Conditions: Age Related Macular Degeneration Polypoidal Choroidal Vasculopathy
Keywords: anti vegf aflibercept treat and extend
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 54
Healthy volunteers: no

Brief summary:
Polypoidal choroidal neovasculopathy (PCV) is a subtype of wet age related macula degeneration (AMD) occuring more commonly in the Asian population. Besides the phenotypic differences, PCV is thought to have a lesser response to anti VEGF therapy which is the mainstay of treatment for other typical wet AMD. Recent trial data suggest that a combination with photodynamic therapy may help in the visual and anatomical outcome of PCV, and emerging evidence shows favourable outcomes the newer anti VEGF agent, aflibercept 2mg monotherapy. These trials however, have assessed aflibercept in a strict 2mg every 8 weekly regime.

In the clinical setting, a significant an unmet need in the management of PCV is a tailored treatment regime. Here we propose a treatment regimen based on disease activity for PCV with aflibercept mono therapy. A limitation of the 2q8 regime is that it is fixed and does not vary regardless of polyp closure or anatomical outcome at the first time point of assessment (month 3). We hypothesize that after the initial 3 monthly injections of aflibercept, about 50% of PCV will close and become quiescent, and in the remaining 50%, a further 3 monthly injections will increase overall polyp closure rate. After a loadings phase of either 3 or 6 months, all eyes will start on a treat and extend regime (T\&E), with a minimum period of 8 weeks and a maximum of 12 weeks between treatments with 2 week increments if PCV remains quiescent. The proposed study aims to evaluate the efficacy of a modified treat and extend regime based on disease activity with aflibercept monotherapy for PCV.

Detailed description:
Age related macular degeneration (AMD) is one of the leading causes of blindness worldwide. In its exudative or wet form, choroidal neovascularization (CNV) causes an exudative maculopathy resulting in sudden loss of vision with severe effects on patients' quality of life.1,2 Intra vitreal injections of anti-vascular endothelial growth factor agents (anti-VEGF) agents have become the mainstay of treatment for AMD CNV and have been shown to have favorable outcomes in most AMD CNV subtypes.3,4 In the Asian population however, a particular subtype called polypoidal choroidal vasculopathy (PCV), which affects about 50% of exudative maculopathy, has been shown to have less favorable response to anti-VEGF therapy.5,6 The EVEREST trial, a randomized controlled trial which compares the efficacy of photodynamic therapy (PDT) with or without ranibizumab for treatment of PCV showed that PDT with or without anti VEGF improved polyp closure rate on angiographic assessment but this trial did not take into account vision as a primary end point.7 PDT appears work through its effects on choroidal vasculature, hence making it relevant to PCV which is increasingly thought to be a condition on the pachychoroid spectrum.8 PDT however, as a treatment modality presents several disadvantages. Firstly, PCV often presents as a widely distributed lesion, making it difficult to treat, with a single beam of PDT. Secondly, PDT is limited in its ability to treat lesions in the peripapillary area as there is risk of damage to the optic nerve. Thirdly, features commonly associated with PCV such as a large pigment epithelial detachment (PED) or extensive submacular hemorrhages are not usually suitable for PDT. Fourthly, there is a risk of long-term choroidal atrophy especially if repeated treatments are administered.8,9

There is emerging evidence for the use of aflibercept monotherapy in PCV. Reports range from small case series and retrospective studies to larger prospective studies. Recent data from the PLANET study showed that monotherapy of aflibercept resulted in similar letter gains in visual acuity as compared to combination treatment with PDT at 1 year. Polyp closure rate was also similar between the two groups at 38.9% with monotherapy and 44.8% with combination therapy. The VAULT and APOLLO studies suggest vision and anatomical improvements with 66-72% polyp closure in 1 year.10 These trials however, use a fixed dosing regimen (3 monthly loading doses of 2mg aflibercept followed by fixed dosing every 8 weeks (2q8) totaling 7 injections in 1 year). In addition to resolution of subretinal fluid, recent studies using the novel OCT-angiography (OCT-A) to evaluate choroidal vasculature suggests re-modelling of choroidal vasculature may also be an important therapeutic effect. We reported more prominent reduction in choroidal vessel calibre after combination treatment with PDT and bevacizumab compared to bevacizumab monotherapy. The effect of Aflibercept on choroidal vasculature has been less well studied. Some evidence however, suggested aflibercept may have more profound effect on choroidal vasculature with the reducing choroidal thickness than ranibizumab or bevacizumab.

A significant unmet need in the management of PCV with anti VEGF monotherapy is a practical way of treating patients in the real world setting that maximizes efficacy with minimal number of visits and injections. Clinical trial regimes follow a rigid treatment algorithm that aim to maximize response. In the clinical setting, these regimes are impractical in "real world" patients. Regular intensive course of treatment involves lengthy visits which include consultation time, clinical examination, retinal imaging, and often an intra vitreal injection. In clinical practice this often result in treatment fatigue and in a co-payment healthcare environment in Singapore, may also result in significant financial burden to the patient and society.

While aflibercept affords an 8 weekly treatment regime which is better than other monthly anti VEGF therapy regimes, trial regimes still do not take into account individual patients' disease patterns. This study aims to take disease activity into account to tailor treatment regimes specific for patients. In addition, it aims to provide insight into the outcomes of patients on a more clinically relevant treat and extend (T\&E) regime which changes the treatment tempo in relation to disease activity.

