarification added for the 
method to be used in the MI procedure 
- 
Section 6.2.3.1.2: Clarification added how to 
derive the dryness endpoint  
- 
Section 6.2.3.2.5: Previously removed text 
added back 
- 
Section 6.4.1: Clarification added that all AEs 
that started at first injection or later will be 
considered treatment-emergent for participants 
who are “ongoing” at the Week 48 analysis and 
at the Week 60 analysis, respectively 
- 
Section 6.4.7: Clarification added that slit lamp 
summaries will only include pre-dose 
assessments for the study eye 
- 
Section 9.4.3: List of PTs added to identify 
nasal mucosal events  
- 
Section 9.5: Footnotes added for clarification of 
missing loading dose injections and reference 
to section 4.5.6 added for prohibited 
medication ICE 
To provide additional 
details 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 61 of 103
 
 
Table 7–1: Document history 
SAP 
Version 
Date 
Change 
Rationale 
- 
Section 4.5.1: Definition of baseline based on 
date of randomization instead of date of first 
study intervention  
- 
Section 4.5.2: Removal of re-mapping of 
unscheduled assessment data  
- 
Section 4.5.3: Removal of re-mapping of 
unscheduled assessment data  
- 
Section 4.5.3: The “last visit” will not be 
summarized on a visit level  
- 
Section 5.2: Age, ethnicity, race and baseline 
BCVA subgroups updated  
- 
Section 6.1.1: Age and baseline BCVA 
categories updated; menarch and childbearing 
potential, IRF, SRF and dryness status 
removed; medical history of hypertension, 
medical history of cerebrovascular disease, 
medical history of ischaemic heart disease, 
medical history of renal impairment, hepatic 
impairment added 
- 
Section 6.1.2: Separate summaries for medical 
history of hypertension, medical history of 
cerebrovascular disease, medical history of 
ischaemic heart disease, medical history of 
renal impairment, hepatic impairment removed  
- 
Section 6.1.4.2: Following added: Proportion of 
participants with q12 or q16 or longer treatment 
interval as the last completed treatment interval 
at Week 48, Week 60, and Week 96 in HDq12 
and HDq16 groups, respectively (based on the 
2 last active injections received before Week 
48, Week 60, and Week 96); Proportion of 
participants maintained with q16 treatment 
interval through through Week 60 in HDq16 
group; Proportion of participants maintained 
with q12 or longer interval through Week 60 in 
the HDq12 and HDq16 groups added; 
Proportion of participants dropping out during 
loading phase; Proportion of participants 
shortening treatment interval to q8 at Week 16 
or Week 20 in HDq12 and HDq16 groups; 
Proportion of participants shortening treatment 
interval due to DRM criterion in HDq12 and 
HDq16 groups; Proportion of participants never 
extending treatment interval in HDq12 and 
HDq16 groups; Proportion of participants 
extending treatment interval due to DRM 
criteria in HDq12 and HDq16 groups 
- 
Section 9.5: clarifying text added, minor 
mistakes corrected 
Minor updates 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 62 of 103
 
 
Table 7–1: Document history 
SAP 
Version 
Date 
Change 
Rationale 
- 
Section 4.5.4: IRF presence in center point and 
SRF presence in center point added 
- 
Section 5.2: Statement added that any 
statistical testing / calculation of p-values for 
subgroups will only be done for exploratory 
purpose 
- 
Section 6.1.4.2: Sequence of exposure 
variables updated and additional treatment 
summaries for patients with bilateral treatment 
added 
- 
Section 6.2.1: Statement for re-production of 
week 48 summaries for week 60 delivery 
removed 
- 
Section 6.2.3.1.2: Clarification for denominator 
for proportion calculation added and additional 
summaries for IRF/SRF at central subfield and 
IRF/SRF/Dryness status at center point added 
- 
Section 6.2.3.2.1, 6.2.3.2.2, 6.2.3.2.5, 6.2.4.3, 
6.2.4.4, 6.2.4.5, 6.2.4.6, 6.2.4.10, 6.2.4.11, 
6.2.4.13, 6.2.4.15: Clarification for denominator 
for proportion calculation added 
- 
Section 6.2.3.2.3, 6.2.3.2.4, 6.2.3.2.7, 6.2.4.7, 
6.2.4.8, 6.2.4.14, 6.2.4.15: Clarification added 
that also data from early termination visits, that 
could not be re-mapped to a regular visit will be 
considered for LOCF summaries 
- 
Section 6.2.4.13: descriptive LOCF summary 
removed 
- 
Section 6.4.1: Sorting changed to alphabetical 
order, summaries for pooled HD group added, 
SOC summaries added for separate intraocular 
inflammation, APTC, hypertension  and nasal 
mucosal finding event tables, further minor text 
updates 
- 
Section 6.4.2: Titer summaries added 
- 
Section 6.4.4: Clarification added for 
summaries of treatment-emergent pre-defined 
lab abnormalities, Statement about SI units 
removed 
- 
Section 6.4.6: Summaries for treatment 
emergent PCSV added, Figures for DPKS 
removed 
- 
Section 9.4.3: PT terms updated 
Updates based on dry 
run and mock CSR 
review comments 
V 3.0 
Date of last 
signature 
- 
Additional pre-specified exploratory efficacy 
endpoints and analyses mentioned in  
Section 2 and details added in Appendix 9.7 
Additional pre-specified 
exploratory efficacy 
endpoints and analyses 
added for submission to 
US FDA  
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 63 of 103
 
 
8. 
References 
1. Basic principles on global clinical trials. PMDA Guidance, 2007. 
https://www.pmda.go.jp/files/000153265.pdf. 
2. Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical 
approaches for multiple comparison procedures using weighted Bonferroni, Simes, or 
parametric tests. Biom J. 2011 Nov;53(6):894-913. 
3. Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially 
rejective multiple test procedures. Statistics in Medicine. 2009;28:586–604 
4. Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ, 'Categorical Data Analysis' in 
Statistical methodology in the pharmaceutical sciences / edited by DA Berry, Marcel 
Dekker, 1990 
5. 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 
6. Rubin D E. Multiple Imputation for Nonresponse in Surveys. Wiley. 1987 
7. Guilbaud Olivier J M. Simultaneous Confidence Intervals Compatible with 
Sequentially Rejective Graphical Procedures, Statistics in Biopharmaceutical 
Research, 2018; 10:3, 220-232 
 
9. 
Appendix 
9.1 
Handling of Questionnaires 
9.1.1 
NEI-VFQ-25 Sub-scale Scores and Total Score 
The calculation for NEI-VFQ-25 sub-scale scores and total score will be performed according 
to The National Eye Institute (2000). The algorithm is then: As a preparation of the VFQ-25 
calculation, the items of the questionnaire will be recoded according to Table 9–1. In the 
further calculations, only the recoded item values will be used. For the recoded values, they 
generally represent the best possible result as “100” and the worst possible result as “0”. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 64 of 103
 
 
Table 9–1: Recoding of NEI-VFQ 25 items 
Item no. 
Original response to 
Recoded item 
1, 3, 4, 15c(a) 
1 
100 
2 
75 
3 
50 
4 
25 
5 
0 
2 
1 
100 
2 
80 
3 
60 
4 
40 
5 
20 
6 
0 
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 
16, 16a 
1 
100 
2 
75 
3 
50 
4 
25 
5 
0 
6 
* 
17, 18, 19, 20, 21, 22, 23, 24, 25 1 
0 
2 
25 
3 
50 
4 
75 
5 
100 
(a) Item 15c has four-response levels but is expanded to a five-levels using item 15b: if 15b=”1”, then 
15c=”0” / if 15b=(”2” or “3”), then 15c=”missing” 
* Here, Response choice “6” indicates that the person does not perform the activity because of non-
vision-related problems. If this choice is selected, the item is coded as “missing”. 
 
