A Phase IV Interventional Post Approval Trial to Assess the Safety of Intravitreal Aflibercept for the Treatment of Diabetic Macular Edema (DME) in Patients in India.
Phase: PHASE4
Conditions: Diabetic Macular Edema
Sponsor: Bayer

 
Document Type: 
Clinical Study Protocol  
Official Title: 
A study to learn how safe the study drug intravitreal (given by an 
injection into the eye) aflibercept is in participants in India with 
diabetic macular edema 
NCT Number: 
NCT05511038 
Document Date: 
09-Apr-2025 
 

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Title Page 
Protocol Title: A Phase IV interventional post approval trial to assess the safety of 
intravitreal aflibercept for the treatment of diabetic macular edema (DME) in patients in India.  
Protocol Number: 21974 
Protocol Version: 3.0 
Amendment Number: 2 
Compound Number: BAY 86-5321 
Short Title: India IPAT (PASS) IVT aflibercept in DME 
Study Phase: IV 
Sponsor Name and Legal Registered Address: Bayer AG, 51373 Leverkusen, Germany  
Regulatory Agency Identifier Number(s): Not applicable 
Protocol Date: 8 JUN 2023 
 
 
 
 
 
 
 
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. 
 
 and contact information 
 
 
Bayer Zydus Pharma Private Limited, 
Central Avenue, Hiranandani Estate,  
Thane – 400607, Maharashtra, India  
Tel: 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.  
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
 
 
PPD
PPD PPD
PPD
PPD PPD
PPD
PPD PPD
PPD

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Document History Table 
DOCUMENT HISTORY 
Document 
Version 
Date  
Comments (if applicable) 
Amendment 2 (Technical) 
3.0 
8 JUN 2023 
Consolidated version created to 
reflect changes as mentioned in 
Protocol Amendment History 
below (technical amendment) 
Amendment 1 (Technical) 
2.0 
07 APR 2022 
Consolidated version created to 
reflect changes as mentioned in 
Protocol Amendment History 
below (technical amendment) 
Clinical Study Protocol 
1.0 
20 DEC 2021 
Version approved by the HA and 
used in the study 
 
Protocol Amendment Summary of Changes Table 
 
Amendment 2: 8 JUN 2023 
This amendment is prepared to include already approved country-specific changes into a 
unique consolidated protocol version. 
Overall Rationale for the Amendment: 
Brief rationale provided for the relevant sections below. 
Section # and Name 
Description of Change 
Brief Rationale 
Page 1: Sponsor Name and 
Legal Registered Address 
Change in Sponsor name and 
address from Bayer Zydus 
Pharma Private Limited, 
Central Avenue, Hiranandani 
Estate, Thane – 400607, 
Maharashtra, India to Bayer 
AG, 51373 Leverkusen, 
Germany  
Typo error noted. Sponsor 
name in the previous 
protocol is Bayer Zydus 
Pharma Private Limited. 
Actual resgistered sponsor 
for this study is Bayer AG. 
Page 1: Country Medical 
Lead / Medical Monitor  
Included change in Country 
Medical Lead/ Medical 
Monitor for the study 
Included details of new 
Country Medical Lead/ 
Medical Monitor 
 
 

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Table of Contents 
Title Page ............................................................................................................................... 1 
Document History Table ...................................................................................................... 2 
Protocol Amendment Summary of Changes Table ........................................................... 2 
Table of Tables ..................................................................................................................... 5 
Table of Figures .................................................................................................................... 5 
1. 
Protocol Summary ........................................................................................................ 6 
1.1 
Synopsis ....................................................................................................................... 6 
1.2 
Schema ......................................................................................................................... 7 
1.3 
Schedule of Activities (SoA) ....................................................................................... 7 
2. 
Introduction ................................................................................................................. 10 
2.1 
Study Rationale .......................................................................................................... 10 
2.2 
Background ................................................................................................................ 11 
2.3 
Benefit/Risk Assessment ........................................................................................... 13 
3. 
Objectives and Endpoints ........................................................................................... 15 
4. 
Study Design ................................................................................................................ 15 
4.1 
Overall Design ........................................................................................................... 15 
4.1.1 
Study visits ............................................................................................................. 15 
4.1.2 
Selection of Study or Fellow Eye ........................................................................... 16 
4.1.3 
Study Committees .................................................................................................. 16 
Study steering committee ...................................................................................................... 16 
4.2 
Scientific Rationale for Study Design ....................................................................... 16 
4.3 
Justification for Dose ................................................................................................. 16 
4.4 
End of Study Definition ............................................................................................. 17 
5. 
Study Population ......................................................................................................... 17 
5.1 
Inclusion Criteria ....................................................................................................... 17 
5.2 
Exclusion Criteria ...................................................................................................... 18 
5.3 
Lifestyle Considerations ............................................................................................ 19 
5.4 
Screen Failures ........................................................................................................... 19 
5.5 
Criteria for Temporarily Delaying Enrollment/Study Intervention ........................... 19 
6. 
Study Intervention(s) and Concomitant Therapy .................................................... 20 
6.1 
Study Intervention Administered ............................................................................... 20 
6.2 
Preparation, Handling, Storage, and Accountability ................................................. 20 
6.3 
Measures to Minimize Bias: Randomization and Blinding ....................................... 21 
6.4 
Study Intervention Compliance ................................................................................. 21 
6.5 
Dose Modification ..................................................................................................... 22 
6.6 
Continued Access to Study Intervention after the End of the Study ......................... 22 
6.7 
Treatment of Overdose .............................................................................................. 22 
6.8 
Prior and concomitant Therapy .................................................................................. 22 
6.8.1 
Prior and concomitant medications ........................................................................ 22 
6.8.2 
Prior and concomitant surgeries/laser treatments ................................................... 23 
6.8.3 
Prohibited Medications ........................................................................................... 23 
6.8.4 
Permitted Medications ............................................................................................ 23 

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6.8.5 
Rescue Medicine..................................................................................................... 24 
6.8.6 
Additional Treatment .............................................................................................. 24 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...................................................................................... 24 
7.1 
Discontinuation of Study Intervention ....................................................................... 24 
7.2 
Participant Discontinuation/Withdrawal from the Study ........................................... 24 
7.3 
Lost to Follow Up ...................................................................................................... 25 
8. 
Study Assessments and Procedures ........................................................................... 25 
8.1 
Efficacy Assessments ................................................................................................ 25 
8.2 
Safety Assessments .................................................................................................... 26 
8.2.1 
Physical Examinations ............................................................................................ 27 
8.2.2 
Vital Signs .............................................................................................................. 27 
8.2.3 
Electrocardiograms ................................................................................................. 27 
8.2.4 
Clinical Safety Laboratory Tests ............................................................................ 27 
8.2.5 
Pregnancy Testing .................................................................................................. 28 
8.3 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety Reporting
 ................................................................................................................................... 28 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information................... 29 
8.3.2 
Method of Detecting AEs and SAEs ...................................................................... 29 
8.3.3 
Follow-up of AEs and SAEs .................................................................................. 29 
8.3.4 
Regulatory Reporting Requirements for SAEs ...................................................... 29 
8.3.5 
Pregnancy ............................................................................................................... 30 
8.3.6 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs or 
SAEs ....................................................................................................................... 30 
8.3.7 
Adverse Events of Special Interest ......................................................................... 30 
8.3.8 
Medical Device Deficiencies .................................................................................. 30 
8.4 
Pharmacokinetics ....................................................................................................... 30 
8.5 
Genetics and/or Pharmacogenomics .......................................................................... 30 
8.6 
Biomarkers ................................................................................................................. 31 
8.7 
Immunogenicity Assessments .................................................................................... 31 
8.8 
Health Economics or Medical Resource Utilization and Health Economics ............ 31 
9. 
Statistical Considerations ........................................................................................... 31 
9.1 
Statistical Hypotheses ................................................................................................ 31 
9.2 
Analysis Sets .............................................................................................................. 31 
9.3 
Statistical Analyses .................................................................................................... 31 
9.3.1 
General Considerations........................................................................................... 31 
9.3.2 
Primary Endpoints Analysis ................................................................................... 32 
9.3.3 
Secondary Endpoints Analysis ............................................................................... 32 
9.3.4 
Other Analysis ........................................................................................................ 32 
9.4 
Interim Analysis ......................................................................................................... 32 
9.5 
Sample Size Determination ....................................................................................... 32 
10. Supporting Documentation and Operational Considerations ................................ 33 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .................... 33 
10.1.1 Regulatory and Ethical Considerations .................................................................. 33 
10.1.2 Financial Disclosure ............................................................................................... 34 
10.1.3 Informed Consent Process ...................................................................................... 34 
10.1.4 Data Protection ....................................................................................................... 35 

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10.1.5 Committees Structure ............................................................................................. 35 
10.1.6 Dissemination of Clinical Study Data .................................................................... 35 
10.1.7 Data Quality Assurance .......................................................................................... 36 
10.1.8 Source Documents .................................................................................................. 37 
10.1.9 Study and Site Start and Closure ............................................................................ 37 
10.1.10 Publication Policy ................................................................................................... 38 
10.2 Appendix 2: Clinical Laboratory Tests ...................................................................... 39 
10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .......................................................................................... 40 
10.3.1 Definition of AE ..................................................................................................... 40 
10.3.2 Definition of SAE ................................................................................................... 41 
10.3.3 Recording and Follow-Up of AE and/or SAE ........................................................ 42 
10.3.4 Reporting of SAEs .................................................................................................. 45 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ..... 45 
10.4.1 Definitions .............................................................................................................. 45 
10.4.2 Contraception Guidance ......................................................................................... 46 
10.5 Appendix 5: Abbreviations and Definitions .............................................................. 48 
11. References .................................................................................................................... 50 
 
Table of Tables 
Table 1–1: Schedule of Activities (SoA) ................................................................................... 8 
Table 2–1: All Treatment-Emergent Adverse Drug Reactions Reported in Patients in Phase III 
Studies ................................................................................................................... 13 
Table 6–1: Study Intervention(s) Administered ....................................................................... 20 
Table 9–1: Estimated 95% confidence intervals for different ocular serious adverse events 
proportions for N=100 patients ............................................................................. 33 
Table 10–1: Protocol-required Safety Laboratory Tests .......................................................... 39 
 
Table of Figures 
Figure 1–1: Study Flow Diagram ............................................................................................... 7 
 
 
 

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1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title: A Phase IV interventional post approval trial to assess the safety of 
intravitreal aflibercept for the treatment of diabetic macular edema (DME) in patients in India.  
Short Title: India IPAT (PASS) intravitreal aflibercept in DME 
Rationale:  
The proposal for approval of intravitreal aflibercept (EYLEA) in DME indication was 
submitted to the Health Authority (HA) of India. 
 