Arms:
arm 1: Fixed Dosing with Aflibercept 2mg will be administered at a fixed regime at 8 week intervals through to week 52. arm 2: Reassessment at week 12 (month 3) by repeat examination for disease activity by OCT and indocyanine green angiography (ICGA). Subsequent treatment regime of Treat and Extend with Aflibercept 2mg will depend on disease activity at this point.

Interventions: intervention 1: Treat and Extend with Aflibercept 2mg intervention 2: Fixed Dosing with Aflibercept 2mg
Intervention descriptions: intervention 1: Drug treatment regime which allows extension of treatment interval based on disease activity intervention 2: Fixed 8 weekly dosing regime throughout the study duration

Protocol document:
Prot_SAP_000.pdf: 
PCVTnE Study Protocol Version 5.0_Dated 26 July 2019 
Page 1 of 17 
 
 
STUDY PROTOCOL 
 
PROTOCOL TITLE: 
An open label-study to compare the efficacy of Aflibercept monotherapy for Polypoidal Choroidal 
Vasculopathy using a modified intensive treat and extend regime to a fixed dosing regimen 
 
PROTOCOL NUMBER:  R1448/31/2017 
 
PROTOCOL VERSION:  
5.0  
PROTOCOL DATE:  
26 July 2019 
 
PRINCIPAL INVESTIGATOR:  
A/Prof Gemmy Cheung,  
Senior Consultant,  
Singapore Eye Research Institute 
Singapore National Eye Centre  
11 Third Hospital Avenue, Singapore 168751 
Contact No: 6322 4500 
 
CO-INVESTIGATORS: 
Prof Wong Tien Yin, Professor, Singapore Eye Research Institute, Singapore National Eye Centre, Duke-
NUS Graduate Medical School 
A/Prof Ian Yeo Yew San, Senior Consultant, Singapore National Eye Centre 
A/Prof Doric Wong Wen Kuan, Senior Consultant, Singapore National Eye Centre 
A/Prof Lee Shu Yen, Senior Consultant, Singapore National Eye Centre 
Dr Anna Tan Cheng Sim, Consultant, Singapore National Eye Centre 
Dr Gavin Tan Siew Wei, Consultant, Singapore National Eye Centre 
Dr Ranjana Mathur, Senior Consultant, Singapore National Eye Centre 
Dr Chan Choi Mun, Consultant, Singapore National Eye Centre 
Dr Kelvin Teo Yi Chong, Associate Consultant, Singapore National Eye Centre 
Dr Wong Chee Wai, Associate Consultant, Singapore National Eye Centre 
Dr Andrew Tsai Shih Hsiang, Associate Consultant, Singapore National Eye Centre  
Dr Daniel Ting Shu Wei, Associate Consultant, Singapore National Eye Centre 
 
 
 
 


PCVTnE Study Protocol Version 5.0_Dated 26 July 2019 
Page 2 of 17 
 
Table of Contents 
1. 
BACKGROUND AND RATIONALE................................................................................................. 4 
2. 
HYPOTHESIS AND OBJECTIVES ................................................................................................. 4 
3. 
EXPECTED RIKS AND BENEFITS ................................................................................................. 5 
4. 
STUDY POPULATION .................................................................................................................. 5 
4.1. 
LIST THE NUMBER AND NATURE OF SUBJECTS TO BE ENROLLED. ................................................................................ 5 
4.2. 
CRITERIA FOR RECRUITMENT AND RECRUITMENT PROCESS ....................................................................................... 5 
4.3. 
INCLUSION CRITERIA ............................................................................................................................................... 5 
4.4. 
EXCLUSION CRITERIA .............................................................................................................................................. 6 
5. 
STUDY DESIGN AND PROCEDURES/METHODOLOGY ................................................................. 6 
6. 
SAFETY MEASUREMENTS.......................................................................................................... 13 
6.1. 
DEFINITIONS ......................................................................................................................................................... 13 
6.2. 
COLLECTING, RECORDING AND REPORTING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS TO CIRB ............ 13 
6.3. 
SAFETY MONITORING PLAN ................................................................................................................................... 14 
6.4. 
COMPLAINT HANDLING .......................................................................................................................................... 14 
7. 
DATA ANALYSIS........................................................................................................................ 15 
7.1. 
DATA QUALITY ASSURANCE ................................................................................................................................... 15 
7.2. 
DATA ENTRY AND STORAGE ................................................................................................................................... 15 
8. 
SAMPLE SIZE AND STATISTICAL METHODS ............................................................................. 15 
8.1. 
DETERMINATION OF SAMPLE SIZE .......................................................................................................................... 15 
8.2. 
STATISTICAL AND ANALYTICAL PLANS .................................................................................................................... 16 
9. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................................... 16 
10. QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 16 
11. ETHICAL CONSIDERATIONS ..................................................................................................... 16 
11.1. 
INFORMED CONSENT ............................................................................................................................................. 16 
11.2. 
CONFIDENTIALITY OF DATA AND PATIENT RECORDS ............................................................................................... 17 
12. PUBLICATIONS ......................................................................................................................... 17 
13. RETENTION OF STUDY DOCUMENTS ........................................................................................ 17 
14. FUNDING AND INSURANCE ...................................................................................................... 17 
 
 
 


PCVTnE Study Protocol Version 5.0_Dated 26 July 2019 
Page 3 of 17 
 
 
PROTOCOL SIGNATURE PAGE 
 
 
 
Protocol Title: An open label-study to compare the efficacy of Aflibercept monotherapy for Polypoidal 
Choroidal Vasculopathy using a treat and extend regime to a fixed dosing regimen 
 
 
 
Protocol Number: R1448/31/2017 
 
 
Protocol Version/ Date: 5.0 / 26 July 2019 
 
 
Sponsor Name: NMRC CTG-ICT  
 
 
 
Declaration of Investigator 
 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct the 
described study in compliance with all stipulations of the protocol, regulations and ICH E6 Guideline for 
Good Clinical Practice (GCP). 
 