For the VFQ questionnaire, 12 sub-scales will be evaluated (see Table 9–2), and 11 of these 
sub‑scales will be included in the total VFQ score. 
Table 9–2: Sub-scales of the NEI-VFQ 25 score 
Sub-scale no. 
Sub-scale 
Number of items (Recoded) items 
to be averaged 
Sub-scale included 
in total scale 
1 
General Health 
1 
1 
No 
2 
General Vision 
1 
2 
Yes 
3 
Ocular Pain 
2 
4, 19 
Yes 
4 
Near Activities 
3 
5, 6, 7 
Yes 
5 
Distance Activities 
3 
8, 9, 14 
Yes 
Vision specific: 
6 
Social Functioning 2 
11, 13 
Yes 
7 
Mental Health 
4 
3, 21, 22, 25 
Yes 
8 
Role Difficulties 
2 
17, 18 
Yes 
9 
Dependency 
3 
20, 23, 24 
Yes 
10 
Driving 
3 
15c, 16, 16a 
Yes 
11 
Color vision 
1 
12 
Yes 
12 
Peripheral Vision 
1 
10 
Yes 
For a single sub-scale, the value will be determined as the average of the non-missing recoded 
item values assigned to this sub-scale. A sub-scale value will only be assessed as missing if 
all items for this sub-scale have “missing” as a result.  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 65 of 103
 
 
The total score is calculated as the arithmetic mean of all non-missing sub-scales (except 
General Health): 
𝑡𝑜𝑡𝑎𝑙 𝑟𝑒𝑠𝑢𝑙𝑡=
(𝑠𝑢𝑚 𝑜𝑓 𝑛𝑜𝑛 −𝑚𝑖𝑠𝑠𝑖𝑛𝑔 𝑠𝑢𝑏− 𝑠𝑐𝑎𝑙𝑒 𝑣𝑎𝑙𝑢𝑒𝑠)
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑠𝑢𝑏− 𝑠𝑐𝑎𝑙𝑒𝑠 𝑤𝑖𝑡ℎ 𝑛𝑜𝑛 −𝑚𝑖𝑠𝑠𝑖𝑛𝑔 𝑟𝑒𝑠𝑢𝑙𝑡 
Due to this calculation approach, the total result will be non-missing if at least one sub-scale 
result is non-missing. 
9.2 
Development of Anti-drug Antibodies 
The measurements of antibody assays (screening and confirmatory assay) at baseline, 
Week 48 and Week 96 will be used to classify the respective antibody status at the respective 
visit in the following Table 9–3 
Table 9–3: Classification of the respective antibody status 
Screening test 
Confirmatory test 
Antibody status at respective 
visit 
Negative 
ND 
Negative 
Negative 
Negative 
Negative 
Negative 
Positive 
Positive 
Positive 
ND 
ND 
Positive 
Negative 
Negative 
Positive 
Positive 
Positive 
ND 
ND 
ND 
ND 
Negative 
Negative 
ND 
Positive 
Positive 
The antibody status for the overall study course until Week 96 will be defined according to 
the following definition.  
• ADA Negative: defined as negative response in the ADA assay at all time points and 
those that exhibit a pre-existing response, regardless of any missing samples 
• ADA positive: defined as those that exhibit a treatment-emergent or treatment-
boosted ADA response, regardless of any missing sample 
 
Pre-existing immunoreactivity: defined as either a positive response in the ADA 
assay at baseline with all post first dose ADA results negative OR a positive response 
at baseline with all post first dose ADA responses less than 4-fold of baseline titer 
levels. 
 
Treatment-boosted ADA response: defined as a positive response post first dose that 
is greater than or equal to 4-fold over baseline titer level, when baseline results are 
positive.  
 
Treatment-emergent positive: defined as an ADA positive response post first dose 
when baseline results are negative or missing, or ADA positive response more than 4-
fold of a positive baseline titer. The treatment-emergent responses will be further 
characterized as Persistent, Indeterminate or Transient. 
o  - Persistent Response – Treatment-emergent ADA positive response with two 
or more consecutive ADA positive sampling time points, with no ADA 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 66 of 103
 
 
negative samples in between, regardless of any missing samples. 
 
- Indeterminate Response –Treatment-emergent ADA positive response with 
only the last collected sample positive in the ADA assay, regardless of any 
missing samples. 
 
- Transient Response –Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 67 of 103
 
 
9.3 
Pre-defined Laboratory Abnormalities 
Table 9–4: Pre-defined laboratory abnormalities 
Parameter 
Pre-defined laboratory abnormalities for phase 2/3 studies 
Clinical chemistry 
ALT 
> 3 ULN 
AST 
> 3 ULN 
Alkaline Phosphatase 
> 1.5 ULN 
Total Bilirubin 
> 1.5 ULN 
Conjugated bilirubin 
> 35% total bilirubin (when total bilirubin >1.5 ULN) 
ALT and Total Bilirubin 
ALT > 3 ULN and Total Bilirubin > 2 ULN 
CPK 
> 3 ULN 
Creatinine 
≥ 150 μmol/L (Adults) 
≥ 30% from baseline 
Uric Acid 
Hyperuricemia: >408 μmol/L 
Hypouricemia: <120 μmol/L 
Blood Urea Nitrogen 
≥ 17 mmol/L 
Chloride 
< 80 mmol/L 
> 115 mmol/L 
Sodium 
≤ 129 mmol/L 
≥ 160 mmol/L 
Potassium 
< 3 mmol/L 
≥ 5.5 mmol/L 
Total Cholesterol 
≥ 7.74 mmol/L (3 g/L) 
Triglycerides 
≥ 4.6 mmol/L (4 g/L) 
Glucose 
- Hypoglycaemia 
- Hyperglycaemia 
≤ 3.9 mmol/L and < LLN 
≥ 11.1 mmol/L (unfasted), ≥ 7 mmol/L (fasted) 
Albumin 
≤ 25 g/L 
Hematology 
WBC 
< 3.0 GIGA/L (non-Black), < 2.0 GIGA/L (Black), ≥ 16.0 GIGA/L 
Lymphocytes 
> 4.0 GIGA/L 
Neutrophils 
< 1.5 GIGA/L (non-Black) 
< 1.0 GIGA/L (Black) 
Monocytes 
> 0.7 GIGA/L 
Basophils 
> 0.1 GIGA/L 
Eosinophils 
> 0.5 GIGA/L or > ULN if ULN ≥ 0.5 GIGA /L 
Hemoglobin 
Males : 115 g/L (≤ 7.14 mmol/L), ≥ 185 g/L (11.48 mmol/L) 
Females : ≤ 95 g/L (5.9 mmol/L), ≥ 165 g/L (10.24 mmol/L) 
Decrease from baseline ≥ 20 g/L (1.24 mmol/L) 
Hematocrit 
Males : ≤ 0.37 v/v, ≥ 0.55 v/v 
Females : ≤ 0.32 v/v, ≥ 0.5 v/v 
RBC 
≥ 6 TERA/L 
Platelets 
< 100 GIGA/L 
LLN: lower limit of normal, ULN: upper limit of normal 
9.4 
Definition of safety subgroups 
In the following the definitions for subgroups based on medical history and adverse events are 
given.  
9.4.1 
Hypertension  
Hypertension will be selected based on the PTs as described in Table 9–5 below, following 
the PBMQ 1275. All PTs given are based on MedDRA version 25.0 and might be subject to 
change in future MedDRA version. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 68 of 103
 
 
Table 9–5: PTs for selection of “Hypertension” 
Preferred term (MedDRA version 25.0) 
Accelerated hypertension 
Blood pressure ambulatory increased 
Blood pressure diastolic increased 
Blood pressure inadequately controlled 
Blood pressure increased 
Blood pressure systolic increased 
Diastolic hypertension 
Endocrine hypertension 
Essential hypertension 
Hypertension 
Hypertension neonatal 
Hypertensive angiopathy 
Hypertensive cardiomegaly 
Hypertensive cardiomyopathy 
Hypertensive cerebrovascular disease 
Hypertensive crisis 
Hypertensive emergency 
Hypertensive encephalopathy 
Hypertensive end-organ damage 
Hypertensive heart disease 
Hypertensive nephropathy 
Hypertensive urgency 
Labile hypertension 
Malignant hypertension 
Malignant hypertensive heart disease 
Malignant renal hypertension 
Maternal hypertension affecting foetus 
Mean arterial pressure increased 
Neurogenic hypertension 
Orthostatic hypertension 
Page kidney 
Prehypertension 
Renal hypertension 
Renovascular hypertension 
Retinopathy hypertensive 
Supine hypertension 
Systolic hypertension 
White coat hypertension 
 
9.4.2 
Intraocular inflammation  
Intraocular inflammation will be selected based on the PTs as described in Table 9–6 below. 
All PTs given are based on MedDRA version 25.0 and might be subject to change in future 
MedDRA version. 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 69 of 103
 
 
Table 9–6: PTs for selection of “Intraocular Inflammation” 
Preferred term (MedDRA version 25.0) 
Anterior chamber fibrin 
Anterior chamber cell 
Anterior chamber flare 
Anterior chamber inflammation 
Aqueous fibrin 
Autoimmune uveitis 
Candida endophthalmitis 
Chorioretinitis 
Choroiditis 
Cyclitis 
Endophthalmitis 
Eye infection bacterial 
Eye infection chlamydial 
Eye infection fungal 
Eye infection intraocular 
Eye infection staphylococcal 
Eye infection 
Eye inflammation 
Hypopyon 
Infectious iridocyclitis 
Infective iritis 
Infective uveitis 
Iridocyclitis 
Iritis 
Mycotic endophthalmitis 
Necrotising retinitis 
Non-infectious endophthalmitis 
Noninfective chorioretinitis 
Pseudoendophthalmitis 
Uveitis 
Vitreal cells 
Vitreous fibrin 
Vitritis 
 