 
 Therefore, this Phase IV interventional study is designed to 
assess the safety of intravitreal aflibercept in routine clinical practice in India in patients 
diagnosed with DME as the primary objective. 
Among the currently available therapies in India, laser and steroid therapies have their own 
limitations in terms of limited visual acuity gain specifically with laser therapy and increased 
risk of clinically important side effects. There is a need for a treatment that can not only 
stabilize but also clinically relevantly improve and maintain vision in patients with DME 
using a regimen that minimizes the burden to patients. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
• 
To investigate the safety of intravitreal 
aflibercept for the treatment of diabetic 
macular edema (DME) in a phase IV setting 
• 
Frequency (number) of ocular and non-
ocular TEAEs 
Secondary 
 
• 
To investigate the efficacy of use of 
intravitreal aflibercept for the treatment of 
diabetic macular edema (DME) in a phase 
IV setting 
• 
The change in best corrected visual acuity 
(BCVA) from baseline to week 52, as 
assessed using the Early Treatment Diabetic 
Retinopathy Study (ETDRS) chart or 
equivalent. 
• 
Change in central retinal thickness (CRT) 
from baseline to week 52 as measured by 
optical coherence tomography (OCT), FA  
• 
Proportion of eyes that gain ≥ 5, 10 and 15 
ETDRS letters from baseline to Week 52.  
• 
Proportion of eyes with a ≥2 step 
improvement in the ETDRS Diabetic 
Retinopathy Severity Scale (DRSS) score 
 
Overall Design: 
Disclosure Statement: 
This study is a phase IV, interventional, open label, single-arm, prospective, multi-centre 
study, to investigate the safety of intravitreal aflibercept for the treatment of DME in Indian 
patients at a dosage of 2 mg according to label with the primary endpoint assessed at 
Week 52.  
CCI

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Number of Participants: 
Approximately 100 patients will be recruited in the study at approximately 10-15 study sites.  
Study steering committee:  
A study steering committee, including HCPs and Investigators, will be set up locally at Bayer 
Zydus. The study steering committee will meet periodically to review safety data as needed.  
 
1.2 
Schema 
This study is composed of the following periods: Screening, treatment, and follow-up (FU). 
Participants will be considered “on study” during screening, treatment, and FU periods. An 
overview of the study schema is presented in Figure 1–1. 
 
 
Figure 1–1: Study Flow Diagram 
 
aThe first dose of study intervention 
bThe last dose of study intervention 
 
1.3 
Schedule of Activities (SoA) 
Study assessments and procedures are presented by study period and visit in Table 1–1. 
 
Screening 
Intervention period 
Visit 1 
(day -21) 
Visit 2
a 
(day 1) 
Week 0 
Visit 10b 
(day 337) 
Week 48 
Visit 11 
(day 365) 
Week 52 
End-of 
study 
Baseline 
FU period 

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Table 1–1: Schedule of Activities (SoA) 
Study Procedure 
Screening 
Screening 
+ Day 11 
Intervention Period 
Active FU 
visit 
Early 
Discontinuation 
FU visit (+4 
weeks)8 
Visit 
 
1 
1 + 2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
- 
Week 
 
- 
0 
0 
4 
8 
12 
16 
24 
32 
40 
48 
52 
 
Day 
 
-21 to -1 
1±3 
1±3 
29±7 
57±7 
85±7 
113±7 
169±7 
225±7 
281±7 
337±7 
365±7 
- 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination4 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Medical/ ophthalmic history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Current medical/ophthalmic conditions 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (WOCBP only)1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (WOCBP only)1 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT & PTT 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Haematology6 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Chemistry panel6 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
HbA1c6 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
Urine analysis6,7 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
12-lead ECG 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Vital signs5, 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study intervention12 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Ocular assessments10 
Visual acuity (ETDRS, bilateral) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit lamp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Indirect ophthalmoscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FP/ FA 
X9 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Safety assessments (ocular and non-ocular events) 
AE review2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAE review2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety FU (phone call)3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE: adverse event; ECG: electrocardiogram; ETDRS: Early Treatment Diabetic Retinopathy Study; FA: fluorescein angiography; FP: fundus photography; FU: Follow-up; HbA1c: 
haemoglobin A1c; IOP: intraocular pressure; OCT: optical coherence tomography; PT: prothrombin time; PTT: partial thromboplastin time; SAE: serious adverse event; WOCBP: women of 
child-bearing potential.  
1. Visits 1 and 2 can be combined, except for WOCBP. Serum pregnancy results are required to determine eligibility. If a participant is not of childbearing potential and screening/baseline visit is 
to be combined, all procedures listed for both visits must be performed, except for the serum pregnancy test. In addition, all women of childbearing potential (WOCBP) will have a urine 
pregnancy test at each visit starting at visit 2 (day 1). A negative urine pregnancy test is required before treatment is administered. 
2. 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. Any medical 
occurrences/conditions that begin in the period between signing ICF and the start of study intervention, will be recorded as an AEs. An AE arising or worsening after the start of study treatment 
administration until 30 days after the last administration of study treatment, will be considered a treatment-emergent adverse event (TEAE). 
3. Safety FU telephone calls will be made 16 to 36 hours after each visit to ensure that no signs or symptoms of retinal detachment, endophthalmitis, or other AEs have occurred. Calls will be 
made after each visit starting at visit 2. Alternatively, the investigator may schedule an additional safety FU visit for the day after treatment. 
4. Physical examination will include, at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight will also be measured and 
recorded at screening. 
5. Participant’s blood pressure and pulse will be measured after the participant has been sitting for 5 minutes. 
6. After screening visit, blood and urine samples must be collected prior to study drug injection. 
7. At visits at which FA is performed, urinalysis samples will be collected before FA in order to avoid false elevations in urine protein values. 
8. If a participant withdraws from the trial before the end of trial (early discontinuation), he/she should undergo all end of study procedures and assessments after a follow-up period of 4 weeks. 
9. FP/FA may be performed at Visit 1 or Visit 2; images must be reviewed by the investigator to confirm eligibility prior to randomization. 
10. All ocular assessments must be reviewed by the investigator to confirm eligibility prior to the start of the study intervention. 
11. Temperature, blood pressure, and pulse will be measured. 
12. Participants will receive one aflibercept injection (2 mg; equivalent to 50 µL solution for injection) per month (every four weeks) for five consecutive doses, followed by one injection every 
alternate month (every 8 weeks) for rest of the duration. 

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2. 
Introduction 
Increasing prevalence of diabetes mellitus is a major public health concern globally, 
especially in middle-income countries such as in India. Diabetes mellitus now affects 77 
million adults in India, which is likely to increase to over 130 million by 2045 (Kulkarni et al. 
2021; Gilbert et al. 2020). 
Systemic and ocular complications of diabetes affect individuals in their most productive 
years of life (Kulkarni et al. 2021). Diabetic retinopathy (DR) is a well-known microvascular 
complication of diabetes mellitus and DME is the most common cause of vision loss in those 
with DR (Fong et al. 2004; Klein et al. 1984; Moss, Klein, and Klein, 1998). DME, a 
manifestation of DR, is a complex disease of multifactorial origin and is the most frequent 
cause of blindness in young and mid-aged adults in the developed world (Stefansson et al. 
2000). 
Global epidemiologic studies have shown that approximately 1 in 3 persons with diabetes has 
DR, and 1 in 10 has proliferative diabetic retinopathy (PDR) or DME. Based on these rates, 
between 100 million and 120 million people have DR and possibly 20 million to 30 million 
have PDR or DME (Wong et al. 2018; Ozturk 2014). Prevalence of DR in India ranges from 
17.6% to 28.2% and less than 10% of the persons with diabetes suffer from DME or PDR 
(Kulkarni et al. 2021). 
Many different therapies are available for the treatment of DME, reflecting its multifocal 
pathogenesis. Previously, laser photocoagulation was the standard of care for DME 
management after the ETDRS demonstrated it was effective in 1985. However, over the past 
several years, intravitreal injection of anti-VEGF (human vascular endothelial growth factor) 
agents has surpassed laser photocoagulation as the first-line treatment for DME because 
randomized clinical trials have demonstrated the superiority of intravitreal anti-VEGF therapy 
in achieving greater visual acuity outcomes compared to laser photocoagulation. Intravitreal 
anti-VEGF agents are effective because they block the abnormally elevated levels of VEGF 
that lead to excessive vascular permeability and neovascularization (Li et al. 2020). 
Aflibercept is a recombinant fusion protein, comprising portions of VEGF receptor (VEGFR)-
1 and VEGFR-2 extracellular domains that are fused to the Fc portion of human IgG1. The 
innovative multitargeted trap of aflibercept is the only anti-VEGF that blocks all VEGFR-1 
ligands, including VEGF and placental growth factor (Carle et al. 2013; Prescribing 
Information, EYLEA 40 mg/mL). Aflibercept is a dimeric glycoprotein with a protein 
molecular weight of 97 kDa and contains glycosylation, constituting an additional 15% of the 
total molecular mass, resulting in a total molecular weight of 115 kDa. Aflibercept is 
produced in recombinant Chinese hamster ovary (CHO) cells (Prescribing Information, 
EYLEA 40 mg/mL). 
2.1 
Study Rationale 
The proposal for approval of IVT aflibercept (EYLEA) in DME indication was submitted to 
the Health Authority (HA) of India. 
 