  
 
 
Principal Investigator Name:  A/Prof Gemmy Cheung Chui Ming 
                                                            
 
Principal Investigator Signature:  ____________
_ 
                                                            
 
Date:  _____26 July 2019_________________________________ 
                                                            
 
 
 
 
 
 
 
 
 
 


PCVTnE Study Protocol Version 5.0_Dated 26 July 2019 
Page 4 of 17 
1. 
BACKGROUND AND RATIONALE 
Age related macular degeneration (AMD) is one of the leading causes of blindness worldwide. In its 
exudative or wet form, choroidal neovascularization (CNV) causes an exudative maculopathy resulting in 
sudden loss of vision with severe effects on patients’ quality of life.  Intravitreal injections of anti vascular 
endothelial growth factor agents (anti-VEGF) agents have become the mainstay of treatment for AMD CNV 
and has been shown to have favorable outcomes in most AMD CNV subtypes. In the Asian population 
however, a particular subtype called polypoidal choroidal vasculopathy (PCV), which affects about 50% of 
exudative maculopathy, has been shown to have less favorable response to anti-VEGF therapy.  The 
EVEREST trial, a randomized controlled trial which compares the efficacy of photodynamic therapy (PDT) 
with or without ranibizumab for treatment of PCV showed that PDT with or without anti VEGF improved 
polyp closure rate on angiographic assessment but this trial did not take into account vision as a primary 
end point. 
 
There is emerging evidence for the use of aflibercept monotherapy in PCV. Reports range from small case 
series and retrospective studies to larger prospective studies.  Recently, the PLANET study showed that 
monotherapy of aflibercept resulted in similar letter gains in visual acuity as compared to combination 
treatment with PDT at 1 year.  Polyp closure rate was also similar between the two groups at 38.9% with 
monotherapy and 44.8% with combination therapy.  The VAULT and APOLLO studies show consistent 
results with this and suggest vision and anatomical improvements with 66-72% polyp closure in 1 year.  
These trials however, use a fixed dosing regime for 12 months of 3 monthly loading doses of 2mg aflibercept 
followed by fixed dosing every 8 weeks (2q8) totaling 7 injections in 1 year.   
 
In the clinical setting, a significant an unmet need in the management of PCV is a tailored treatment regime.  
Here we propose a treatment regimen based on disease activity for PCV with aflibercept mono therapy.  A 
limitation of the 2q8 regime is that it is fixed and does not vary regardless of polyp closure or anatomical 
outcome at the first time point of assessment (month 3).  We hypothesize that after the initial 3 monthly 
injections of aflibercept, about 50% of PCV will close and become quiescent, and in the remaining 50%, a 
further 3 monthly injections will increase overall polyp closure rate.  After a loadings phase of either 3 or 6 
months, all eyes will start on a treat and extend regime (T&E), with a minimum period of 8 weeks and a 
maximum of 12 weeks between treatments with 2 week increments if PCV remains quiescent.  The 
proposed study aims to evaluate the efficacy of a modified treat and extend regime based on disease activity 
with aflibercept monotherapy for PCV.  
 
This study will be the first to assess not only the T&E regime in PCV but also the use of activity to guide 
treatment early in the disease to ensure more intense intervention in non-responsive patients.  The results 
from this study will add to the existing evidence that monotherapy with aflibercept for PCV is a viable option 
and build on refining treatment regimes for real world clinical settings.  In clinical practice, these results will 
also provide clinicians with the confidence to use the T&E regime in their patients with PCV allowing for a 
more balanced treatment regime with longer follow up in patients with quiescent disease yet not 
compromising on response.  
 
We also aim to build on our previous work, and aim to evaluate longitudinal choroidal changes and their 
correlation with functional outcomes using swept source OCT-A in patients with PCV treated with aflibercept. 
 
 
2. 
HYPOTHESIS AND OBJECTIVES 
Specific Aim 1: To compare the efficacy and safety of intravitreal aflibercept in eyes with PCV using 
a modified treat and extend regime with versus fixed dosing regimen 
 


PCVTnE Study Protocol Version 5.0_Dated 26 July 2019 
Page 5 of 17 
Hypothesis:  That after the initial 3 monthly injections of aflibercept, about 50% of PCV will close and 
become quiescent, and in the remaining 50%, a further 3 monthly injections will increase overall polyp 
closure rate.  
 
Specific Aim 2: To evaluate longitudinal choroidal changes and their correlation with functional 
outcomes using swept source OCT-A in patients with PCV treated with aflibercept. 
 
Hypothesis:  That aflibercept will result in choroidal vascular changes, specifically a reduction in 
haller’s layer vessel calibre which forms the basis of treatment response. 
 
Seondary Aim: To analyze whether imaging parameters (e.g. choroidal thickness, pachyvessels, 
choroidal hyperpermeability, PCV subtype) influence the visual outcome at month 12. 
 