9.4.3 
Nasal mucosal events 
Nasal mucosal events will be selected based on the PTs as described in Table 9–7 below. All 
PTs given are based on MedDRA version 25.0 and might be subject to change in future 
MedDRA version. 
Table 9–7: PTs for selection of “Nasal mucosal events” 
Preferred term (MedDRA version 25.0) 
Epistaxis 
Nasal inflammation 
Nasal mucosal erosion 
Nasal mucosal ulcer 
Nasal ulcer 
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 70 of 103
 
 
9.4.4 
Medical history of cerebrovascular disease (e.g. CVA / Stroke) 
Defined by MSSO SMQ 20000060 ‘Central nervous system vascular disorders’as described 
in Table 9–8 below. All PTs given are based on MedDRA version 25.0 and might be subject 
to change in future MedDRA version. 
Table 9–8: PTs for selection of medical history of “Cerebrovascular 
Disease” 
Preferred Term (MedDRA version 25.0)  
Agnosia 
Amaurosis fugax 
Amyloid related imaging abnormalities 
Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits 
Amyloid related imaging abnormality-oedema/effusion 
Angiogram cerebral abnormal 
Aphasia 
Balint's syndrome 
Basal ganglia haematoma 
Basal ganglia haemorrhage 
Basal ganglia infarction 
Basal ganglia stroke 
Basilar artery aneurysm 
Basilar artery occlusion 
Basilar artery perforation 
Basilar artery stenosis 
Basilar artery thrombosis 
Benedikt's syndrome 
Blood brain barrier defect 
Brachiocephalic arteriosclerosis 
Brachiocephalic artery occlusion 
Brachiocephalic artery stenosis 
Brain hypoxia 
Brain injury 
Brain stem embolism 
Brain stem haematoma 
Brain stem haemorrhage 
Brain stem infarction 
Brain stem ischaemia 
Brain stem microhaemorrhage 
Brain stem stroke 
Brain stem thrombosis 
Brain stent insertion 
CADASIL 
CARASIL syndrome 
CSF bilirubin positive 
CSF red blood cell count positive 
Capsular warning syndrome 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 71 of 103
 
 
Table 9–8: PTs for selection of medical history of “Cerebrovascular 
Disease” 
Preferred Term (MedDRA version 25.0)  
Carotid aneurysm rupture 
Carotid angioplasty 
Carotid arterial embolus 
Carotid arteriosclerosis 
Carotid artery aneurysm 
Carotid artery bypass 
Carotid artery disease 
Carotid artery dissection 
Carotid artery dolichoectasia 
Carotid artery insufficiency 
Carotid artery occlusion 
Carotid artery perforation 
Carotid artery restenosis 
Carotid artery stenosis 
Carotid artery stent insertion 
Carotid artery stent removal 
Carotid artery thrombosis 
Carotid endarterectomy 
Carotid revascularisation 
Central nervous system haemorrhage 
Central nervous system vasculitis 
Central pain syndrome 
Cerebellar artery occlusion 
Cerebellar artery thrombosis 
Cerebellar atherosclerosis 
Cerebellar embolism 
Cerebellar haematoma 
Cerebellar haemorrhage 
Cerebellar infarction 
Cerebellar ischaemia 
Cerebellar microhaemorrhage 
Cerebellar stroke 
Cerebral amyloid angiopathy 
Cerebral aneurysm perforation 
Cerebral aneurysm ruptured syphilitic 
Cerebral arteriosclerosis 
Cerebral arteriovenous malformation haemorrhagic 
Cerebral arteritis 
Cerebral artery embolism 
Cerebral artery occlusion 
Cerebral artery perforation 
Cerebral artery restenosis 
Cerebral artery stenosis 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 72 of 103
 
 
Table 9–8: PTs for selection of medical history of “Cerebrovascular 
Disease” 
Preferred Term (MedDRA version 25.0)  
Cerebral artery stent insertion 
Cerebral artery thrombosis 
Cerebral capillary telangiectasia 
Cerebral cavernous malformation 
Cerebral circulatory failure 
Cerebral congestion 
Cerebral cyst haemorrhage 
Cerebral endovascular aneurysm repair 
Cerebral gas embolism 
Cerebral haematoma 
Cerebral haemorrhage 
Cerebral haemorrhage foetal 
Cerebral haemorrhage neonatal 
Cerebral haemosiderin deposition 
Cerebral hypoperfusion 
Cerebral infarction 
Cerebral infarction foetal 
Cerebral ischaemia 
Cerebral microangiopathy 
Cerebral microembolism 
Cerebral microhaemorrhage 
Cerebral microinfarction 
Cerebral reperfusion injury 
Cerebral revascularisation 
Cerebral septic infarct 
Cerebral small vessel ischaemic disease 
Cerebral thrombosis 
Cerebral vascular occlusion 
Cerebral vasoconstriction 
Cerebral venous sinus thrombosis 
Cerebral venous thrombosis 
Cerebral ventricular rupture 
Cerebrovascular accident 
Cerebrovascular accident prophylaxis 
Cerebrovascular arteriovenous malformation 
Cerebrovascular disorder 
Cerebrovascular insufficiency 
Cerebrovascular pseudoaneurysm 
Cerebrovascular stenosis 
Charcot-Bouchard microaneurysms 
Chronic cerebrospinal venous insufficiency 
Claude's syndrome 
Congenital cerebrovascular anomaly 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 73 of 103
 
 
Table 9–8: PTs for selection of medical history of “Cerebrovascular 
Disease” 
Preferred Term (MedDRA version 25.0)  
Congenital hemiparesis 
Delayed ischaemic neurological deficit 
Diplegia 
Dural arteriovenous fistula 
Dysarthria 
Embolic cerebellar infarction 
Embolic cerebral infarction 
Embolic stroke 
Epidural haemorrhage 
Extra-axial haemorrhage 
Extradural haematoma 
Extradural haematoma evacuation 
Extraischaemic cerebral haematoma 
Foetal cerebrovascular disorder 
Foville syndrome 
Haemorrhage intracranial 
Haemorrhagic cerebellar infarction 
Haemorrhagic cerebral infarction 
Haemorrhagic stroke 
Haemorrhagic transformation stroke 
Heidelberg classification 
Hemianaesthesia 
Hemiasomatognosia 
Hemiataxia 
Hemidysaesthesia 
Hemihyperaesthesia 
Hemihypoaesthesia 
Hemiparaesthesia 
Hemiparesis 
Hemiplegia 
Hunt and Hess scale 
Hypertensive cerebrovascular disease 
Hypoxic-ischaemic encephalopathy 
Inner ear infarction 
Internal capsule infarction 
Internal carotid artery deformity 
Intra-cerebral aneurysm operation 
Intracerebral haematoma evacuation 
Intracranial aneurysm 
Intracranial artery dissection 
Intracranial haematoma 
Intracranial haemorrhage neonatal 
Intracranial tumour haemorrhage 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 74 of 103
 
 
Table 9–8: PTs for selection of medical history of “Cerebrovascular 
Disease” 
Preferred Term (MedDRA version 25.0)  
Intraventricular haemorrhage 
Intraventricular haemorrhage neonatal 
Ischaemic cerebral infarction 
Ischaemic stroke 
Lacunar infarction 
Lacunar stroke 
Lateral medullary syndrome 
Lateropulsion 
Malignant middle cerebral artery syndrome 
Medullary compression syndrome 
Meningorrhagia 
Metabolic stroke 
Migrainous infarction 
Millard-Gubler syndrome 
Modified Rankin score decreased 
Modified Rankin score increased 
Monoparesis 
Monoplegia 
Moyamoya disease 
NIH stroke scale abnormal 
NIH stroke scale score decreased 
NIH stroke scale score increased 
Paralysis 
Paraparesis 
Paraplegia 
Paresis 
Perinatal stroke 
Periventricular haemorrhage neonatal 
Pituitary apoplexy 
Pituitary haemorrhage 
Post cardiac arrest syndrome 
Post procedural stroke 
Post stroke depression 
Posthaemorrhagic hydrocephalus 
Precerebral arteriosclerosis 
Precerebral artery aneurysm 
Precerebral artery dissection 
Precerebral artery embolism 
Precerebral artery occlusion 
Precerebral artery thrombosis 
Primary familial brain calcification 
Pseudo-occlusion of internal carotid artery 
Putamen haemorrhage 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 75 of 103
 