  
Therefore, this Phase IV interventional study is designed to assess the safety of IVT 
aflibercept (EYLEA) in routine clinical practice in India in patients diagnosed with DME as 
the primary objective.  
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There is an urgent need to identify and treat DME optimally in India. A recent study reported 
the prevalence of any DME to be 8.9% and that of referable DME as 2.4% of the total Indian 
diabetic population of 77 million. Considering conservative estimate of 2% diabetic 
population having DME, likely magnitude of treatable DME is 15,40,000 persons (Kulkarni 
et al. 2019; Das et al. 2016). Vision impairment and blindness from DR and DME will 
increase unless systems and services are put in place with an increased access to diagnosis and 
effective treatment (Gilbert et al. 2020). 
The standard of care for DME treatment has gradually shifted from macular laser 
photocoagulation to anti-VEGF injections with more options becoming available over the 
years. Real-world studies have shown that around 7-8 anti-VEGF injections per year have 
desirable impact on centre involving DME (Kulkarni et al. 2021). Intravitreal anti-VEGF 
therapy is now accepted worldwide as the current gold standard for the treatment of centre 
involving DME (Kelkar et al. 2020). The therapy has been shown to be effective and safe in 
the treatment of DME in numerous randomized clinical trials with improvements in visual 
acuity and reductions in retinal thickness (Li et al. 2020). 
The 3 most commonly used intravitreal anti-VEGF agents are aflibercept, ranibizumab, and 
bevacizumab. Efficacy and safety of IVT aflibercept in the DME indication has already been 
established globally based on positive results from two pivotal Phase III trials, VIVID and 
VISTA (refer to Section 2.2 and Section 2.3). In a pivotal, large, parallel-arm, randomized 
study conducted by “The Diabetic Retinopathy Clinical Research Network,” aflibercept has 
been found to be superior to bevacizumab and ranibizumab for participants with lower vision, 
whereas differences between the three drugs were unimportant for participants with better 
vision in a 1-year outcome. Visual acuity outcomes at 2 years were also similar for eyes with 
better baseline VA with all the three agents. Among eyes with worse baseline VA (20/50 to 
20/320), aflibercept continued to show superior 2-year VA outcomes compared with 
bevacizumab; and comparable outcome with better safety to ranibizumab. 
Real-world studies have also demonstrated the efficacy of aflibercept. A prospective cohort 
study (n = 147) from France published in 2020 showed that aflibercept was associated with 
improved functional and anatomical outcomes in both treatment-naïve and previously treated 
patients with DME. After 12 months, treatment-naïve patients gained a mean of +7.8 EDTRS 
letters and previously treated patients gained +5.0 letters. There was also a decrease in mean 
CST in both groups. Another 2-year retrospective study (n = 30) from Greece that was 
published in 2019 showed that using aflibercept in DME patients was highly effective, with 
significant increase in median logarithm of the minimum angle of resolution (logMAR) 
BCVA and lower CST compared to baseline (Li et al. 2020). 
Intravitreal Aflibercept (EYLEA; Bayer) is a product approved by the FDA and EMA since 
2014 for the treatment of visual impairment due to DME. The product is approved for the 
treatment DME in over 105 countries and has the potential to address the unmet need for 
patients in India with DME. 
2.2 
Background 
The efficacy of VEGF inhibitors has been examined and proven in numerous clinical trials. 
These agents have the potential not only to stabilize but also to improve visual function and 
are considered the standard of care (SoC) for visual impairment due to DME. Whilst the first 
generation of anti-VEGF treatments have undoubtedly improved patient’s outcomes, the 
requirement for regular injections and monthly monitoring have been a huge burden on 
patients, their caregivers, physicians, and the healthcare system in general. Aflibercept is a 

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potent, specific VEGF inhibitor with a high affinity for all isoforms of VEGF and placental 
growth factor. 
Efficacy and safety of IVT aflibercept in the DME indication has already been established 
globally based on positive results from two pivotal Phase III trials: VIVID (406 patients) and 
VISTA (461 patients), which also included Asian patients. The VIVID and VISTA studies 
provide the first head-to-head comparisons of anti-VEGF blockade alone versus laser therapy 
alone (Korobelnik et al. 2014). Results from these pivotal trials demonstrate that IVT 
aflibercept given either every 4 or every 8 weeks (after 5 initial monthly doses) is superior to 
laser and results in both significant visual acuity (VA) gains and prevention of severe VA 
loss. The primary efficacy endpoint (change from baseline in best corrected visual acuity 
[BCVA] at 52 weeks) was superior in both IVT aflibercept arms (2 mg every 4 weeks, and 2 
mg every 8 weeks after 5 initial monthly doses), compared with the laser group in both 
studies. The percentage of eyes in the laser group that lost ≥15 letters of vision was 9.1% in 
VISTA and 10.6% in VIVID, replicating the 10% loss in the laser group reported in the 
literature. Overall, the 1-year results of the VISTA/VIVID studies demonstrated that IVT 
aflibercept significantly improves visual outcomes and significantly decreases severe vision 
loss, while simultaneously improves the diabetic retinopathy severity score, compared with 
focal laser photocoagulation (Korobelnik et al. 2014). 
A pivotal, large, parallel-arm, randomized study conducted by “The Diabetic Retinopathy 
Clinical Research Network” compared the relative efficacy and safety of IVT aflibercept, 
bevacizumab, and ranibizumab in the treatment of DME [DRCRnet Protocol T]. One-year 
outcomes found aflibercept to be superior to bevacizumab and ranibizumab for participants 
with lower vision, whereas differences between the three drugs were unimportant for 
participants with better vision. When the initial VA letter score was 78 to 69 (equivalent to 
approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with 
aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P > 0.50 for each pairwise 
comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), 
the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with 
ranibizumab (P <0.001 for aflibercept vs. bevacizumab, P = 0.003 for aflibercept vs. 
ranibizumab, and P = 0.21 for ranibizumab vs. bevacizumab). There were no significant 
differences among the study groups in the rates of serious adverse events (SAEs), 
hospitalization, death, or major cardiovascular events (Wells et al. 2015). VA outcomes at 2 
years were also similar for eyes with better baseline VA with all the three agents. Among eyes 
with worse baseline VA (20/50 to 20/320), aflibercept continued to show superior 2-year VA 
outcomes compared with bevacizumab; and comparable outcome with better safety to 
ranibizumab: mean improvement was 18.3, 13.3, and 16.1 letters, respectively (aflibercept vs. 
bevacizumab, P = 0.02; aflibercept vs. ranibizumab, P = 0.18; ranibizumab vs. bevacizumab, 
P = 0.18) (Wells et al. 2016). 
Based on these results, a Cochrane review on anti-VEGFs in DME has also concluded that 
IVT aflibercept confers an advantage over ranibizumab and bevacizumab in people with 
DME at 1 year in visual and anatomic outcomes; similar inference was also drawn by a 
further network metanalysis incorporating individual participant data (Virgili et al. 2018; 
Muston et al. 2018). International guidelines viz. the European Society of Retina Specialists 
(EURETINA) and evidence-based treatment recommendations for DME for the Asian 
countries also recognize the advantages of IVT aflibercept for the treatment of visual 
impairment due to DME and reinforce the superiority of IVT aflibercept over other anti-
VEGF agents in participants with baseline VA of less than 69 letters (worse than 20/50) 
(Schmidt-Erfurth et al. 2017;Cheung et al. 2018). 

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2.3 
Benefit/Risk Assessment 
The participants for this study will be included from government and private hospitals across 
geographies in India to be representative of the population with DME in India. 
As discussed in Section 2.2, the safety and efficacy of IVT aflibercept in the DME indication 
has already been established globally based on positive results from Phase III trials (VIVID 
and VISTA), a pivotal study DRCRnet Protocol T, a Cochrane review, a meta-analysis, and 
EURETINA guidelines. 
Aflibercept has been generally well tolerated when administered by IVT injection. The 
adverse event (AEs) and SAEs that have been reported during the clinical development 
programs are consistent with the rates that have been reported with other IVT administered 
VEGF inhibitors. These events are often attributable to either the IVT injection procedure, the 
demographics of the patient population, or to progression of the disease being treated 
(Investigator's Brochure).  
A total of 2,501 participants have been treated with the recommended dose of 2 mg 
aflibercept across eight Phase III studies. Table 2–1 displays all ARs (serious and non-
serious) from eight Phase III studies with a reasonable possibility of causality to the injection 
procedure or medicinal product (Investigator's Brochure). 
 
Table 2–1: All Treatment-Emergent Adverse Drug Reactions Reported in Patients in Phase III 
Studies 
System Organ 
Class 
Very common 
Common 
Uncommon 
Rare 
Immune 
system 
disorders 
 
 
Hypersensitivitya  
 
Eye disorders Conjunctival 
hemorrhage, 
Eye pain 
Retinal pigment epithelial tearb, 
Detachment of the retinal 
pigment epithelium, 
Cataract, 
Cataract cortical, 
Cataract nuclear, 
Cataract subcapsular,  
Corneal erosion,  
Corneal abrasion, 
Intraocular pressure increased, 
Vision blurred, 
Vitreous floaters, 
Vitreous detachment, 
Injection site pain, 
Foreign body sensation in 
eyes,  
Lacrimation increased, 
Eyelid edema, 
Injection site hemorrhage,  
Punctate keratitis, 
Conjunctival hyperemia, 
Ocular hyperemia 
Endophthalmitisc, 
Retinal detachment, 
Retinal tear, 
Uveitis, 
Iritis, 
Iridocyclitis, 
Lenticular opacities, 
Corneal epithelium 
defect,  
Anterior chamber flare, 
Corneal edema 
Cataract traumatic, 
Vitritis, 
Hypopyon 
aDuring the post-marketing period, reports of hypersensitivity included rash, pruritus, urticaria, and isolated cases 
of severe anaphylactic/anaphylactoid reactions 
bConditions known to be associated with neovascular AMD. Observed in the neovascular AMD studies only. 
cCulture positive and culture negative endophthalmitis 
Source: Investigator's Brochure 
 