 
3. 
EXPECTED RIKS AND BENEFITS 
The benefits to the patients will be a tailored treatment regimes based on disease activity for PCV.  
Patients will have more individualised treatment specific to their disease progression and may either 
benefit from 1) less injections with prolonged intervals if quiescent or 2) a more intensive treatment 
initially to arrest the development of more active disease progress. The recruited patient will also have 
a direct benefit in receiving free intravitreal aflibercept treatment during the course of the study 
regardless of treatment arm. Risks to the patient would be the adverse events from the intravitreal 
injections like endophthalmitis, cerebral or cardiac complications, which are very rare.  
 
 
4. 
STUDY POPULATION 
4.1. 
List the number and nature of subjects to be enrolled.  
A minimum of total 55 study participants aged 45 years and above diagnosed with PCV and are 
treatment naïve. Study participants can only have one study eye. If both eyes are eligible for the study, 
the eye without previous intravitreal anti-VEGF treatment will be selected. If both eyes are treatment 
naïve, the eye with worse VA should be selected as the study eye. There will be no restriction of 
recruitment according to the race of the patient.  
 
 
4.2. 
Criteria for Recruitment and Recruitment Process 
Potential eligibility will be assessed as part of a routine-care examination. Prior to completing any 
procedures or collecting any data that are not part of usual care, written informed consent will be 
obtained. For potential study participants who are considered potentially eligible for the study based 
on a routine-care exam, the study protocol will be discussed with the potential study participant by a 
study investigator and study coordinator. The potential study participant will be given the informed 
consent form to read. Potential study participants will be encouraged to discuss the study with family 
members and their personal physician(s) before deciding whether to participate in the study.  
 
4.3. 
Inclusion Criteria 
Participant 
1. Male or female study participants, age >=45 years of age at the time of informed consent. 
2. Best corrected ETDRS visual acuity score between 78 to 25 (ie 20/32 to 20/320) 
3. Diagnosis of PCV based on ICGA 
a. Presence of intra retinal or subretinal fluid/blood at the fovea as seen on OCT 
b. Treatment naïve 


PCVTnE Study Protocol Version 5.0_Dated 26 July 2019 
Page 6 of 17 
*NO previous treatment with intravitreal anti-VEGF agents, regardless of the indication 
*NO previous thermal laser in the macular region, or verteporfin photodynamic therapy (vPDT), regardless of indication 
*NO other previous treatment for nAMD, except oral supplements and traditional Chinese medicine  
4. Media clarity, pupillary dilation and individual cooperation sufficient for study procedure 
including fundus photography. 
5. Able and willing to provide informed consent. 
 
4.4. 
Exclusion Criteria 
Participant 
1. Medical condition that, in the opinion of the investigator, would preclude participation in the study 
(e.g.unstable medical status including blood pressure, cardiovascular disease, and glycaemic 
control).  
2. Participation in an investigational trial within 30 days of enrolment which involves treatment with 
unapproved investigational drug 
3. Known allergy to any component of the study drug.  
4. Blood pressure > 180/110 (systolic above 180 OR diastolic above 110 on repeated measurements). 
If blood pressure is brought below 180/110 by anti-hypertensive treatment, individual can become 
eligible.  
5. Myocardial infarction, other acute cardiac event requiring hospitalization, stroke, transient ischemic 
attack, or treatment for acute congestive heart failure within 4 months prior to randomization. 
6. Systemic anti-VEGF or pro-VEGF treatment within four months prior to randomization or anticipated 
use during the study.   
 
Study Eye 
1. Eye with intra retinal or subretinal fluid due to other causes than PCV  
2. An ocular condition is present (other than PCV) that, in the opinion of the investigator, might affect 
intra or sub retinal fluid or alter visual acuity during the course of the study (e.g., DME, vein occlusion, 
uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.) 
3. Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 
more than three lines (i.e., cataract would be reducing acuity to worse than 20/40 if eye was otherwise 
normal). 
4. Any intraocular surgery within 3 months of enrollment 
5. Treatment with intra vitreal corticosteroids  
6. History of retinal detachment or surgery for retinal detachment 
7. History of vitrectomy 
8. History of macular hole 
9. Evidence of vitreomacular traction that may preclude resolution of macular edema > 4 disc areas of 
intra/sub retinal hemorrhage 
10. Aphakia 
11. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis 
 
 
Other Eye 
1. Active intraocular inflammation 
2. History of uveitis 
 
 
5. 
STUDY DESIGN AND PROCEDURES/METHODOLOGY 
Prospective, 2-arm, Non-inferiority, interventional study to evaluate the efficacy of intravitreal 
aflibercept in eyes with PCV using a disease activity guided T&E regimen versus fixed dosing 
regimen.  


PCVTnE Study Protocol Version 5.0_Dated 26 July 2019 
Page 7 of 17 
 
Duration for each participant: 52 weeks 
 
Medical record of participants will be reviewed 1 year after they completed the study. This is to better 
understand the percentage of patients that continue to require standard of care therapy after exiting study. 
Further to that, patients’ clinical status (e.g. anatomical outcomes) at the end of 1 year may influence future 
treatment needs.  
 
Randomization/Stratification 
Patients will be randomized to 2 treatment groups (2Q8, and T&E) using a ratio of 1:3; 2Q8: T&E.  
Randomization will be performed using a blocked randomization method. This will be carried out by drawing 
lots for randomization in blocks of 20 for 40 participants. The balance lots for randomization for 12 participants 
will make up the difference. The addition of the 3 study participants is to replace those who have been 
withdrawn from the study. Thus, no randomization is required for these 3 study participants. 
 