 
Table 9–8: PTs for selection of medical history of “Cerebrovascular 
Disease” 
Preferred Term (MedDRA version 25.0)  
Quadriparesis 
Quadriplegia 
Reversible cerebral vasoconstriction syndrome 
Reversible ischaemic neurological deficit 
Right hemisphere deficit syndrome 
Ruptured cerebral aneurysm 
Septic cerebral embolism 
Sigmoid sinus thrombosis 
Sneddon's syndrome 
Spinal artery embolism 
Spinal artery thrombosis 
Spinal cord haematoma 
Spinal cord haemorrhage 
Spinal cord infarction 
Spinal cord ischaemia 
Spinal epidural haematoma 
Spinal epidural haemorrhage 
Spinal stroke 
Spinal subarachnoid haemorrhage 
Spinal subdural haematoma 
Spinal subdural haemorrhage 
Spinal vascular disorder 
Spinal vessel congenital anomaly 
Stroke in evolution 
Subarachnoid haematoma 
Subarachnoid haemorrhage 
Subarachnoid haemorrhage neonatal 
Subclavian steal syndrome 
Subdural haematoma 
Subdural haematoma evacuation 
Subdural haemorrhage 
Subdural haemorrhage neonatal 
Superficial siderosis of central nervous system 
Superior sagittal sinus thrombosis 
Susac's syndrome 
Thalamic infarction 
Thalamus haemorrhage 
Thrombotic cerebral infarction 
Thrombotic stroke 
Transient ischaemic attack 
Transverse sinus thrombosis 
Vascular encephalopathy 
Vascular stent occlusion 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 76 of 103
 
 
Table 9–8: PTs for selection of medical history of “Cerebrovascular 
Disease” 
Preferred Term (MedDRA version 25.0)  
Vascular stent stenosis 
Vein of Galen aneurysmal malformation 
Vertebral artery aneurysm 
Vertebral artery arteriosclerosis 
Vertebral artery dissection 
Vertebral artery occlusion 
Vertebral artery perforation 
Vertebral artery stenosis 
Vertebral artery thrombosis 
Vertebrobasilar dolichoectasia 
Vertebrobasilar insufficiency 
Vertebrobasilar stroke 
Visual agnosia 
Visual midline shift syndrome 
Weber's syndrome 
 
9.4.5 
Medical history of ischaemic heart disease (e.g., myocardial infarction) 
PBMQ ‘Myocardial Infarction’ is defined by selected PTs only (from MSSO SMQs below): 
• 20000043: Ischaemic heart disease (MSSO SMQ) 
• 20000047: Myocardial infarction (MSSO SMQ)  
as described in Table 9–9 below. All PTs given are based on MedDRA version 25.0 and 
might be subject to change in future MedDRA version. 
Table 9–9: PTs for selection of medical history of “Ischaemic Heart 
Disease” 
Preferred Term (MedDRA version 25.0)  
Acute coronary syndrome 
Acute myocardial infarction 
Angina pectoris 
Angina unstable 
Anginal equivalent 
Arterial revascularisation 
Arteriogram coronary abnormal 
Arteriosclerosis coronary artery 
Arteriospasm coronary 
Cardiac perfusion defect 
Cardiac ventricular scarring 
Chronic coronary syndrome 
Computerised tomogram coronary artery abnormal 
Coronary angioplasty 
Coronary arterial stent insertion 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 77 of 103
 
 
Table 9–9: PTs for selection of medical history of “Ischaemic Heart 
Disease” 
Preferred Term (MedDRA version 25.0)  
Coronary artery bypass 
Coronary artery compression 
Coronary artery disease 
Coronary artery dissection 
Coronary artery embolism 
Coronary artery insufficiency 
Coronary artery occlusion 
Coronary artery reocclusion 
Coronary artery restenosis 
Coronary artery stenosis 
Coronary artery surgery 
Coronary artery thrombosis 
Coronary brachytherapy 
Coronary bypass stenosis 
Coronary bypass thrombosis 
Coronary endarterectomy 
Coronary no-reflow phenomenon 
Coronary ostial stenosis 
Coronary revascularisation 
Coronary steal syndrome 
Coronary vascular graft occlusion 
Coronary vascular graft stenosis 
ECG electrically inactive area 
ECG signs of myocardial infarction 
ECG signs of myocardial ischaemia 
Electrocardiogram PR segment depression 
Electrocardiogram PR segment elevation 
Electrocardiogram ST segment abnormal 
Electrocardiogram ST segment depression 
Electrocardiogram ST segment elevation 
Electrocardiogram ST-T segment abnormal 
Electrocardiogram ST-T segment depression 
Electrocardiogram ST-T segment elevation 
External counterpulsation 
Haemorrhage coronary artery 
Infarction 
Ischaemic cardiomyopathy 
Ischaemic contracture of the left ventricle 
Kounis syndrome 
Myocardial hypoperfusion 
Myocardial hypoxia 
Myocardial infarction 
Myocardial ischaemia 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 78 of 103
 
 
Table 9–9: PTs for selection of medical history of “Ischaemic Heart 
Disease” 
Preferred Term (MedDRA version 25.0)  
Myocardial necrosis 
Myocardial reperfusion injury 
Myocardial stunning 
Papillary muscle infarction 
Percutaneous coronary intervention 
Periprocedural myocardial infarction 
Positive vessel remodelling 
Post angioplasty restenosis 
Post procedural myocardial infarction 
Postinfarction angina 
Prinzmetal angina 
Scan myocardial perfusion abnormal 
Silent myocardial infarction 
Stent patency maintenance 
Stress cardiomyopathy 
Subclavian coronary steal syndrome 
Subendocardial ischaemia 
Vascular device occlusion 
Vascular graft occlusion 
Vascular graft restenosis 
Vascular graft stenosis 
Vascular graft thrombosis 
Vascular stent occlusion 
Vascular stent stenosis 
Ventricular compliance decreased 
Wellens' syndrome 
 
9.4.6 
Medical history of renal impairment 
Renal impairment is defined by creatinine clearance (CrCl) values. 
Categories for renal impairment: 
• CLCR >80ml/min (normal), 
• CLCR >50-80ml/min (mild), 
• CLCR >30-50 ml/min (moderate), 
• CLCR <=30ml/min or ‘requiring dialysis’ (severe). 
CLCR will be calculated using baseline values (creatinine, age, weight, sex) using the 
Cockcroft-Gault equation: 
Males: CLCR = (140-age)*body weight / (72*creatinine) 
Females: CLCR = (140-age)*body weight*0.85 / (72*creatinine) 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 79 of 103
 
 
‘Requiring dialysis’ is defined by PT from Table 9–10. All PTs given are based on MedDRA 
version 25.0 and might be subject to change in future MedDRA version. 
Table 9–10: PTs for selection of medical history of “Requiring dialysis” 
Preferred Term (MedDRA version 25.0)  
Continuous haemodiafiltration 
Dialysis 
Dialysis device insertion 
Haemodialysis 
Haemofiltration 
Peritoneal dialysis 
Removal of renal transplant 
Renal replacement therapy 
Renal transplant 
 
9.4.7 
Medical history of hepatic impairment 
Defined by MSSO SMQ: Hepatic disorders 20000005 excluding sub-SMQ 20000018: 
Pregnancy-related hepatic disorders as described in Table 9–11 below. All PTs given are 
based on MedDRA version 25.0 and might be subject to change in future MedDRA version. 
Table 9–11: PTs for selection of medical history of “Hepatic Impairment” 
Preferred term (MedDRA version 25.0)  
5'nucleotidase increased 
AST to platelet ratio index increased 
AST/ALT ratio abnormal 
Accessory liver lobe 
Acquired antithrombin III deficiency 
Acquired factor IX deficiency 
Acquired factor V deficiency 
Acquired factor VIII deficiency 
Acquired factor XI deficiency 
Acquired hepatocerebral degeneration 
Acquired protein S deficiency 
Acute graft versus host disease in liver 
Acute hepatic failure 
Acute hepatitis B 
Acute hepatitis C 
Acute on chronic liver failure 
Acute yellow liver atrophy 
Adenoviral hepatitis 
Alagille syndrome 
Alanine aminotransferase abnormal 
Alanine aminotransferase increased 
Alcoholic encephalopathy 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 80 of 103
 
 
Table 9–11: PTs for selection of medical history of “Hepatic Impairment” 
Preferred term (MedDRA version 25.0)  
Alcoholic liver disease 
Allergic hepatitis 
Alloimmune hepatitis 
Ammonia abnormal 
Ammonia increased 
Anorectal varices 
Anorectal varices haemorrhage 
Anti factor X activity abnormal 
Anti factor X activity decreased 
Anti factor X activity increased 
Anti-liver cytosol antibody type 1 positive 
Antithrombin III decreased 
Ascites 
Aspartate aminotransferase abnormal 
Aspartate aminotransferase increased 
Asterixis 
Asymptomatic viral hepatitis 
Autoimmune hepatitis 
Bacterascites 
Benign hepatic neoplasm 
Benign hepatobiliary neoplasm 
Benign recurrent intrahepatic cholestasis 
Bile output abnormal 
Bile output decreased 
Biliary ascites 
Biliary cirrhosis 
Biliary fibrosis 
Bilirubin conjugated abnormal 
Bilirubin conjugated increased 
Bilirubin excretion disorder 
Bilirubin urine present 
Biopsy liver abnormal 
Blood alkaline phosphatase abnormal 
Blood alkaline phosphatase increased 
Blood bilirubin abnormal 
Blood bilirubin increased 
Blood bilirubin unconjugated increased 
Blood cholinesterase abnormal 
Blood cholinesterase decreased 
Blood fibrinogen abnormal 
Blood fibrinogen decreased 
Blood thrombin abnormal 
Blood thrombin decreased 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 81 of 103
 