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Serious adverse reactions (ARs) related to the injection procedure have occurred in less than 1 
in 2,400 IVT injections with aflibercept and included endophthalmitis, retinal detachment, 
cataract traumatic, cataract, vitreous detachment and intraocular pressure increased 
(Investigator's Brochure).  
The most frequently observed adverse reactions (in at least 5% of patients treated with 
aflibercept) were conjunctival haemorrhage (25.0%), eye pain (10.2%), cataract (7.6%) 
intraocular pressure increased (7.5%), vitreous detachment (7.4%), and vitreous floaters 
(6.9%) (Investigator's Brochure). 
IVT injections, including those with aflibercept, have been associated with endophthalmitis. 
Nevertheless, the cases can be minimized by employing proper aseptic injection technique 
while administering aflibercept and can be managed appropriately by counselling the 
participants to report any symptoms suggestive of endophthalmitis without delay (Prescribing 
Information, EYLEA 40 mg/mL).Prescribing Information, EYLEA 40 mg/mL).  
Increases in intraocular pressure (IOP) have been seen within 60 minutes of an IVT injection, 
including with aflibercept. A special precaution is required in patients with poorly controlled 
glaucoma, and such patients are not intended to be enrolled in this study (Prescribing 
Information, EYLEA 40 mg/mL). 
There are no data on the use of aflibercept in pregnant women. Studies in animals have shown 
reproductive toxicity after systemic administration. The pregnant women are not intended to 
be enrolled in this study (Prescribing Information, EYLEA 40 mg/mL).  
All the participants in the trial may derive general medical benefit from careful and close 
monitoring by medical personnel during the study. However, study participation does not 
guarantee a direct or indirect benefit for the participant. Safety will be ensured by monitoring 
the participants for AEs both clinically and by laboratory testing. 
The planned study incorporates standard clinical procedures that are used in Phase IV studies 
with DME. The study design is supported, and study execution will be followed by a Steering 
Committee of experts to ensure participant safety on an ongoing basis (refer Section 4.1.3). 
All participants in this trial will be treated in accordance with best SoC in compliance with 
guidelines and recommendations. Relevant emerging safety data, e.g., SAEs, suspected 
unexpected serious adverse reactions (SUSARs), and serious safety-related protocol 
deviations, will be communicated as soon as possible between the sponsor, all study sites and 
investigators and trial participants.  
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 (IB) and 
the Prescribing Information (PI). 
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with aflibercept are justified by the anticipated benefits 
that may be afforded to participants with DME. 

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3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To investigate the safety of IVT aflibercept 
for the treatment of DME in a phase IV 
setting 
• 
Frequency (number) of ocular and non-
ocular TEAEs 
Secondary 
 
• 
To investigate the efficacy of use of IVT 
aflibercept for the treatment of DME in a 
phase IV setting 
• 
The change in BCVA from baseline to week 
52, as assessed using the ETDRS chart or 
equivalent. 
• 
Change in CRT from baseline to week 52 as 
measured by OCT, FA  
• 
Proportion of eyes that gain ≥ 5, 10 and 15 
ETDRS letters from baseline to Week 52.  
• 
Proportion of eyes with a ≥2 step 
improvement in the ETDRS DRSS score 
 
4. 
Study Design 
4.1 
Overall Design 
This study is a phase IV, interventional, open label, single-arm, prospective, multi-centre 
study, to investigate the safety of IVT aflibercept for the treatment of DME in Indian 
participants in routine clinical practice in India at a dosage of 2 mg according to label with the 
primary endpoint assessed at Week 52. The trial will be conducted at approximately 10-15 
study sites across India. Approximately 100 participants will be recruited in the study.  
4.1.1 
Study visits 
The study duration will be up to 13 months covering 11 visits:  
• Screening period (Visit 1 [Day-21 to Day-1]): The start of the study period is defined by 
signing of the informed consent form (ICF). 
• Baseline visit (Visit 2 [Day 1]): HbA1c and ocular assessments check have to be 
confirmed at the baseline visit before the intravitreal administration of aflibercept. 
• Visits 1 and 2 can be combined (as Visit 1+2) except in women of childbearing potential 
(see Section 1.3). Participants who met all of the inclusion and none of the exclusion 
criteria, will be assigned to aflibercept treatment on Day 1, Week 0 (at Visit 2 or Visit 
1+2). 
• Treatment period (Visit 2 [Day 1, Week 0] to Visit 10 [Day 337, Week 48]) that include 
study intervention per month for five consecutive doses (Visit 2-6), followed by one 
injection every alternate month for rest of the duration (Visit 7-10). 
• FU period: from month 11 to month 12 (visit 11)  
Once patients complete Visit 11/Week 52, can be switched over to commercially available 
supply or other suitable treatment options at the discretion of the Investigator (see 
Section 6.6). 

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4.1.2 
Selection of Study or Fellow Eye 
Only 1 eye per patient will be enrolled in the study (Section 6.8). 
For patients who meet eligibility criteria in both eyes, the eye with the worst VA will be 
selected as the study eye. If a patient has DME with similar BCVA in both eyes, the eye with 
the clearest media will be selected as the study eye. If the ocular media of both eyes are 
similar in clarity, the patient’s non-dominant eye (if identifiable) will be selected as the study 
eye. If neither eye is dominant, the right eye will be designated as the study eye. For treatment 
of the fellow eye, see Section 6.8. 
4.1.3 
Study Committees 
Study steering committee  
A study steering committee, which is composed of a panel of experts in the field including 
HCPs and Investigators, will be set up locally at Bayer Zydus that will meet periodically to 
review safety data as needed. These data may include, but are not limited to: 
• Treatment-Emergent Adverse Events (TEAEs) that result in an early study withdrawal. A 
TEAE is defined as any event arising or worsening after the start of study treatment 
administration until 30 days after the last administration of study treatment. 
• SAEs 
• Selected laboratory tests, as deemed appropriate by the study steering committee  
• Specific AEs as defined by the SMT, such as cardiovascular AEs 
Appropriate action, if needed, will be taken based upon this review and in consultation with 
the medical monitor. 
4.2 
Scientific Rationale for Study Design 
Please refer to Section 2.1 for the study rationale. 
 
 
  
The intervention model of the study includes single group assignment of IVT aflibercept in an 
open-label fashion. It is justified to not use any comparator or masking in the study as the 
primary objective of the study is to collect additional safety data for IVT aflibercept in Indian 
patients with DME. The efficacy of aflibercept is well-established in global clinical trials and 
real-world studies, and therefore the data for changes in BCVA scores and CRT will be 
collected as the secondary objective. The study will adhere to standard provisions of an 
interventional study like drug supply, defined sample size, treatment/dosing schedule per 
label, safety follow-ups, and AE reporting. 
4.3 
Justification for Dose 
The participants in the study will receive one aflibercept injection (2 mg; equivalent to 50 µL 
solution for injection) per month (every four weeks) for five consecutive doses, followed by 
one injection every alternate month (every 8 weeks) for rest of the duration. This dosage 
regimen is as per the label (prescribing Information) approved by the HA of India. 
CCI

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4.4 
End of Study Definition 
The end of the study (EOS) is defined as the date when the last visit of the last participant has 
been achieved in all participating centres. 
Last participant last visit (LPLV) of a participant is reached if he/she has completed the last 
scheduled visit shown in the SoA (this also includes phone contacts during long-term FU) 
unless the participant withdrew consent or is lost to FU. 
Furthermore, to reach EOS, all participants should have discontinued aflibercept treatment.  
At the EOS visit (Visit 11), the study participant can be switched over to commercially 
available supply or other suitable treatment options at the discretion of the Investigator.  
5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.  
The study will be conducted in 100 participants across 10-15 centres in India. Participants 
will be included from government and private hospitals across geographies in India to be 
representative of the population. At each study centre, not less than 70% of the participants 
should be naïve. The logistics will be applied in the electronic data capture (EDC) system to 
identify the patient as naïve or pre-treated, and to alert the investigator when the naïve and 
pre-treated patients cap is reached at the study centre. 
Participants who did not receive any previous/ prior treatment (i.e., participants that 
previously have not been treated with IVT anti-VEGF or steroids) within the last 3 months of 
the Day 1 of the study, without laser treatment, and without ocular surgery of the study eye 
are considered as naive.  
The target study population is men and women 18 years and older with DME secondary to 
diabetes mellitus involving the centre of the macula (central subfield on OCT that is defined 
as circular area of 1 mm diameter around the centre point of fovea). Participants must meet all 
eligibility criteria at screening and baseline visits; however, participants do not need repeat 
assessments if the screening and baseline visits are combined (see SoA). Refer to Section 5.4 
to refer to re-screening criteria. If a subject fails screening, i.e., does not meet all inclusion 
criteria or meets 1 or more of the exclusion criteria, the participants can be re-screened. If the 
screen failure is due to an inability to meet the BCVA inclusion criterion, at least 30 days 
since the previous assessment must pass before re-screening of BCVA. A patient can be re-
screened upto two times as long as he meets the re-screening criteria.  
5.1 
Inclusion Criteria 
A participant must meet the following criteria at screening and day 1 to be eligible for 
inclusion in the study: 
1. Female or male adult participant ≥18 years of age, with type 1 or 2 diabetes mellitus. 
2. Participant must have DME secondary to diabetes mellitus, involving the centre of the 
macula (defined as the area of the centre subfield of OCT) in the study eye. 
3. Decrease in vision, determined to be primarily the result of DME in the study eye.  
4. Retinal thickness of ≥300 µm in the study eye, as assessed by OCT.  
5. BCVA ETDRS letter score of 73 to 24 (i.e., VA of 20/50 to 20/320) or equivalent in 