Study Treatment Groups and Regimen: 
 
All patients fitting the recruitment criteria will undergo 2mg aflibercept administered at baseline (day 1) and 
weeks 4 and 8 (loading phase) followed by: 
 
1. 
Fixed dosing group (2Q8): fixed doses at 8 week intervals through to week 52 
 
2. 
Treat and Extend group (T&E): Reassessment at week 12 (month 3) by repeat examination for 
disease activity by OCT and ICGA.  Subsequent treatment regime will depend on disease activity at 
this point. 
 
a. If disease is considered inactive, as defined by a dry OCT and complete polyp closure on ICGA, 
patients will undergo a treat and extend protocol.  The next dose would occur at week 16 (8 week 
interval from last dose at week 8) and each subsequent dose and visit will be extended by 2 weeks 
up to a maximum interval of 12 weeks and minimum interval of 8 weeks between treatments if 
disease remains quiescent.  If signs of activity are noted at any visit point, dose and visit interval 
will be reduced by 2 weeks. (Activity is signified by subretinal or intra retinal fluid and/or blood seen 
on OCT or clinical examination.) 
 
b. If disease is still active, patients will receive additional doses at week 12, week 16 and week 20 
(intensive loading). Thereafter, patients will start on the treat and extend protocol as described 
above. 
 
 


PCVTnE Study Protocol Version 5.0_Dated 26 July 2019 
Page 8 of 17 
 
 
Study Visits and Procedures 
 
Screening Evaluation  
Historical Information  
A history will be elicited from the potential study participant and extracted from available medical records. 
Data to be collected will include: age, gender, ethnicity and race, past medical history and medications being 
used, as well as ocular diseases, surgeries, and treatment. 
 
An assessment of visual related quality of life will be performed using the impact of visual impairment (IVI) 
questionnaire. 
 
Screening Testing Procedures  
The following procedures are needed to assess eligibility and/or to serve as baseline measures for the study.  
 
If a procedure has been performed (using the study technique and by delegated personnel) as part of usual 
care, it does not need to be repeated specifically for the study if it was performed within the defined time 
(within 21 days prior to baseline) windows specified below. 
 
1. 
Best-corrected Visual Acuity: BCVA will be measured using the ETDRS VA protocol following 
manifest refraction. 
2. 
Optical Coherence Tomography/ OCT Angiography: OCT and OCTA will be performed. Both 
standard and enhanced depth imaging scans will be performed. 


PCVTnE Study Protocol Version 5.0_Dated 26 July 2019 
Page 9 of 17 
3. 
Ocular examination on each eye including slit lamp, measurement of intraocular pressure, lens 
assessment, and dilated ophthalmoscopy (within 21 days prior to randomization). 
4. 
Fundus Photography  
5. 
Fundus fluorescein and Indocyanine Green angiography: FFA and ICGA will be performed. 
 
Disease characteristics of the study eye assessed by the investigator at screening (visit 1):  
 
Diagnosis of PCV based on ICGA.  
 
Presence of activity clinically as evidence by presence of haemorrhage, edema. 
 
Presence of activity as evidence by intra retinal or sub retinal fluid on OCT. 
 
Visit Schedule 
 
All patients will have visits at screening, baseline (day 1), and every 4 weeks until week 8.  Subsequent visits 
will depend on regime arm and disease activity as assessed at week 12. 
 
Maximum and minimum visits are summarised in the table 2 below. 
 
1 year after study completion 
 
Medical records inclusive of VA, treatment received and ocular imaging scans such as OCT, OCTA, Fundus 
photography, FFA and ICGA will be reviewed. 
 
 
Table 1: Study Visits & Procedures 
 
Study Procedure 
 
Last visit 1 year after 
completion 
Visit  
1 
(Screen) 2(BL) 3 
4 
5 
 
 
7(8^) 6(7^)-N 
N+1 
 
Month 
0 
0 
1 
2 
3 
4 
5 
6 
6-12 
12 
 
Week 
- 3 to 0 
0 
4 
8 
12 
16 
18 24-52 12-52 
52 
 
Day ( 7), except Visit 
2 (3) 
-21 to 0 
1 
29 57 85 113 127 
141 113-337 
365 
 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
Questionnaires  
 
 
 
 
 
 
 
 
 
 
 
Medical / ophthalmic 
history 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion 
 
 
 
 
 
 
 
 
 
 
 
Study drug injection 
 
 
 
 
 
 
 
 
 
 
 
    Fixed dosing arm 
 
 
 
 
Fixed dosing every 8 weeks 
 
 
    T&E: Complete 
closure at month 3 
 
 
 
 
 
Treat and Extend 
X 
X 
X 
X 
 
 


PCVTnE Study Protocol Version 5.0_Dated 26 July 2019 
Page 10 of 17 
    T&E: Incomplete 
closure at month 3 
 
 
 
 
* * 
* 
Treat and 
Extend 
 
 
BCVA LogMAR letter 
score 
   
   
 
 
 
 
 
At every 
visit   
 
 
 
At every 
visit 
 
 
Indirect 
ophthalmoscopy
 
 
 
 
 
 
 
 
Slit lamp 
 
 
 
 
 
 
 
 
IOP  
 
 
 
 
 
 
 
 
OCT 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
Colour FP  
 
- 
 
 
 
- 
- 
 
- 
 
 
FA  
 
- 
- 
- 
 
- 
- 
 
- 
 
 
ICGA 
 
- 
- 
- 
 
- 
- 
 
- 
 
 
Review of medical 
record 
 
 
 
 
 
 
 
 
 
 
 
BL – Baseline visit 
Screen – screening visit 
 Will occur 
* If PCV is active at week 12, 3 more injections will be administered increasing visit by 1 within first 24 weeks 
(see MAX treatment table 2) 
 
Screening (visit 1) and baseline (visit 2) can be done on the same day at PI/ Co-I discretion.  
 