 
Table 9–11: PTs for selection of medical history of “Hepatic Impairment” 
Preferred term (MedDRA version 25.0)  
Blood thromboplastin abnormal 
Blood thromboplastin decreased 
Bromosulphthalein test abnormal 
Cardiohepatic syndrome 
Cerebrohepatorenal syndrome 
Child-Pugh-Turcotte score abnormal 
Child-Pugh-Turcotte score increased 
Cholaemia 
Cholangiosarcoma 
Cholestasis 
Cholestatic liver injury 
Cholestatic pruritus 
Chronic graft versus host disease in liver 
Chronic hepatic failure 
Chronic hepatitis 
Chronic hepatitis B 
Chronic hepatitis C 
Cirrhosis alcoholic 
Coagulation factor IX level abnormal 
Coagulation factor IX level decreased 
Coagulation factor V level abnormal 
Coagulation factor V level decreased 
Coagulation factor VII level abnormal 
Coagulation factor VII level decreased 
Coagulation factor X level abnormal 
Coagulation factor X level decreased 
Coagulation factor decreased 
Coma hepatic 
Complications of transplanted liver 
Computerised tomogram liver abnormal 
Congenital absence of bile ducts 
Congenital hepatic fibrosis 
Congenital hepatitis B infection 
Congenital hepatitis C infection 
Congenital hepatobiliary anomaly 
Congenital hepatomegaly 
Congenital viral hepatitis 
Congestive hepatopathy 
Cryptogenic cirrhosis 
Cystic fibrosis hepatic disease 
Cytokeratin 18 increased 
Cytomegalovirus hepatitis 
Deficiency of bile secretion 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 82 of 103
 
 
Table 9–11: PTs for selection of medical history of “Hepatic Impairment” 
Preferred term (MedDRA version 25.0)  
Diabetic hepatopathy 
Dilatation intrahepatic duct congenital 
Drug-induced liver injury 
Duodenal varices 
Fatty liver alcoholic 
Flood syndrome 
Focal nodular hyperplasia 
Foetor hepaticus 
Galactose elimination capacity test abnormal 
Galactose elimination capacity test decreased 
Gallbladder varices 
Gamma-glutamyltransferase abnormal 
Gamma-glutamyltransferase increased 
Gastric variceal injection 
Gastric variceal ligation 
Gastric varices 
Gastric varices haemorrhage 
Gastrooesophageal variceal haemorrhage prophylaxis 
Gianotti-Crosti syndrome 
Glutamate dehydrogenase increased 
Glycocholic acid increased 
Glycogen storage disease type I 
Glycogen storage disease type III 
Glycogen storage disease type IV 
Glycogen storage disease type VI 
Graft versus host disease in liver 
Granulomatous liver disease 
Guanase increased 
HBV-DNA polymerase increased 
Haemangioma of liver 
Haemorrhagic ascites 
Haemorrhagic hepatic cyst 
Hepaplastin abnormal 
Hepaplastin decreased 
Hepatectomy 
Hepatic adenoma 
Hepatic amoebiasis 
Hepatic angiosarcoma 
Hepatic artery flow decreased 
Hepatic atrophy 
Hepatic calcification 
Hepatic cancer 
Hepatic cancer metastatic 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 83 of 103
 
 
Table 9–11: PTs for selection of medical history of “Hepatic Impairment” 
Preferred term (MedDRA version 25.0)  
Hepatic cancer recurrent 
Hepatic cancer stage I 
Hepatic cancer stage II 
Hepatic cancer stage III 
Hepatic cancer stage IV 
Hepatic candidiasis 
Hepatic cirrhosis 
Hepatic cyst 
Hepatic cyst infection 
Hepatic cyst ruptured 
Hepatic cytolysis 
Hepatic echinococciasis 
Hepatic encephalopathy 
Hepatic encephalopathy prophylaxis 
Hepatic enzyme abnormal 
Hepatic enzyme decreased 
Hepatic enzyme increased 
Hepatic failure 
Hepatic fibrosis 
Hepatic fibrosis marker abnormal 
Hepatic fibrosis marker increased 
Hepatic function abnormal 
Hepatic gas gangrene 
Hepatic haemangioma rupture 
Hepatic hamartoma 
Hepatic hydrothorax 
Hepatic hypertrophy 
Hepatic hypoperfusion 
Hepatic infection 
Hepatic infection bacterial 
Hepatic infection fungal 
Hepatic infection helminthic 
Hepatic infiltration eosinophilic 
Hepatic lesion 
Hepatic lipoma 
Hepatic lymphocytic infiltration 
Hepatic mass 
Hepatic necrosis 
Hepatic neoplasm 
Hepatic neuroendocrine tumour 
Hepatic pain 
Hepatic perfusion disorder 
Hepatic sarcoma 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 84 of 103
 
 
Table 9–11: PTs for selection of medical history of “Hepatic Impairment” 
Preferred term (MedDRA version 25.0)  
Hepatic sequestration 
Hepatic steato-fibrosis 
Hepatic steatosis 
Hepatic vascular resistance increased 
Hepatic venous pressure gradient abnormal 
Hepatic venous pressure gradient increased 
Hepatitis 
Hepatitis A 
Hepatitis A antibody abnormal 
Hepatitis A antibody positive 
Hepatitis A antigen positive 
Hepatitis A immunity confirmed 
Hepatitis A virus test positive 
Hepatitis B 
Hepatitis B DNA assay positive 
Hepatitis B DNA increased 
Hepatitis B antibody abnormal 
Hepatitis B antibody positive 
Hepatitis B antigen positive 
Hepatitis B core antibody positive 
Hepatitis B core antigen positive 
Hepatitis B e antibody positive 
Hepatitis B e antigen positive 
Hepatitis B immunity confirmed 
Hepatitis B reactivation 
Hepatitis B surface antibody positive 
Hepatitis B surface antigen positive 
Hepatitis B virus test positive 
Hepatitis C 
Hepatitis C RNA increased 
Hepatitis C RNA positive 
Hepatitis C antibody positive 
Hepatitis C core antibody positive 
Hepatitis C virus test positive 
Hepatitis D 
Hepatitis D RNA positive 
Hepatitis D antibody positive 
Hepatitis D antigen positive 
Hepatitis D virus test positive 
Hepatitis E 
Hepatitis E RNA positive 
Hepatitis E antibody abnormal 
Hepatitis E antibody positive 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 85 of 103
 
 
Table 9–11: PTs for selection of medical history of “Hepatic Impairment” 
Preferred term (MedDRA version 25.0)  
Hepatitis E antigen positive 
Hepatitis E immunity confirmed 
Hepatitis E virus test positive 
Hepatitis F 
Hepatitis G 
Hepatitis H 
Hepatitis acute 
Hepatitis alcoholic 
Hepatitis cholestatic 
Hepatitis chronic active 
Hepatitis chronic persistent 
Hepatitis fulminant 
Hepatitis infectious mononucleosis 
Hepatitis mumps 
Hepatitis neonatal 
Hepatitis non-A non-B 
Hepatitis non-A non-B non-C 
Hepatitis post transfusion 
Hepatitis syphilitic 
Hepatitis toxic 
Hepatitis toxoplasmal 
Hepatitis viral 
Hepatitis viral test positive 
Hepato-lenticular degeneration 
Hepatobiliary cancer 
Hepatobiliary cancer in situ 
Hepatobiliary cyst 
Hepatobiliary disease 
Hepatobiliary infection 
Hepatobiliary neoplasm 
Hepatobiliary scan abnormal 
Hepatoblastoma 
Hepatoblastoma recurrent 
Hepatocellular carcinoma 
Hepatocellular damage neonatal 
Hepatocellular foamy cell syndrome 
Hepatocellular injury 
Hepatomegaly 
Hepatopulmonary syndrome 
Hepatorenal failure 
Hepatorenal syndrome 
Hepatosplenic abscess 
Hepatosplenic candidiasis 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 86 of 103
 