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the study eye.  
6. Participant for whom the decision to initiate treatment with IVT aflibercept has been 
made by the treating Investigator/Physician. 
7. Willing and able to comply with clinic visits and study-related procedures. 
8. Provide a signed ICF prior to any study procedures. 
5.2 
Exclusion Criteria  
A participant who meets any of the following criteria at either the screening visit or day 1 will 
be excluded from the study: 
1. Having any contraindications to the use of IVT aflibercept as listed in the local 
prescribing information (i.e., ocular or periocular infection, active severe intraocular 
inflammation, and known hypersensitivity to aflibercept or to any of the excipients). 
2. History of vitreoretinal surgery and/or scleral buckling in the study eye. 
3. Ocular conditions with a poorer prognosis in the fellow eye than in the study eye. 
4. Known history of allergy to fluorescein used in fluorescein angiography, and 
indocyanine green used in indocyanine green angiography. As indocyanine green dye 
contains iodine, so severe allergic reactions are possible in patients allergic to iodine. 
5. Any laser photocoagulation (panretinal or macular) in the study eye within the last 3 
months of Day 1. 
6. Any cataract surgery in the study eye within the last 3 months of Day 1. 
7. Any intraocular surgery in the study eye within the last 3 months of Day 1.  
8. Received previous/ prior treatment as mentioned below: 
a) Received anti-VEGF drugs in the study eye (pegaptanib sodium, bevacizumab, 
ranibizumab, etc., including aflibercept) within the last 3 months of Day 1. 
b) Received IVT dexamethasone or triamcinolone in the study eye within the last 3 
months of Day 1. 
c) Received intraocular or periocular corticosteroids in the study eye within the last 4 
months of Day 1. 
d) Had fluocinolone implant in the study eye within the last 3 years of Day 1. 
e) Had dexamethasone implant in the study eye within the last 6 months of Day 1. 
f) systemic anti-angiogenic agents within 6 months of Day 1. 
9. Uncontrolled glaucoma in the study eye (patient who has had filtration surgery in the 
past, or likely to need filtration surgery in the future). 
10. IOP ≥25 mm Hg in the study eye. 
11. Only 1 functional eye even if that eye is otherwise eligible for the study. 
12. Ocular media of insufficient quality to obtain fundus and OCT images. 
13. Uncontrolled DM in the opinion of the investigator. 
14. Uncontrolled blood pressure (BP) (defined as systolic >160 mm Hg or diastolic >95 mm 

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Hg while patient is sitting). 
15. History of cerebrovascular accident or MI within 6 months of Day 1. 
16. Renal failure, dialysis, or history of renal transplant. 
17. Participated in an investigational study within 30 days prior to screening visit that 
involved treatment with any drug (excluding vitamins and minerals) or device. 
18. Pregnant or breast-feeding women. 
19. Sexually active men or WOCBPa who are unwilling to practice adequate contraception 
during the study (adequate contraceptive measures include stable use of oral 
contraceptives or other prescription pharmaceutical contraceptives for 2 or more 
menstrual cycles prior to screening; intrauterine device [IUD]; bilateral tubal ligation; 
vasectomy; condom plus contraceptive sponge, foam, or jelly or diaphragm plus 
contraceptive sponge, foam, or jelly). 
20. WOCBPa with either a positive pregnancy test result or no pregnancy test at baseline. 
5.3 
Lifestyle Considerations 
No restrictions are required.  
5.4 
Screen Failures 
A screen failure occurs when a participant consents to participate in the clinical study but is 
not subsequently 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. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Whether the participant can repeat the screening will be discussed with the 
Sponsor. Sponsor’s approval of re-screening for a participant must be documented. If the 
screen failure is due to an inability to meet the BCVA inclusion criterion, at least 30 days 
since the previous assessment must pass before re-screening of BCVA. A patient can be re-
screened upto two times times as long as the re-screening criteria are met.  
Also, for re-screening, the participant has to re-sign the ICF, even if it was not changed after 
the participant’s previous screening. The screening failure will be registered in Interactive 
Voice/Web Response System (IxRS) to close the patient identification number (PID), and re-
screening will start again by signing a new ICF and being assigned a new PID via IxRS. 
5.5 
Criteria for Temporarily Delaying Enrollment/Study Intervention 
Not applicable for this protocol.  
 
aPostmenopausal women must be amenorrheic for at least 12 months in order not to be considered of 
childbearing potential. 

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6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
6.1 
Study Intervention Administered 
Participants will receive one aflibercept injection (2 mg; equivalent to 50 µL solution for 
injection) per month (every four weeks) for five consecutive doses, followed by one injection 
every alternate month (every 8 weeks) for rest of the duration.  
The injection will be administered by a qualified physician experienced in administering IVT 
injections. Immediately following the IVT injection, the participant will be monitored for 
elevation in IOP. Appropriate monitoring may consist of a check for perfusion of the optic 
nerve head or tonometry. If required, sterile equipment for paracentesis should be available. 
Following IVT injection, the participant will be instructed to report any symptoms suggestive 
of endophthalmitis (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without 
delay.  
Table 6–1: Study Intervention(s) Administered 
Intervention Label 
Aflibercept 
Intervention Name 
Eylea 
Intervention Description 
Each vial provides a usable amount to deliver a single dose of 50 
microliters containing 2 mg aflibercept.  
Aflibercept treatment is initiated with one injection per month (every 
four weeks) for five consecutive doses, followed by one injection 
every two months (8 weeks). 
Type  
Drug 
Dose Formulation 
Vial 
Unit Dose Strength(s) 
IVT injections of 50 μL (2 mg) of aflibercept 
Dosage Level(s) 
2 mg aflibercept and initiated with one injection per month (every 
four weeks) for five consecutive doses, followed by one injection 
every two months (8 weeks) 
Route of Administration 
IVT injection 
Use 
Experimental 
Packaging and Labeling 
Study intervention will be provided in vial. Each vial will be labeled 
as required per country requirement 
 
6.2 
Preparation, Handling, Storage, and 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.  

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Study intervention should be stored in a refrigerator and at the recommended label 
temperature (2°C to 8°C / 35.6°F to 46.4 °F) in vial in the outer carton in order to protect from 
light.  
The vial is for single use in one eye only. The recommended dose for Eylea is 2 mg aflibercept 
(equivalent to 50 microlitres solution for injection). The study drug will be withdrawn using 
aseptic techniques through an 18-gauge filter needle attached to a 1-mL syringe. The filter 
needle will be discarded after withdrawal of the vial contents and should not be used for IVT 
injection. The filter needle should be replaced with a 30G x 1/2-inch injection needle for the 
IVT injection. The contents in the syringe should be expelled until the plunger is aligned with 
the line that marks 0.05 mL on the syringe. It is recommended to visually inspect the solution 
for injection prior to administration. The vial is not to be used if particulates, cloudiness, or 
discoloration are visible. Prior to usage, the unopened vial of aflibercept may be stored at 
room temperature (25 °C / 77°F) for up to 24 hours. After opening the vial, proceed under 
aseptic conditions.. 
All study intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labelled 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 a separate document.  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Randomization and blinding are not applicable for this study.  
This is an open-label study and all open label intervention at all visits must be assigned by the 
IxRS for tracking and accountability purpose. 
Patient identification 
After a participant has signed the PI/ICF, the patient identification number will be provided to 
the investigators through an IxRS. Participants will be identified by a 9-digit patient 
identification number consisting of: 
Digits 1 to 5 = Unique centre number 
Digits 6 to 9 = Current patient number within the centre 
 
The IxRS procedure is described in detail in a separate IxRS instruction manual that will be 
maintained in the electronic trial master file (eTMF) and in each centre’s investigator site file. 
6.4 
Study Intervention Compliance 
The administration of IVT aflibercept will be performed in the clinic for 5 monthly treatments 
(5 loading doses) followed by treatment every 8 weeks. The date and time of each injection 
administered in the clinic will be recorded in the source documents and recorded in the 
electronic case report form (eCRF). Reasons for dose delay or infusion interruption will also 

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be recorded in the source data and in the eCRF. The drug accountability will be managed 
through IxRS. 
The participants will receive study intervention directly from the investigator or designee at 
the site, under medical supervision. The dose of study intervention, study participant 
identification, and study eye (right/left) will be confirmed at the time of dosing by a member 
of the study site staff other than the person administering the study intervention.  
6.5 
Dose Modification 
This study does not permit changes in the study regimen.  
6.6 
Continued Access to Study Intervention after the End of the Study 
At the end-of-study visit (Visit 11), the study participant can be switched over to 
commercially available supply or other suitable treatment options at the discretion of the 
Investigator.  
6.7 
Treatment of Overdose 
Overdosing with increased injection volume may increase IOP. Therefore, in case of an 
overdose, IOP should be monitored, and if deemed necessary by the investigator/treating 
physician, adequate treatment should be initiated.  
Sponsor does not recommend specific treatment for an overdose.  
In the event of an overdose, the investigator/treating physician should: 
• 
Contact the medical monitor immediately. 
• 
Evaluate the participant to determine, in consultation with the medical monitor, 
whether study intervention should be interrupted or whether the dose should be 
reduced. 
• 
Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
study intervention can no longer be detected systemically (at least 30 days). 
• 
Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
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. 
For more details, refer to prescribing information of Eylea.  
6.8 
Prior and concomitant Therapy 
6.8.1 
Prior and concomitant medications 
All medications taken before study start (initiated and stopped before first intravitreal 
aflibercept injection) are termed prior medications. Prior medications meeting the criteria 
listed below have to be documented: 
• 
Considered relevant for the study indication (DME) such as: 
o 
Intravitreal injections with steroids (inclusive of steroid implants) or other VEGF 
inhibitors 
o 
Peribulbar injections with steroids or other VEGF inhibitors 