Table 2: schedule of procedures 
 
 
Table 3: maximum and minimum visits including intravitreal injections for each regime 
 
Regime 
VISITS/PATIENT INJECTIONS/PATIENT 
T&E (N =39) 
Minimum 
11 
7 
Maximum 
12 
9 
Q8 (N=13) 
11 
8 
 
Treatment Procedures 
 
Intravitreal Injections 
 
Aflibercept (Eylea) 


PCVTnE Study Protocol Version 5.0_Dated 26 July 2019 
Page 11 of 17 
Study eyes will receive a dose of 2mg in 0.05 ml of aflibercept. 
 
Intravitreal Injection Technique  
Antibiotics in the pre-, peri-, or post-injection period are not necessary but can be used at investigator 
discretion if such use is part of his/her usual routine. 
 
Prior to the injection, the study eye will be anaesthetized with topical anesthetic, followed by a povidone iodine 
prep of the conjunctiva. (Instill 5% povidone iodide on to the ocular surface and allow adequate time prior to 
injection)  
 
The injection will be performed using sterile technique. Investigator will use a surgical hand disinfection 
technique and wear sterile gloves. Periocular skin and eyelid margins and eye lashes will be cleaned with 5-
10% povidone iodine. 
 
Skin will be dried and drape will be applied. Investigator will insert eyelid speculum, ensuring that it is well 
positioned underneath the eyelids to direct the eyelashes away from the field. Callipers should be used to 
mark the injection site. The entry site of the needle should be 3.0-3.5 mm from the limbus in pseudophakic 
patients, and 3.5-4.0 mm in phakic patients.  
 
The conjunctiva may be displaced anteriorly using either forceps or cotton tipped applicator so that no direct 
route between vitreous and ocular surface remains. The needle is inserted perpendicular through sclera with 
the tip aimed towards the centre of the globe (to avoid any contact with the posterior lens).  
 
IOP measurement post-injection is not mandatory. While small volume injections (0.05ml) are unlikely to 
cause IOP rise, it should be considered in patients with ocular hypertension or glaucoma, and in all cases 
where patients are symptomatic for pain or reduced vision immediately following injection. Should a high 
intraocular pressure resulting in non-perfusion of the central retinal artery occur, indicated by no perception 
of light (NPL) in the treated eye, an anterior chamber paracentesis is indicated. Such decompression needs 
to be achieved within 3-5 minutes. Patients should be instructed to report any symptoms regarding eye pain 
or discomfort, increased redness of the eye, or additional blurring of vision (which may indicate 
endophthalmitis) to the treating ophthalmologist without delay. 
 
Delay in Giving Injections  
If a scheduled injection is not given on the day of study visit, it may be administered within 7 days after the 
occurrence of the study visit. If it is not given by that time, it will be considered missed. If an injection is given 
late, the next scheduled injection should occur no sooner than three weeks after the previous injection. 
 
Non-Study Eye Injections  
If the non-study eye is going to be treated for any condition which requires treatment with an anti-VEGF agent, 
it may be treated at the discretion of the investigator. Treatment of the fellow-eye with aflibercept is possible.  
 
Treatment Regimen Adjustments 
If the study eye develops a treatment-related adverse event at any time during the study, treatment dose may 
be temporarily held and the reason for dose holding will be recorded in the CRF. 
 
The treatment regimen will be adjusted based on the following criteria: 
 
• Intraocular inflammation: may hold dose at the investigator’s discretion, eg, if intraocular 
inflammation is >= 2+ in the study eye. Treatment may resume when the inflammation has resolved. 
 
• IOP: hold dose if IOP is >= 30 mm Hg in the study eye. Treatment may resume when IOP is <= 30 
mm Hg, either spontaneously or by treatment, as determined by evaluating physician. 


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• New retinal break or retinal detachment: hold dose for the study eye. Treatment may resume after 
the retinal break/detachment had been successfully treated. 
 
• Ocular and/or periocular infection: hold dose until the infection is resolved in both eyes. 
 
The investigator may hold or discontinue study treatment for other safety reasons at his/her discretion. 
 
Warnings and Precautions 
 
Injection Procedure-related Reactions 
 
Treatments such as aflibercept that are administered via intravitreal injections can be associated with a 
number of adverse events. These include conjunctival haemorrhage, conjunctival hyperaemia, eye irritation, 
eye pain, eye pruritus, endophthalmitis, foreign body sensation in eyes, intraocular inflammation, 
rhegmatogenous retinal detachment, retinal tear, increases in IOP, vitreous detachment, and iatrogenic 
traumatic cataract. 
 
 
Intraocular Inflammation, Endophthalmitis, and Retinal Detachments 
 
Intravitreal injections have the potential to be associated with intraocular inflammation, infectious and non-
infectious endophthalmitis, and retinal detachments which could be sight-threatening. Proper aseptic injection 
technique should always be used when administering aflibercept. In addition, patients should be 
monitored following the injection to permit early treatment should inflammation, infection, or 
retinal detachment occur. Patients should be informed that in the days following administration of aflibercept 
intravitreally, patients are at risk for the development of endophthalmitis. If the eye becomes red, sensitive to 
light, painful, or develops a worsening in vision, the patient should seek immediate care with their 
ophthalmologist.  
 