 
Table 9–11: PTs for selection of medical history of “Hepatic Impairment” 
Preferred term (MedDRA version 25.0)  
Hepatosplenomegaly 
Hepatosplenomegaly neonatal 
Hepatotoxicity 
Hereditary haemochromatosis 
Herpes simplex hepatitis 
Hyperammonaemia 
Hyperbilirubinaemia 
Hyperbilirubinaemia neonatal 
Hypercholia 
Hyperfibrinolysis 
Hypertransaminasaemia 
Hypoalbuminaemia 
Hypocoagulable state 
Hypofibrinogenaemia 
Hypoprothrombinaemia 
Hypothrombinaemia 
Hypothromboplastinaemia 
Icterus index increased 
Immune-mediated cholangitis 
Immune-mediated hepatic disorder 
Immune-mediated hepatitis 
Increased liver stiffness 
International normalised ratio abnormal 
International normalised ratio increased 
Intestinal varices 
Intestinal varices haemorrhage 
Intrahepatic portal hepatic venous fistula 
Ischaemic hepatitis 
Jaundice 
Jaundice cholestatic 
Jaundice hepatocellular 
Jaundice neonatal 
Kayser-Fleischer ring 
Kernicterus 
Leucine aminopeptidase increased 
Liver abscess 
Liver and pancreas transplant rejection 
Liver carcinoma ruptured 
Liver dialysis 
Liver disorder 
Liver function test abnormal 
Liver function test decreased 
Liver function test increased 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 87 of 103
 
 
Table 9–11: PTs for selection of medical history of “Hepatic Impairment” 
Preferred term (MedDRA version 25.0)  
Liver induration 
Liver injury 
Liver iron concentration abnormal 
Liver iron concentration increased 
Liver opacity 
Liver operation 
Liver palpable 
Liver sarcoidosis 
Liver scan abnormal 
Liver tenderness 
Liver transplant 
Liver transplant failure 
Liver transplant rejection 
Liver-kidney microsomal antibody positive 
Lupoid hepatic cirrhosis 
Lupus hepatitis 
Magnetic resonance imaging hepatobiliary abnormal 
Magnetic resonance proton density fat fraction measurement 
Mitochondrial aspartate aminotransferase increased 
Mixed hepatocellular cholangiocarcinoma 
Mixed liver injury 
Model for end stage liver disease score abnormal 
Model for end stage liver disease score increased 
Molar ratio of total branched-chain amino acid to tyrosine 
Multivisceral transplantation 
Necrolytic acral erythema 
Neonatal cholestasis 
Neonatal hepatomegaly 
Nodular regenerative hyperplasia 
Non-alcoholic fatty liver 
Non-alcoholic steatohepatitis 
Non-cirrhotic portal hypertension 
Ocular icterus 
Oedema due to hepatic disease 
Oesophageal varices haemorrhage 
Omental oedema 
Osteopontin increased 
Parenteral nutrition associated liver disease 
Perihepatic discomfort 
Perinatal HBV infection 
Peripancreatic varices 
Periportal oedema 
Peritoneal fluid protein abnormal 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 88 of 103
 
 
Table 9–11: PTs for selection of medical history of “Hepatic Impairment” 
Preferred term (MedDRA version 25.0)  
Peritoneal fluid protein decreased 
Peritoneal fluid protein increased 
Peritoneovenous shunt 
Pneumobilia 
Polycystic liver disease 
Porphyria acute 
Porphyria non-acute 
Portal fibrosis 
Portal hypertension 
Portal hypertensive colopathy 
Portal hypertensive enteropathy 
Portal hypertensive gastropathy 
Portal pyaemia 
Portal shunt 
Portal shunt procedure 
Portal tract inflammation 
Portal vein cavernous transformation 
Portal vein dilatation 
Portal vein flow decreased 
Portal vein pressure increased 
Portal venous system anomaly 
Portopulmonary hypertension 
Primary biliary cholangitis 
Progressive familial intrahepatic cholestasis 
Protein C decreased 
Protein S abnormal 
Protein S decreased 
Prothrombin level abnormal 
Prothrombin level decreased 
Prothrombin time abnormal 
Prothrombin time prolonged 
Prothrombin time ratio abnormal 
Prothrombin time ratio increased 
Radiation hepatitis 
Regenerative siderotic hepatic nodule 
Renal and liver transplant 
Retinol binding protein decreased 
Retrograde portal vein flow 
Reye's syndrome 
Reynold's syndrome 
Schistosomiasis liver 
Small-for-size liver syndrome 
Spider naevus 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 89 of 103
 
 
Table 9–11: PTs for selection of medical history of “Hepatic Impairment” 
Preferred term (MedDRA version 25.0)  
Splenic artery embolisation 
Splenic varices 
Splenic varices haemorrhage 
Splenorenal shunt 
Splenorenal shunt procedure 
Spontaneous bacterial peritonitis 
Spontaneous intrahepatic portosystemic venous shunt 
Steatohepatitis 
Stomal varices 
Subacute hepatic failure 
Sugiura procedure 
Sustained viral response 
Thrombin time abnormal 
Thrombin time prolonged 
Total bile acids increased 
Transaminases abnormal 
Transaminases increased 
Ultrasound liver abnormal 
Urine bilirubin increased 
Urobilinogen urine decreased 
Urobilinogen urine increased 
Varices oesophageal 
Varicose veins of abdominal wall 
Viral hepatitis carrier 
Weil's disease 
White nipple sign 
Withdrawal hepatitis 
X-ray hepatobiliary abnormal 
Yellow skin 
Zieve syndrome 
 
 
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 90 of 103
 
 
9.5 
Strategies for occurrence of intercurrent events 
Analysis strategies for intercurrent events occurring through week 48 are described in Table 9–12 below for BCVA and other continuous efficacy 
endpoint variables. Intercurrent events for the analysis of BCVA and other continuous efficacy endpoint variables (or binary endpoints which are 
based on continuous variables) at week 60 and later will be handled analogously.  
Table 9–12: Strategies for occurrence of intercurrent events for analysis at week 48 for BCVA and other continuous endpoint 
variables 
 
 
Primary Estimand 
 
Potential post-randomization 
event 
Intercurrent event 
(yes/no) 
Strategy 
Primary Analysis 
Sensitivity Analysis 
Premature discontinuation of 
study intervention  
for any reason before week 48 
(and discontinuation of study) (a) 
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 
Premature discontinuation of 
study intervention  
for any reason before week 48 
(but continuation of study) (b) 
Yes 
Hypothetical 
Observed data beyond last active 
injection (that was administered 
before the premature 
discontinuation of study 
intervention) + current treatment 
interval +5 days will be excluded 
from analysis and resulting missing 
data will be covered implicitly in 
the MMRM 
Observed data beyond last active 
injection (that was administered 
before the premature 
discontinuation of study intervention) 
+ current treatment interval +5 days 
will be excluded from analysis and 
resulting missing data will be 
imputed by LOCF 
 
 
 
 
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 91 of 103
 
 
Table 9–12: Strategies for occurrence of intercurrent events for analysis at week 48 for BCVA and other continuous endpoint 
variables 
 
 
Primary Estimand 
 
Potential post-randomization 
event 
Intercurrent event 
(yes/no) 
Strategy 
Primary Analysis 
Sensitivity Analysis 
Missed (skipped) study 
intervention  
for any reason before week 48: 
 
 
- 
Missed study intervention 
was planned to be a 
sham injection 
Yes, but no impact 
since no active 
treatment was missed 
Not applicable 
Observed data beyond missed 
sham injection will be included in 
the analysis and the MMRM 
Observed data beyond missed 
sham injection will be included in the 
analysis 
- 
Missed study intervention 
was planned to be an 
active injection, but at the 
next scheduled visit a 
make-up injection was 
given to compensate for 
the missed active 
injection (c) 
Yes 
Treatment policy 
All observed data will be included 
in the analysis and the MMRM  
All observed data will be included in 
the analysis 
- 
Missed study intervention 
was planned to be an 
active injection, but at the 
next scheduled visit 
make-up injection was 
not given to compensate 
for the missed active 
injection (d) 
Yes 
Hypothetical 
Observed data beyond last active 
injection (that was administered 
before the first missed active 
injection) + current treatment 
interval +5 days will be excluded 
from analysis and resulting missing 
data will be covered implicitly in 
the MMRM 
Observed data beyond last active 
injection (that was administered 
before the the first missed active 
injection) + current treatment interval 
+5 days will be excluded from 
analysis and resulting missing data 
will be imputed by LOCF 
 
 
 
 
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 92 of 103
 
 
Table 9–12: Strategies for occurrence of intercurrent events for analysis at week 48 for BCVA and other continuous endpoint 
variables 
 
 
Primary Estimand 
 
Potential post-randomization 
event 
Intercurrent event 
(yes/no) 
Strategy 
Primary Analysis 
Sensitivity Analysis 
Wrong study intervention before 
week 48: 
 