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• 
Treatments for any of the concomitant diseases of interest 
• 
Other ophthalmological treatments 
All medications taken in addition to aflibercept for any indication (either initiated at the time 
of enrollment or during the study) are termed concomitant medications.  
Information to be collected for medication includes: trade name or INN, start date, stop 
date/ongoing, dose, unit, frequency, application route, indication and, if applicable, the eye(s) 
treated. 
Please note that any action during the study performed for the fellow eye is to be recorded as 
concomitant medication.  
6.8.2 
Prior and concomitant surgeries/laser treatments 
Prior surgeries are considered relevant to the study indication and have to be documented: 
• 
Macular laser treatment 
• 
Pan retinal or focal retinal laser treatment 
• 
Ocular surgeries 
All ocular surgeries after the first aflibercept injection are termed concomitant surgeries.  
For surgeries, the name of the surgery, the date, the reason, and the eye operated have to be 
recorded. 
6.8.3 
Prohibited Medications 
Participants may not receive any medications (approved or investigational) for their DME in 
the study eye other than the assigned study treatment as specified in this protocol, until they 
have completed the end of study (week 52) visit assessments or assessments after the early 
discontinuation of study intervention.  
This includes medications administered locally (e.g., IVT, topical, juxtascleral or periorbital 
routes), as well as those administered systemically, with the intent of treating the study and/or 
fellow eye. 
For IVT treatment of the fellow eye, other anti-VEGF agents will not be allowed unless 
aflibercept is not available due to logistical reasons. However, bevacizumab will not be 
permitted. 
6.8.4 
Permitted Medications 
If the fellow eye has DME involving or threatening the centre of the macula, starting at 
week 4 (Visit 3), participant may receive treatment with aflibercept 2 mg using a dosing 
regimen of 5 initial monthly doses, followed by 2q8. The fellow eye treatment will not utilize 
clinical supply for the study eye. Other anti-VEGF agents will not be allowed unless 
aflibercept (Eylea) is not available due to logistical reasons. The participant can receive the 
commercially available anti-VEGF for the treatment of fellow eyes, and in such case, the 
medication will not be supplied by the Sponsor. 
However, bevacizumab will not be permitted.  
The participant’s fellow eye may receive treatment on the same day as the study eye or at an 
unscheduled visit. All fellow eye treatments must be recorded on the eCRF as a concomitant 
medication and/or procedure for the fellow eye. The fellow eye will not be considered an 
additional study eye. Participants who receive treatment for the fellow eye will not be 

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required to be withdrawn from the study. Safety of the fellow eye will be monitored, and all 
AEs will be collected. Other conditions in the fellow eye may be treated with approved 
therapies. 
Any other medication that are considered necessary for the participant’s welfare, and that are 
not expected to interfere with the evaluation of the study drug, may be given at the discretion 
of the investigator. 
6.8.5 
Rescue Medicine 
Not applicable for this protocol.  
6.8.6 
Additional Treatment  
Patients will be evaluated for additional treatment starting at week 24 at the discretion of the 
investigator. Criteria for additional treatment (at least 1 criterion must be met): 
• Loss at any single visit of ≥15 letters from the best previous VA score due to DME and 
the patient’s current VA score is not better than the baseline score. 
• Loss at 2 consecutive visits at least 7 days apart (second visit may be an unscheduled 
visit) of ≥10 letters from the best previous VA score due to DME and the patient’s current 
VA score is not better than the baseline score. 
The participants who qualify for additional treatment, will receive an active laser treatment at 
the current visit, and will continue with aflibercept at the current and all future visits. 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Unnecessary withdrawal of subjects from the study should be avoided and all efforts should 
be taken to motivate subjects to adhere to all study procedures until the end of the trial. 
7.1 
Discontinuation of Study Intervention  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in 
the study until end of active FU period which is referred to as early discontinuation visit 
(4 weeks post permanent discontinuation of study intervention). See the SoA for the data to be 
collected at the early discontinuation FUvisit.  
The reason for study drug interruption or permanent study drug discontinuation/ withdrawn 
from the study should be recorded in the eCRF and in the subject's medical records. 
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, behavioural, or 
compliance reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. Refer to SoA for data to be collected and evaluations to be completed at the 
time of early discontinuation. 
The participant will be permanently discontinued from the study intervention and the study at 
that time. 

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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. 
7.3 
Lost to Follow Up 
A participant will be considered lost to FU if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a 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, counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to FU, the investigator or designee must make 
every effort to regain contact with the participant (where possible, telephone calls, and 
if necessary, a certified letter to the participant’s last known 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. 
• 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 timeframe defined in the SoA. 
8.1 
Efficacy Assessments  
Planned timepoints for all efficacy assessments are provided in the SoA. 
Best Corrected Visual Acuity (BCVA) 
Visual function of the study eye and the fellow eye will be assessed using the ETDRS 
protocol (The Early Treatment Diabetic Retinopathy Study Group, 1985) at 4 meters at each 
study visit. VA examiners and BCVA examination lane must be certified to ensure consistent 

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measurement of BCVA. The procedure for conducting BCVA and measurement for BCVA 
must be in the same throughout the study at each site. 
Slit Lamp Examination 
Participants’ anterior eye structure and ocular adnexa will be examined at each study visit 
using a slit lamp by the investigator. The procedure for conducting slit lamp examination 
must be in the same throughout the study at each site. 
Intraocular Pressure (IOP) 
IOP of the study eye will be measured at every visit using a calibrated Goldmann applanation 
tonometry or Tono-pen™. The same method of IOP measurement must be used in each 
participant throughout the study. IOP will be measured pre-dose and at approximately 30 
minutes post-dose. The physician (or designee) will measure IOP pre-injection (bilateral), and 
approximately 30 minutes post-injection (study eye). 
A more detailed description for IOP can be found in PI. 
Indirect Ophthalmoscopy 
Participants’ posterior pole and peripheral retina will be examined by indirect 
ophthalmoscopy at each study visit pre-dose (bilateral) and post-dose (study eye). Post-dose 
evaluation must be performed immediately after injection (active drug or sham). 
Optical Coherence Tomography (OCT) 
Retinal characteristics will be evaluated at every visit using spectral domain OCT. Starting 
with the screening visit (visit 1), images will be captured for both eyes. OCT technicians must 
be qualified to ensure consistency and quality in image acquisition. OCT images will be read 
by the investigator/ qualified reader at the site. All OCTs will be electronically archived at the 
study sites as part of the source documentation.  OCT machine and image setting for OCT 
must be in the same throughout the study at each site. 
Fundus Photography/Fluorescein Angiography (FP/ FA) 
The anatomical state of the retinal vasculature will be evaluated by FP and FA. The study eye 
will be the transit eye. FP and FA will be captured for both eyes. Photographers must be 
qualified to ensure consistency and quality in image acquisition. FP and FA images will be 
read by the investigator/qualified reader at the site. All FPs and FAs will be archived at the 
site as part of the source documentation.  FP/ FA machines and image setting for FP/FA must 
be in the same throughout the study at each site. 
FP and FA evaluations will be performed at screening (visit 1 or visit 2), week 24, and week 
52. FA must also be performed whenever any laser re-treatment criterion is met, and at least 
12 weeks have passed since the last laser or sham laser. 
8.2 
Safety Assessments  
Investigators should refer to the Safety Information section of the current IB for the expected 
side effects including unexpected AEs and hypersensitivity reactions. The IB will be updated 
if any new relevant safety data are obtained. 
Safety will be assessed by monitoring and recording all AEs and SAEs, cardiac, hematologic 
and blood chemistry parameters, vital signs, ECG, and any abnormal findings observed 
during the performance of physical examinations. 

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Planned timepoints for all safety assessments are provided in the SoA. 
Therapeutic monitoring should be performed following dose modification of study drug in a 
manner consistent with the local clinical SoC. In general, participants should be closely 
monitored for adverse drug reactions of all concomitant medications regardless of the path of 
drug elimination. 
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g., clotted or haemolyzed) and to verify the results. The 
results from such additional analyses may neither be included in the clinical database of this 
study nor evaluated further. If the results are relevant, the Investigator will be informed to 
determine FU activities outside of this protocol. 
Abnormal physical examination findings are recorded either as medical history or as AEs (see 
Section 8.3). Additional assessments may be indicated at any time during the course of the 
study at the discretion of the Investigator. In addition, lab tests may be repeated at the 
discretion of the Investigator, if clinically indicated. 
8.2.1 
Physical Examinations 
A full physical examination will be performed by the investigator or qualified designee at 
screening and at the end-of-study. A complete physical examination will include, at a 
minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and neurological 
systems. Height and weight will also be measured and recorded.  
8.2.2 
Vital Signs 
Participant’s vital signs will be measured at screening visit and at every study visit.  
Vital signs will be measured in a sitting position after 5 minutes rest with a completely 
automated device and will include temperature, systolic and diastolic BP, and pulse. Three 
readings of BP and pulse will be taken. The first reading should be rejected. The second and 
third readings should be averaged to give the measurement to be recorded. Manual techniques 
will be used only if an automated device is not available. 
8.2.3 
Electrocardiograms 
Single 12-lead ECG(s) will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
8.2.4 
Clinical Safety Laboratory Tests 
See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA for the 
timing and frequency.  
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant 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 30 days 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. 

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• If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, the aetiology should be identified, and the 
sponsor notified. 
• All protocol-required laboratory tests, 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 tests 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. 
8.2.5 
Pregnancy Testing 
Serum and urine pregnancy tests are performed at Screening and during treatment. Specific 
time points can be found in the SoA. The frequency of pregnancy tests may be higher, if 
required by local regulations. More details can be found in Section 10.4. 
8.3 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety 
Reporting 
The intensity of AEs should be documented using the NCI-CTCAE, v5.0. 
The study treatment action should be recorded separately for each study treatment as detailed 
in the eCRF. 
• Drug withdrawn 
• Drug interrupted 
• Drug delayed 
• Dose reduced 
• Dose not changed 
• Dose increased 
• Not applicable 
• Unknown  
The definitions of AEs and SAEs can be found in Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative [LAR]). 
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 all AEs or AEs that are serious, considered related to the study intervention or 
study procedures, or that caused the participant to discontinue the study (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
Investigators should refer to the Safety Information section of the current IB of aflibercept for 
the expected side effects. As with any agent, there is always the potential for unexpected AEs, 
including hypersensitivity reactions. The IB will be updated if any new relevant safety data 
are obtained. 