Increases in Intraocular Pressure 
 
Increases in IOP have been noted following intravitreal injection with anti-VEGF agents. The increase in IOP 
is typically transient in nature and is probably due to the volume increase in the eye after injection. Therefore, 
IOP as well as the perfusion of the optic nerve head should be monitored and managed appropriately 
following the intravitreal injection. 
 
 
Cataract Formation 
 
Intravitreal injections have the potential to be associated with iatrogenic traumatic cataract formation. 
 
 
Anti-VEGF Agents Class Effects 
 
Hypertension, non-ocular hemorrhage and thromboembolic events have been reported with systemic anti-
VEGF therapy. There is a potential risk of arterial thromboembolic events following intravitreal use of inhibitors 
of VEGF. Arterial thromboembolic events are defined as nonfatal stroke, nonfatal myocardial infarction, or 
vascular death (including deaths of unknown causes). 
 
Study Participant Withdrawal and Losses to Follow-up  
 


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A study participant has the right to withdraw from the study at any time. If a study participant is considering 
withdrawal from the study, the principal investigator should personally speak to the individual about the 
reasons, and every effort should be made to accommodate him or her.  
 
Study participants who withdraw will be asked to have a final closeout visit at which the testing described for 
the protocol visits will be performed. Study participants who have an adverse effect attributable to a study 
treatment or procedure will be asked to continue in follow-up until the adverse event has resolved or stabilized.  
 
Discontinuation of Study  
 
The study may be discontinued by the Data and Safety Monitoring Committee [DSMC] prior to the preplanned 
completion of follow-up for all study participants. 
 
Study Participant Reimbursement  
 
The study will be providing the study participant with $20.00 per completed protocol visit to cover travel and 
other visit-related expenses.  
 
6. 
SAFETY MEASUREMENTS 
6.1. 
Definitions 
Serious adverse event (SAE) in relation to human biomedical research, means any untoward medical 
occurrence as a result of any human biomedical research which: 
 
results in or contributes to death 
 
is life-threatening 
 
requires in-patient hospitalisation or prolongation of existing hospitalisation 
 
results in or contributes to persistent or significant disability/incapacity or 
 
results in or contributes to a congenital anomaly/birth defect 
 
results in such other events as may be prescribed  
 
Adverse event (AE) in relation to human biomedical research means any untoward medical 
occurrence as a result of any human biomedical research which is NOT serious.  Adverse event 
can be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease possibly/ probably/ definitely associated with the participant in the human 
biomedical research. 
 
6.2. 
Collecting, Recording and Reporting of Adverse Events and Serious Adverse Events to CIRB 
 
Reporting of adverse events involves the Principal Investigator submitting to CIRB the SAE Reporting 
Form to CIRB within the stipulated timeframe. The Principal Investigator is responsible for informing 
the institution representative, the chairman medical board (when required by the institution for local 
SAE resulting in death), sponsor or regulatory bodies as required and appropriate. 
 
Reporting timeline to CIRB:  
 
 
Local unexpected SAE resulting in death that are related events should be reported 
immediately - within 24 hours of the Principal Investigator becoming aware of the event.  
 
Local unexpected, life-threatening SAE that are related events should be reported as soon as 
possible but no later than 7 calendar days after the Principal Investigator is aware of the event, 
followed by a  full report within 8 additional calendar days. 


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 
Local unexpected, not life-threatening SAE that are related events, should be reported no later 
than 15 calendar days after the Principal Investigator is aware of the event. 
 
An increase in the rate of occurrence of Local expected SAE that are related events, which is 
judged to be clinically important, should be reported within 15 calendar days after the Principal 
Investigator is aware of the event.  
 
Local unexpected AE that are related events should be reported at least annually (together 
with Study Status Report for annual review). 
Non-local unexpected SAE that are fatal or life threatening and related should be reported not later than 30 
calendar days after the Principal Investigator is aware of the event. 
The review will be done on a monthly basis for Standard Aggregate Adverse Event (AE) Safety Data reports.  
 
The following standard aggregate AE safety data reports will be reviewed: 
 
Number and percentage of enrolled subjects reporting adverse events (AEs) by body system (i.e., 
primary system organ class) and preferred term in descending frequency order 
 
Serious Adverse Events (SAE) (treatment or procedure related and not related)-Cumulative 
 
All AEs  
 
The following reports of additional study-specific data will be reviewed: 
1. Targeted adverse events  
 
Intraocular inflammation/infection including AC inflammation, uveitis, vitritis, iritis, iridocyclitis, 
choroiditis, retinal vasculitis and endophthalmitis  
 
Visual acuity reduced  
 
Intraocular pressure increase  
 
Retinal tear  
 
Retinal detachment 
 
Vitreous haemorrhage 
 
Retinal haemorrhage  
 
Macular scar 
 
Systemic VEGF inhibition 
 
2. Biomicroscopy/ indirect ophthalmoscopy ( by visit per subject)  
 
≥ 2 grade increase in each separate parameter (Corneal edema, Conjunctival hyperemia, Anterior 
chamber cells, Anterior chamber flare, Keratic precipitates, Vitreous cells, Vitreous flare/haze) and 
documented changes in vitreous, optic disc and retina from baseline.     
  