 
- 
Active injection instead of 
a sham injection  
(note, this does not refer 
to potential make-up 
injections which should 
be given at the next 
scheduled visit in case of 
any missed active 
injection) 
Yes 
Treatment policy 
Observed data beyond the wrong 
active injection  
will be included in the analysis and 
the MMRM 
Observed data beyond the wrong 
active injection  
will be included in the analysis 
- 
Sham injection instead of 
an active injection 
Yes 
Hypothetical 
Observed data beyond last active 
injection (that was administered 
before the wrong sham injection) + 
current treatment interval +5 days 
will be excluded from analysis and 
resulting missing data will be 
covered implicitly in the MMRM 
Observed data beyond last active 
injection (that was administered 
before the wrong sham injection) + 
current treatment interval +5 days 
will be excluded from analysis and 
resulting missing data will be 
imputed by LOCF 
- 
Wrong dose (for 
participants randomized 
to the 2q8 group):  
High dose 8 mg injection 
instead of 2 mg injection 
Yes 
Treatment policy 
Observed data beyond the wrong 
high dose 8 mg injection  
will be included in the analysis and 
the MMRM 
Observed data beyond the wrong 
high dose 8 mg injection  
will be included in the analysis 
- 
Wrong dose (for 
participants randomized 
to the HDq12 or HDq16 
group):  
2 mg injection instead of 
high dose 8 mg injection 
Yes 
Treatment policy 
Observed data beyond the wrong 
high dose 2 mg injection  
will be included in the analysis and 
the MMRM 
Observed data beyond the wrong 
high dose 2 mg injection  
will be included in the analysis 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 93 of 103
 
 
Table 9–12: Strategies for occurrence of intercurrent events for analysis at week 48 for BCVA and other continuous endpoint 
variables 
 
 
Primary Estimand 
 
Potential post-randomization 
event 
Intercurrent event 
(yes/no) 
Strategy 
Primary Analysis 
Sensitivity Analysis 
Use of a prohibited medication 
(as defined in section 4.5.6) 
before week 48  
Yes 
Hypothetical 
Observed data beyond first 
administration of the prohibited 
medication in study eye 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 in study eye will be 
excluded from analysis and resulting 
missing data will be imputed by 
LOCF 
Shortening of dosing interval 
according to DRM criteria before 
week 48 
No, since DRM is 
considered part of the 
randomized treatment 
regimen 
Not applicable 
Observed data beyond shortening 
of dosing interval will be included 
in the analysis and the MMRM 
Observed data beyond shortening of 
dosing interval will be included in the 
analysis 
Any missing assessment of BCVA at a certain visit is not considered an intercurrent event per se but is considered missing at random and covered 
implicitly in the MMRM. 
It is assumed that a COVID-19 illness does not affect the treatment effect but at most the treatment schedule. Therefore, any deviations from the 
treatment schedule due to a COVID-19 illness (i.e. missed study intervention due to the COVID-19 illness) will be handled as described in the 
table above. Any other study disruption related to the COVID-19 pandemic (discontinuations or missed study intervention, e.g. due to site closed, 
local travel restrictions, participant not willing to go to the site) will also be handled as described in the table above. 
(a) This ICE covers the situation when the treatment intervention and the study was discontinued early (prior to Week 48) at the same time 
(b) This ICE covers the situation when the treatment intervention was discontinued early (prior to Week 48) and the participant either remained in the 
study or discontinued from the study, but at a later time. 
(c) This ICE covers situation when an injection during the loading dose was missed but an injection was given at the next visit (i.e. Baseline injection 
was missed but Week 4 injection was given, Week 4 injection was missed but Week 8 injection was given, Week 8 injection was missed but make-
up injection was given at Week 12).  
(d) This ICE covers situation when an injection during the loading dose was missed and no injection was given at the next visit (i.e. Baseline injection 
was missed and Week 4 injection was missed, Week 4 injection was missed and Week 8 injection was missed, Week 8 injection was missed and 
no make-up injection was given at Week 12). 
Analysis strategies for intercurrent events occurring post-baseline are described in Table 9–13 below for the analysis of participants with no 
intraretinal fluid (IRF) and no subretinal fluid (SRF) in central subfield. Other binary efficacy endpoint summaries will handled analogously. 
 
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 94 of 103
 
 
Table 9–13: Strategies for occurrence of intercurrent events for analysis of proportions of participants with no IRF and no SRF in central 
subfield and other binary endpoint variables 
Potential post-randomization event* 
Intercurrent event 
(yes/no) 
Primary Estimand 
Strategy 
Primary Estimand Analysis 
Premature discontinuation of study intervention  
for any reason (and discontinuation of study) (a) 
Yes 
Hypothetical 
Non-observed data beyond discontinuation of study 
intervention will be imputed using LOCF 
Premature discontinuation of study intervention  
for any reason (but continuation of study) (b) 
Yes 
Hypothetical 
Observed data beyond last active injection (that was 
administered before the premature discontinuation of study 
intervention) + current treatment interval +5 days will be 
excluded from analysis and resulting missing data will be 
imputed using LOCF 
Missed (skipped) study intervention  
for any reason: 
 
 
- 
Missed study intervention was planned to 
be a sham injection 
Yes, but no impact 
since no active 
treatment was 
missed 
Not applicable 
Observed data beyond missed sham injection will be 
included in the analysis 
- 
Missed study intervention was planned to 
be an active injection, but at the next 
scheduled visit a make-up injection was 
given to compensate for the missed active 
injection (c) 
Yes 
Treatment policy 
All observed data will be included in the analysis 
- 
Missed study intervention was planned to 
be an active injection, but at the next 
scheduled visit make-up injection was not 
given to compensate for the missed active 
injection (d) 
Yes 
Hypothetical 
Observed data beyond last active injection (that was 
administered before the the first missed active injection) + 
current treatment interval +5 days will be excluded from 
analysis and resulting missing data will be imputed by 
LOCF 
 
 
 
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 95 of 103
 
 
Table 9–13: Strategies for occurrence of intercurrent events for analysis of proportions of participants with no IRF and no SRF in central 
subfield and other binary endpoint variables 
Potential post-randomization event* 
Intercurrent event 
(yes/no) 
Primary Estimand 
Strategy 
Primary Estimand Analysis 
Wrong study intervention 
 
 
- 
Active injection instead of a sham injection  
(note, this does not refer to potential make-
up injections which should be given at the 
next scheduled visit in case of any missed 
active injection) 
Yes 
Treatment policy 
Observed data beyond the wrong active injection  
will be included in the analysis 
- 
Sham injection instead of an active 
injection 
Yes 
Hypothetical 
Observed data beyond last active injection (that was 
administered before the wrong sham injection) + current 
treatment interval +5 days will be excluded from analysis 
and resulting missing data will be imputed by LOCF 
- 
Wrong dose (for participants randomized to 
the 2q8 group):  
High dose 8 mg injection instead of 2 mg 
injection 
Yes 
Treatment policy 
Observed data beyond the wrong high dose 8 mg injection  
will be included in the analysis 
- 
Wrong dose (for participants randomized to 
the HDq12 or HDq16 group):  
2 mg injection instead of high dose 8 mg 
injection 
Yes 
Treatment policy 
Observed data beyond the wrong high dose 2 mg injection  
will be included in the analysis 
Use of a prohibited medication (as defined in 
section 4.5.6) 
Yes 
Hypothetical 
Observed data beyond first administration of the prohibited 
medication in study eye will be excluded from analysis and 
resulting missing data will be imputed by LOCF 
Shortening of dosing interval according to DRM 
criteria 
No, since DRM is 
considered part of 
the randomized 
treatment regimen 
Not applicable 
Observed data beyond shortening of dosing interval will be 
included in the analysis 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 96 of 103
 
 
Table 9–13: Strategies for occurrence of intercurrent events for analysis of proportions of participants with no IRF and no SRF in central 
subfield and other binary endpoint variables 
Potential post-randomization event* 
Intercurrent event 
(yes/no) 
Primary Estimand 
Strategy 
Primary Estimand Analysis 
* Not all intercurrent events are applicable for all endpoints and visits. 
Any missing assessment of SD-OCT data at a certain visit is not considered an intercurrent event per se but is considered missing at random. 
It is assumed that a COVID-19 illness does not affect the treatment effect but at most the treatment schedule. Therefore, any deviations from the treatment 
schedule due to a COVID-19 illness (i.e. missed study intervention due to the COVID-19 illness) will be handled as described in the table above. Any other 
study disruption related to the COVID-19 pandemic (discontinuations or missed study intervention, e.g. due to site closed, local travel restrictions, 
participant not willing to go to the site) will also be handled as described in the table above. 
(a) This ICE covers the situation when the treatment intervention and the study was discontinued early at the same time 
(b) This ICE covers the situation when the treatment intervention was discontinued early and the participant either remained in the study or discontinued from 
the study, but at a later time. 
(c) This ICE covers situation when an injection during the loading dose was missed but an injection was given at the next visit (i.e. Baseline injection was 
missed but Week 4 injection was given, Week 4 injection was missed but Week 8 injection was given, Week 8 injection was missed but make-up injection 
was given at Week 12).  
(d) This ICE covers situation when an injection during the loading dose was missed and no injection was given at the next visit (i.e. Baseline injection was 
missed and Week 4 injection was missed, Week 4 injection was missed and Week 8 injection was missed, Week 8 injection was missed and no make-up 
injection was given at Week 12). 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
Page: 97 of 103
 