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8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until the end of FU visit at 
the timepoints specified in the SoA. SAEs which are related to protocol-required study 
procedures (e.g., SAE related to invasive study procedures) will be recorded as SAEs from the 
signing of the ICF. 
Any medical occurrences/conditions that begin in the period between signing ICF and the 
start of study intervention will be recorded as an AE. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of learning of the event, as indicated in 
Section 10.3. 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 information on AEs or SAEs after conclusion 
of the study participation. However, if the investigator learns of any SAE, including a death, 
at any time after a 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 AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3.  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading 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 FU (as defined in 
Section 7.3). Further information on FU 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, independent ethics committees (IECs), and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the IB/Prescribing Information and will notify the IEC, if appropriate 
according to local requirements. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 

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8.3.5 
Pregnancy 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until the end of follow up 
period. 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the female 
participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner) pregnancy. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs, and will be reported as such. 
The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The investigator will collect FU information on the participant/pregnant female 
partner and the neonate, and the information will be forwarded to the sponsor. 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 8.3.4. 
While the investigator is not obligated to actively seek this information in former study 
participants/pregnant female partner, 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 or be withdrawn from the study. 
Prior to continuation of study intervention following pregnancy, the following must occur: 
• The sponsor and the relevant IEC give written approval. 
• The participant gives signed informed consent. 
• The investigator agrees to monitor the outcome of the pregnancy and the status of the 
participant and her offspring. 
8.3.6 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs 
Not applicable for this protocol.  
8.3.7 
Adverse Events of Special Interest  
Not applicable for this protocol.  
8.3.8 
Medical Device Deficiencies 
Not applicable for this protocol.  
8.4 
Pharmacokinetics 
Pharmacokinetics and pharmacodynamic parameters are not evaluated in this study.  
8.5 
Genetics and/or Pharmacogenomics 
Not applicable for this protocol. 

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8.6 
Biomarkers 
Not applicable for this protocol. 
8.7 
Immunogenicity Assessments 
Not applicable for this protocol. 
8.8 
Health Economics or Medical Resource Utilization and Health 
Economics 
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 
9. 
Statistical Considerations  
The statistical analysis plan will be finalized prior to study database lock, and it will include a 
more technical and detailed description of the statistical analyses described in this section. 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
A final analysis will be performed after the EOS which is the date the analytical dataset is 
completely available. 
9.1 
Statistical Hypotheses 
There is no hypothesis to confirm or reject in this study. 
9.2 
Analysis Sets 
The primary population for the efficacy analysis is the Full analysis set (FAS) population that 
will be comprised of all participants assigned to study intervention (aflibercept injection).  
The population for the safety analysis is the safety analysis set (SAF) population that will be 
comprised of all participants who received at least one dose of study intervention (aflibercept 
injection).  
The FAS is used to analyse endpoints related to the efficacy objectives and the SAF is used to 
analyse the endpoints and assessments related to safety. 
9.3 
Statistical Analyses 
9.3.1 
General Considerations 
All outcomes will be analysed descriptively by either frequency tables or summary statistics 
for the total study population. Whenever meaningful, continuous variables will also be 
categorized. If applicable, the analysis will be stratified by baseline factors.  
All analyses will be performed for each of the following cohorts: 
• Naïve 
• Pre-treated 
and for the total study population. 

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9.3.2 
Primary Endpoints Analysis 
AEs will be summarized for the SAF using the MedDRA coding system. Occurrence rates for 
single AEs will be calculated based on the total number of patients valid for safety and 95% 
confidence intervals (CIs) will be provided. AEs will be categorized according to ocular or non- 
ocular nature, relatedness, seriousness, discontinuation of therapy, action taken and outcome.  
The analyses will be performed on incident TEAE. Events which are not treatment-emergent 
will be tabulated without further stratification. Events are considered as TEAE, if they started 
after 1st IVT-aflibercept injection and not later than 30 days after last IVT- aflibercept injection. 
Laboratory data will be listed only. 
Further details will be specified in the statistical analysis plan (SAP). 
9.3.3 
Secondary Endpoints Analysis  
All secondary outcomes will be analysed by frequency tables or summary statistics such as 
mean, standard deviation, minimum, percent quartiles, median, maximum and 95% 
confidence intervals for the total population. Whenever meaningful, continuous variables will 
also be categorised.  
Summary statistics for absolute BCVA values and respective changes from baseline will be 
displayed. For sensitivity analysis, an analysis of covariance (ANCOVA) model with baseline 
BCVA as covariate will be performed to estimate the baseline adjusted BCVA change. No 
formal comparison will be made. 
More details will be provided in the SAP. 
9.3.4 
Other Analysis 
Further sensitivity analyses like subgroup analysis by baseline BCVA will be performed. 
BCVA values cut-off for groups division for subgroup analysis: VA letter score ranging 
from78 to 69, or 20/32 to 20/40 Snellen; and those with fewer than 69 letters, equivalent to 
about 20/50 or worse. Details on subgroup analyses will be specified in the SAP. 
Frequency (number) of IVT aflibercept injections in the study eye over 12 months of the 
study period will be provided with 95% CI. 
Further sensitivity analysis which take lost to follow up into consideration will be applied 
(like TEAE incidence rates per person years and TEAE incidence rates per injections) and 
will be described in the SAP. 
9.4 
Interim Analysis 
No formal interim analysis is planned in this study. 
9.5 
Sample Size Determination 
The study aims to enrol 100 patients from 10-15 sites. 
The sample size of 100 patients 
 to 
describe the safety profile of the study intervention. In an analysis of the data from the clinical 
trials VIVID and VISTA, the reported proportion for any ocular SAE was 1.7% over the 
course of 52 weeks. Table 9–1 shows the precision that might be expected in terms of 95% 
CIs for different AE proportions and 100 patients.  
CCI

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Table 9–1: Estimated 95% confidence intervals for different ocular serious adverse 
events proportions for N=100 patients 
Assumed AE proportion 
95% confidence interval 
Width 
1% 
(0%, 5.4%) 
5.4% 
2% 
(0.2%, 7%) 
6.8% 
3% 
(0.6%, 8.5%) 
7.9% 
4% 
(1.1%, 9.9%) 
8.8% 
Clopper-Pearson Confidence Intervals, PASS Version 13.0.11 
 
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 ICH Good Clinical Practice (GCP) guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IEC by the investigator and 
reviewed and approved by the IEC before the study is initiated.  
Any amendments to the protocol will require 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 GCP 
and national and international regulations. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IEC 
• Notifying the IEC of SAEs or other significant safety findings as required by IEC 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IEC, and all other applicable local regulations. 

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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 
All relevant information on the study will be summarized in an integrated patient information 
sheet and ICF provided by the Sponsor or the study centre.  
Sample patient information and ICFs are provided as documents separate to this protocol.  
Based on this patient information sheet, the Investigator or designee will explain all relevant 
aspects of the study to each participant prior to his/her entry into the study (i.e., before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms). 
The Investigator will also mention that written approval of the IEC has been obtained. 
Each participant will be informed about the following aspects of premature withdrawal: 
Each participant has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.  
The participant’s data that have been collected until the time of withdrawal will be retained 
and statistically analysed in accordance with the SAP.  
Participant-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g., image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analysed in 
accordance with the SAP. The participant has the right to object to the generation and 
processing of this post-withdrawal data. The participant’s oral objection may be documented 
in the participant’s source data. 
Each participant will have ample time and opportunity to ask questions: 
The investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participants or their LAR, and answer all questions regarding the 
study.  
Participants must be informed that their participation is voluntary. Participants or their LARs 
will be required to sign a statement of informed consent that meets the requirements of 21 
CFR 50, local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IEC or study centre.  
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 participants or their LAR.  

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10.1.4 
Data Protection 
All records identifying the participant will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available. 
• Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets or biological samples 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 IEC members, and by inspectors from regulatory authorities. 
10.1.5 
Committees Structure 
Study Steering Committee 
The main task of study steering committee, which is composed of a panel of experts in the 
field including HCPs and Investigators, is to support the conduct of the study and to advise 
the Sponsor on clinical, medical, and scientific questions. Details of the committee will be 
specified in the Steering Committee charter. 
10.1.6 
Dissemination of Clinical Study Data 
The Sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. All data and results and all intellectual property rights in 
the data and results derived from the study will be the property of the Sponsor who may 
utilize them in various ways, such as for submission to government regulatory authorities or 
disclosure to other Investigators. Regarding public disclosure of study results, the Sponsor 
will fulfill its obligations according to all applicable laws and regulations. The Sponsor is 
interested in the publication of the results of every study it performs. 
The Sponsor recognizes the right of the Investigator to publish the results upon completion of 
the study. However, the Investigator, whilst free to utilize study data derived from his/her 
centre for scientific purposes, must obtain written consent of the Sponsor on the intended 
publication manuscript before its submission. To this end, the Investigator must send a draft 
of the publication manuscript to the Sponsor within a time period specified in the contract. 
The Sponsor will review the manuscript promptly and will discuss its content with the 
Investigator to reach a mutually agreeable final manuscript. 
Result Summaries of Bayer's sponsored clinical trials in drug development Phases II, III, and 
IV and Phase I 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 ClinicalTrials.gov and EU Clinical 
Trials Register in line with the applicable regulations. 
Bayer commits to sharing upon request from qualified scientific and medical researchers 
participant-level clinical trial data, study-level clinical trial data, and protocols from clinical 

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trials in participants for medicines and indications approved in the US and European Union 
(EU) on or after January 01, 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. 
10.1.7 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRFs unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
Guidance on completion of CRFs will be provided . 
The investigator must permit study-related monitoring, audits, IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the monitoring plan/contracts. 
The data collection tool for this study will be a validated electronic data capture system. 
Participant data necessary for analysis and reporting will be transmitted into a validated 
database or data system. 
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet-based EDC software system/Bayer system. Bayer will ensure that 
extensive software logics are applied to ensure data are complete and reflect the clinical data 
requirements of the study. Data queries resulting from the application of the software logic are 
resolved by the site personnel. The data are stored at a secured host facility and transferred on 
a periodic basis to Bayer's internal computer system via a secure Virtual Private Network. 
All access to the EDC system will be through a password-protected security system. All 
internal Bayer and external Investigator site personnel seeking access must go through a 
thorough EDC software training before they are granted access to the EDC for use in Bayer's 
clinical studies. Training records are maintained. 
The EDC System will contain a system-generated audit trail to capture any changes made to a 
data field, including who made the change, why the change was made and the date and time it 
was made. This information will be available both at the Investigator’s site and at Bayer. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, 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. 

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• The Contract Research Organization (CRO) 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., 
CROs). 
• 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 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor.  
 
10.1.8 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s 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, and its origin can be found in the Source 
Data Location List (SDLL) or equivalent. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The sponsor will perform monitoring to confirm that data entered into the CRF by 
authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of 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.  
 