3. Best corrected visual acuity (by visit per subject) 
 
≥ 15 letters decrease from baseline at any visit  
 
6.3. 
Safety Monitoring Plan 
A Data and Safety Monitoring Committee will approve the protocol, template informed consent form, 
and substantive amendments and provide independent monitoring of adverse events. Cumulative 
adverse event data are semi-annually tabulated for review by the DSMC. Following each DSMC 
data review, a summary will be made available for submission to Institutional Review Board. A list 
of specific adverse events to be reported to the DSMC expeditiously will be compiled and included 
as part of the DSMC Standard Operating Procedures. 
 
 
6.4. 
Complaint Handling  
Complaints will be handled by the PI and study coordinators and if required the Quality Assurance 
team at the Singapore National Eye Centre  


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7. 
DATA ANALYSIS 
7.1. 
Data Quality Assurance 
The Investigator(s)/ Singapore National Eye Centre will permit study-related monitoring audits, 
MCRC and or EC review and regulatory inspection(s), providing direct access to source data/ 
document. 
 
7.2. 
Data Entry and Storage 
Research data will be stored in excel/ word format and encrypted with password. It will be kept in 
controlled shared folder where confidentiality and participant privacy will be maintained. The data will 
be coded and the participants will be de-identified and the master list will be encrypted with the 
password. Case files will be under lock and key, with restricted access to the key, as defined within 
the study delegation log. 
 
8. 
SAMPLE SIZE AND STATISTICAL METHODS 
8.1. 
Determination of Sample Size  
Mean difference of Best corrected visual acuity at month 12 will be compared between treatment arms 
looking for non inferiority between treat and extend regimen and fixed dosing regimen. 
 
T test will be used to assess the change in mean BCVA between groups. 
 
Primary outcome: BCVA as outcome  
Assumptions: 
1. No prior data available for T&E regiment for treatment of PCV with Aflibercept 
2. Mean Standard deviation of difference of letters between baseline and final outcome in VAULT 
study is 4.1 letters  
3. 3:1 N ratio of T&E versus fixed dosing  
Based on the above assumptions with 80% power and 95% confidence, 
If n=13 for fixed dosing (total n = 52) 
Minimum difference of 3.9 letters can be shown  
 
Secondary Outcome: Proportion of closure as outcome 
Assumptions: 
1. Based on PLANET study results, we estimate the polyp closure rate in the fixed dosing arm will 
be 40% (Monotherapy closure rate). 
2. 3:1 N ratio of T&E versus fixed dosing 


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3. Non inferiority margin, δ set at 10%* 
*statistically significant differences between the proportions may not be of interest unless the 
difference is greater than a threshold, δ 
To detect polyp closure rate of 70% in the T&E arm, with 80% power and 95% confidence, we 
submit that a sample size of 39 in the T&E arm will be required. 
 
8.2. 
Statistical and Analytical Plans 
The proportion of study patients achieving positive response in primary outcome will be estimated with 
95% confidence interval. Summary statistics will be tabulated to describe patient demographics and 
characteristics. Statistical analysis will be performed using standard statistical software. Outcome at 
month 12 will be compared to baseline. In addition, we will use linear mixed-effect model to analyze 
longitudinal data of visual acuity over the first year to account for the repeated measurements on the 
same eye. Both random and fixed effects of number of injections will be added to control the 
heterogeneous effect among eyes. Stepwise model selection (forward and backward selection) will 
be performed to investigate the effect on visual acuity at month 12, from a set of variables, including 
age, gender, vision at baseline and follow up, change of vision and OCT thickness. Binary or linear 
regression analysis with multivariate models will be performed on imaging features to determine 
association with 12 month visual outcomes. 
 
9. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator(s)/institution(s) will permit study-related monitoring, audits and/or IRB review and 
regulatory inspection(s), providing direct access to source data/document. 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator(s)/ Singapore National Eye Centre will permit study-related monitoring audits, MCRC 
and or EC review and regulatory inspection(s), providing direct access to source data/ document. 
 
11. 
ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with the ICH E6 Guideline for Good Clinical Practice 
(GCP) and the applicable regulatory requirements. 
 
This final study protocol, including the final version of the Participant Information Sheet and Consent 
Form, must be approved in writing by the Centralised Institutional Review Board (CIRB), prior to 
enrolment of any patient into the study. 
 
The principal investigator is responsible for informing the CIRB of any amendments to the protocol or 
other study-related documents, as per local requirement. 
 
11.1. Informed Consent 
Potential eligibility will be assessed as part of a routine-care examination. Prior to completing any 
procedures or collecting any data that are not part of usual care, written informed consent will be 
obtained. For potential study participants who are considered potentially eligible for the study based 
on a routine-care exam, the study protocol will be discussed with the potential study participant by a 
study investigator and study coordinator. The potential study participant will be given the Informed 
Consent Form to read. Potential study participants will be encouraged to discuss the study with family 
members and their personal physician(s) before deciding whether to participate in the study. 
 


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11.2. Confidentiality of Data and Patient Records 
Research data will be anonymized as soon as possible and both identification key and the de-identified 
data will store in separate folders in the SERI access-controlled shared folders. Case files will be kept 
under lock and key, with restricted access to the key, as defined within the study delegation log. 
 
12. 
PUBLICATIONS 
Please refer to the SERI publication policy 
 
13. 
RETENTION OF STUDY DOCUMENTS 
The research data will be stored for at least 15 years and then destroyed/deleted. 
 
14. 
FUNDING and INSURANCE 
Grant funding from NMRC CTG-ICT.