 
9.6 
Participating Regions and Countries 
The following regions and countries are participating in this study and are shown in Table 9–
14.  
Table 9–14: Participating Regions and Countries 
Region 
Country 
APAC 
AUSTRALIA 
CHINA 
JAPAN 
KOREA, REPUBLIC OF 
SINGAPORE 
TAIWAN 
Europe 
AUSTRIA 
BULGARIA 
CZECH REPUBLIC 
ESTONIA 
FRANCE 
GEORGIA 
HUNGARY 
ISRAEL 
ITALY 
LATVIA 
LITHUANIA 
PORTUGAL 
RUSSIAN FEDERATION 
SERBIA 
SLOVAKIA 
SPAIN 
SWITZERLAND 
UKRAINE 
UNITED KINGDOM 
Latin America 
ARGENTINA 
North America 
CANADA 
UNITED STATES 
 
 
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
 
 
9.7 
Additional Pre-Specified Exploratory Efficacy Variables and Analyses 
This section pre-specifies the statistical approaches for defining and analyzing additional pre-
specified exploratory efficacy variables at week 48, for submission to the US FDA (based on 
the G-SAP that constitutes the primary analysis for the study).  
9.7.1 
Analysis Populations  
The following populations of analysis will be used for the additional pre-specified exploratory 
efficacy analyses.  
9.7.1.1 
Full Analysis Set (FAS)  
Refer to Section 5.1.  
9.7.1.2 
Modified Full Analysis Set (mFAS)  
The modified full analysis set 1 (mFAS1) includes all randomized patients who completed the 
initial treatment phase and maintained their dosing interval (i.e., 
• maintained post 3-dose loading on a q12 interval for HDq12 group and never having 
their dosing interval shortened to less than q12w;  
• maintained post 3-dose loading on a q16 interval for the HDq16 group and never 
having their dosing interval shortened to less than q16w; and 
• all participants in the 2q8 group receive fixed q8 dosing).   
The modified full analysis set 2 (mFAS2) includes all randomized participants who completed 
the initial treatment phase and maintained their dosing interval (i.e., 
• maintained post 3-dose loading for All HD group (pooled HDq12 and HDq16 groups) 
on either q12 or q16 interval and never having their dosing interval shortened to less 
than q12w; and 
• all participants in the 2q8 group receive fixed q8 dosing). 
Both analysis sets, mFAS1 and mFAS2, are based on the treatment assigned to the participant 
at baseline (as randomized).  
9.7.2 
Additional Pre-Specified Exploratory Efficacy Variable(s)  
Additional pre-specified exploratory efficacy analyses will be conducted for the following 
variables: 
• Change from baseline in BCVA (as measured by ETDRS letter score) at week 48 
(previously defined primary efficacy variable; see Section 6.2.2) 
• Change from 8-weeks post initial treatment phase in BCVA (as measured by ETDRS 
letter score) at week 48 (additional pre-specified exploratory efficacy variable) 
Note that per the dosing schedule shown in Figure 1–2 of the protocol, the initial treatment 
phase is through week 8 (3 doses) for all treatment groups (i.e. HDq12, HDq16, 2q8).  Hence 
8-weeks post initial treatment phase is Week 16 for all treatment groups.  
9.7.3 
Additional Pre-Specified Exploratory Efficacy Analyses  
The additional pre-specified exploratory efficacy analyses will be an alternative tipping point 
analysis on the efficacy variables in Section 9.7.2.  


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
 
 
For analysis set (FAS and mFAS) and each variable, the following algorithm will be applied:  
1. Within each treatment group, for participants with data at both week 48 and at the 
designated baseline for the analysis, sort the participant level data for change in 
BCVA at week 48 from smallest to largest, e.g., ranging from -60, -59, …, -1, 0, +1, 
…to +50 ETDRS letter score. Participants without data at both week 48 and 
designated baseline are removed from numerator and denominator calculations 
described below. 
2. For the analysis (sub)set, compare mean change in BCVA at week 48 between HDq12 
with the mean change in BCVA at week 48 for the 2q8 control group.   
3. If the mean change in BCVA for HDq12 group ≥ [mean change in BCVA for 2q8 
group + Δ] where Δ=0 or -2, then  
a. report the number, percentage of participants in the (sub)set relative to the 
original analysis set, and 2-sided 95% CI (continuity-corrected Wilson (score) 
method) for HDq12 group, 
b. report the tipping point value in the HDq12 group analysis subset that is the 
lowest letter change in BCVA, and  
c. stop. 
4. Otherwise, exclude participants with the next worst score in HDq12 group to obtain a 
new subset. Retain original analysis set in 2q8 control group. Repeat steps 2 and 3, 
until stopping condition is reached or all participant level data is used in the HDq12 
group.  
Repeat the above algorithm for HDq16 group and the All HD group. 
The above analyses specified for completers may also be repeated using the estimand 
framework (see Section 6.2.2). 
The reported results from these additional analyses will be as follows (see Table 9–15). 
 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
 
 
Table 9–15: Additional Pre-Specified Exploratory Efficacy Analyses – Alternative 
Tipping Point Analyses 
 
Population Variable 
Analysis Results 
Δ 
Tipping 
Point in 
HD group 
1a FASa 
Change from 
baseline in BCVA 
at week 48 
• Number and Percentage of 
participants in the HDq12 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the HDq16 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the All HD analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
0 
 
 
 
 
0 
 
 
 
 
0 
x1 letters 
 
 
 
 
y1 letters 
 
 
 
 
z1 letters 
1b FASa 
Change from 
baseline in BCVA 
at week 48 
• Number and Percentage of 
participants in the HDq12 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the HDq16 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the All HD analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
-2 
 
 
 
 
-2 
 
 
 
 
-2 
x2 letters 
 
 
 
 
y2 letters 
 
 
 
 
z2 letters 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
 
 
 
Population Variable 
Analysis Results 
Δ 
Tipping 
Point in 
HD group 
2a FASa 
Change from 
8-weeks post 
initial treatment in 
BCVA at week 48 
• Number and Percentage of 
participants in the HDq12 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the HDq16 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the All HD analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
0 
 
 
 
 
0 
 
 
 
 
0 
x3 letters 
 
 
 
 
y3 letters 
 
 
 
 
z3 letters 
2b FASa 
Change from 
8-weeks post 
initial treatment in 
BCVA at week 48 
• Number and Percentage of 
participants in the HDq12 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the HDq16 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the All HD analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
-2 
 
 
 
 
-2 
 
 
 
 
-2 
x4 letters 
 
 
 
 
y4 letters 
 
 
 
 
z4 letters 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
 
 
 
Population Variable 
Analysis Results 
Δ 
Tipping 
Point in 
HD group 
3a mFAS1b; 
mFAS2c 
Change from 
baseline in BCVA 
at week 48 
• Number and Percentage of 
participants in the HDq12 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the HDq16 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the All HD analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
0 
 
 
 
 
0 
 
 
 
 
0 
x5 letters 
 
 
 
 
y5 letters 
 
 
 
 
z5 letters 
3b mFAS1b; 
mFAS2c 
Change from 
baseline in BCVA 
at week 48 
• Number and Percentage of 
participants in the HDq12 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the HDq16 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the All HD analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
-2 
 
 
 
 
-2 
 
 
 
 
-2 
x6 letters 
 
 
 
 
y6 letters 
 
 
 
 
z6 letters 


Statistical Analysis Plan 
No. BAY 86-5321/ IMPACT 20968 
 
 
 
Population Variable 
Analysis Results 
Δ 
Tipping 
Point in 
HD group 
4a mFAS1b; 
mFAS2c 
Change from 
8-weeks post 
initial treatment in 
BCVA at week 48 
• Number and Percentage of 
participants in the HDq12 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the HDq16 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the All HD analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
0 
 
 
 
 
0 
 
 
 
 
0 
x7 letters 
 
 
 
 
y7 letters 
 
 
 
 
z7 letters 
4b mFAS1b; 
mFAS2c 
Change from 
8-weeks post 
initial treatment in 
BCVA at week 48 
• Number and Percentage of 
participants in the HDq12 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the HDq16 analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
• Number and Percentage of 
participants in the All HD analysis 
subset for whom mean change in 
BCVA ≥ [mean change in BCVA 
for 2q8 group – Δ] 
-2 
 
 
 
 
-2 
 
 
 
 
-2 
x8 letters 
 
 
 
 
y8 letters 
 
 
 
 
z8 letters 
a FAS = Full Analysis Set, which includes all randomized participants who received at least 1 dose of study 
intervention. 
b mFAS1 = Modified Full Analysis Set 1, which includes all randomized participants who completed the initial 
treatment phase and maintained dosing interval (HDq12, HDq16, and 2q8 groups). 
c mFAS2 = Modified Full Analysis Set 2, which includes all randomized participants who completed the initial 
treatment phase and maintained dosing interval (All HD group and 2q8 group).