10.1.9 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date.  
The principal Investigator of each centre must sign the protocol signature page and must 
receive all required external approvals (e.g., health authority, ethics committee, Sponsor) 
before participant recruitment may start at the respective centre. Likewise, all amendments to 

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the protocol must be signed by the principal Investigator and must have received all required 
external approvals before coming into effect at the respective centre. 
 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs, the regulatory authorities, and any CRO(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 FU. 
 
10.1.10 
Publication Policy 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the Sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other Investigators. 
Regarding public disclosure of study results, the Sponsor will fulfil its obligations according 
to all applicable laws and regulations. The Sponsor is interested in the publication of the 
results of every study it performs. 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.  
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicentre studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 

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• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors (ICMJE) authorship requirements.  
10.2 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in  
• Table 10–1 will be performed by the local laboratory.  
• Protocol-specific 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 Tests 
Laboratory 
Tests 
Parameters 
Haematology 
Platelet count 
RBC indices: 
Mean corpuscular 
volume (MCV) 
Mean corpuscular 
haemoglobin 
(MCH) 
%Reticulocytes 
White blood cell (WBC) count 
with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell (RBC) 
count 
Haemoglobin 
Haematocrit 
Clinical 
chemistry1 
Blood urea 
nitrogen (BUN) 
Potassium 
Aspartate 
aminotransferase 
(AST)/ serum 
glutamic-
oxaloacetic 
transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
aminotransferase 
 (ALT)/ serum 
glutamic-pyruvic 
transaminase 
(SGPT) 
Total protein 
 
Glucose (fasting 
or nonfasting) 
Calcium 
Alkaline 
phosphatase2 
HbA1c 
Routine 
urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, 
leukocyte esterase] by dipstick  
• 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy 
testing 
• 
Highly sensitive [serum or urine] human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential)3 

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Table 10–1: Protocol-required Safety Laboratory Tests 
Laboratory 
Tests 
Parameters 
NOTES: 
1 Details of liver chemistry stopping criteria and required actions and FU are given in Section [7.1.1 Liver 
Chemistry Stopping Criteria] and Section [10.6 Liver Safety: Suggested Actions and FU Assessments 
[and Study Intervention Rechallenge Guidelines]]]. All events of ALT [or AST] ≥3 × upper limit of normal 
(ULN) and bilirubin ≥2 × ULN (>35% direct bilirubin) or ALT [or AST] ≥3 × ULN and international 
normalized ratio (INR) >1.5 (if INR measured) which may indicate severe liver injury (possible Hy’s law), 
must be reported to [sponsor] in an expedited manner (excluding studies of hepatic impairment or 
cirrhosis). 
2 If alkaline phosphatase is elevated, consider fractionating. 
3 Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IEC 
Investigators must document their review of each laboratory safety report. 
 
10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 
Definition of AE 
AE Definition 
• 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. 
• NOTE: An AE can therefore be any unfavourable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
associated with the use of study intervention. 
• Treatment-Emergent Adverse Event (TEAE): A TEAE is defined as any event 
arising or worsening after the start of study treatment administration until 30 days 
after the last administration of study treatment. 
 
Events Meeting the AE Definition  
• Any abnormal laboratory test results (haematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 

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• Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as an AE or SAE if they fulfil the definition of an AE or SAE. Lack of 
efficacy or failure of expected pharmacological action also constitutes an AE or 
SAE. 
 
Events NOT Meeting the AE Definition  
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen 
10.3.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose, meets the 
one or more of the criteria listed: 
a. 
Results in death 
b. 
Is life threatening 
• The term life threatening in the definition of serious refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 

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c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfils any 
other serious criteria, the event is serious. When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. 
Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
g. 
Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment 
for allergic bronchospasm, blood dyscrasias, convulsions, or development of 
intervention dependency or intervention abuse. 
10.3.3 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Bayer in lieu of completion of the AE/SAE eCRF/required 
form. 
• There may be instances when copies of medical records for certain cases are 
requested by Bayer. In this case, all participant identifiers, with the exception 

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of the participant number, will be redacted on the copies of the medical records 
before submission to the Sponsor. 
• The investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. Whenever possible, the 
diagnosis (not the individual signs/symptoms) will be documented as the 
AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories:  
• Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Moderate: Minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL). Instrumental ADL 
refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.  
• Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self-care ADL. Self-care ADL refers to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden.  
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 

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Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. The investigator will use clinical judgment 
to determine the relationship 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to Bayer. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to Bayer. 
• The investigator may change his/her opinion of causality in light of FU information 
and send an SAE FU report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
• Immune-mediated adverse events (IMAEs) are AEs consistent with an immune 
mediated mechanism or immune-mediated component for which non-inflammatory 
aetiologies (e.g., infection or tumour progression) have been ruled out. IMAEs can 
include events with an alternate aetiology which were exacerbated by the induction 
of autoimmunity. Information supporting the assessment will be collected on the 
participant’s eCRF. 
• Every AE must be assessed by the investigator with regard to whether it is 
considered immune-mediated. 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Bayer 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized FU 
period, the investigator will provide Bayer with a copy of any post-mortem 
findings including histopathology.  
• New or updated information will be recorded in the originally submitted 
documents. 
• The investigator will submit any updated SAE data to Bayer within 24 hours of 
receipt of the information. 

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10.3.4 
Reporting of SAEs 
SAE Reporting to Bayer via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to Bayer will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
transmission (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the EDC tool will be taken off-line to 
prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the EDC tool has been taken off-
line, then the site can report this information on a paper SAE form (see next 
section) or to the PVCH by telephone. 
• Contacts for SAE reporting can be found in Safety Management Plan (SMP) and 
ICF. 
 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
Women in the following categories are considered WOCBP (fertile) 
1. Following menarche 
2. From the time of menarche until becoming premenopausal unless permanently sterile (see 
below): 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal 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. In addition, females under the 
age of 55 years must have a serum follicle stimulating hormone, (FSH) 
level > 40 mIU/mL to confirm menopause.  
• Females on HRT and whose menopausal status is in doubt will be required 
to use one of the non-oestrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal status 
before study enrolment. 

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• Permanent sterilization methods (for the purpose of this study) include: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
• For individuals with permanent infertility due to an alternate medical cause 
other than the above, (e.g., Mullerian agenesis, androgen insensitivity, 
gonadal dysgenesis), investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
1. Premenopausal female with permanent infertility due to one of the following: 
a) 
Documented hysterectomy 
b) 
Documented bilateral salpingectomy 
c) 
Documented bilateral oophorectomy 
d) 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), investigator discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview 
2. 
Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal 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. In addition, females under the 
age of 55 years must have a serum follicle stimulating hormone, (FSH) 
level > 40 mIU/mL to confirm menopause.  
• Females on HRT and whose menopausal status is in doubt must discontinue 
HRT to allow confirmation of postmenopausal status before study 
enrolment. 
 
10.4.2 
Contraception Guidance 
WOCBP are excluded from the study (refer section 5.2).  

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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of < 1% per year when used 
consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS)c 
• Bilateral tubal occlusion 
• Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner 
of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent Failure rate of < 1% per year when used consistently 
and correctly. 
Combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
− oral 
− intravaginal 
− transdermal 
− injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
− oral 
− injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.) 
Effective Methodsd That Are Not Considered Highly Effective Failure rate of ≥ 1% per year when used 
consistently and correctly. 
• Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of 
action 
• Male or female condom with or without spermicide 
• Cervical cap, diaphragm, or sponge with spermicide 
• A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-
barrier methods)c 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from 
those when used consistently and correctly. 
c.)If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.  
d) Considered effective, but not highly effective - failure rate of ≥ 1% per year.  
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. 
Male condom and female condom should not be used together (due to risk of failure from friction). 
 
 

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10.5 
Appendix 5: Abbreviations and Definitions 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AMD 
Age-related macular degeneration 
ANCOVA 
Analysis of covariance 
APTC 
Anti-Platelet Trialists’ Collaboration 
AR 
Adverse Reaction 
AST 
Aspartate aminotransferase 
ATE 
Arterial thrombotic event 
BCVA 
Best Corrected Visual Acuity 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CHO 
Chinese hamster ovary 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CRO 
Contract Research Organization 
CRT 
Central Retinal Thickness 
CTCAE 
Common Terminology Criteria for Adverse Event 
DME  
Diabetic Macular Edema 
DR 
Diabetic Retinopathy 
DRSS 
Diabetic Retinopathy Severity Scale 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
Electronic Data Capture 
EMA 
European Medicine Agency 
EOS 
End of study 
ETDRS  
Early Treatment Diabetic Retinopathy Study 
eTMF 
Electronic trial master file 
EU 
European Union 
EURETINA 
European Society of Retina Specialists 
FA 
Fluorescein angiography 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FP 
Fundus photography 
FU 
Follow-up 
GCP 
Good Clinical Practice 
HA 
Health Authority 
HbA1c  
Haemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HEOR 
Health Economics and Outcomes Research 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 

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ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IMAE 
Immune-mediated adverse events 
INN 
International Nonproprietary Name 
INR 
International normalized ratio 
IOP 
Intraocular pressure 
IUD 
Intrauterine device 
IVT 
Intravitreal 
IxRS 
Interactive Voice/Web Response System 
LAR 
Legally Authorized Representative 
LPLV 
Last Participant Last Visit 
MAH 
Marketing Authorization Holder 
MCH 
Mean corpuscular haemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
NCI 
National cancer institute 
OCT 
Optical Coherence Tomography 
PDR 
Progressive Diabetic Retinopathy 
PI 
Prescribing information 
PID 
Patient identification number 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
QTL 
Quality tolerance limits 
RBC 
Red blood cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDLL 
Source Data Location List 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SMP 
Safety Management Plan 
SMT 
Safety monitoring team 
SoA 
Schedule of Activities 
SoC 
Standard of care 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
upper limit of normal 
US 
United States 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
WBC 
White blood cell 
WHO DD 
World Health Organization Drug Dictionary 
WOCBP 
Women of child-bearing potential 

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11. 
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Internal Document 
Bayer plc. EYLEA – Prescribing information; September 2021.