An Open Label-study to Compare the Efficacy of Aflibercept Monotherapy for Polypoidal Choroidal Vasculopathy

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Age Related Macular Degeneration, Polypoidal Choroidal Vasculopathy

Intervention / Treatment
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* Drug: Treat and Extend with Aflibercept 2mg
* Drug: Fixed Dosing with Aflibercept 2mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Participant Male or female study participants, age >=45 years of age at the time of informed consent. Best corrected ETDRS visual acuity score <= 78 (ie 20/32 or worse) Diagnosis of PCV based on ICGA Presence of intra retinal or subretinal fluid/blood at the fovea as seen on OCT Treatment naïve Media clarity, pupillary dilation and individual cooperation sufficient for study procedure including fundus photography. Able and willing to provide informed consent. 1.2. Exclusion Criteria Participant 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 glycemic control). Participation in an investigational trial within 30 days of enrolment which involves treatment with unapproved investigational drug Known allergy to any component of the study drug. 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. 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. Systemic anti-VEGF or pro-VEGF treatment within four months prior to randomization or anticipated use during the study. Study Eye Eye with intra retinal or subretinal fluid due to other causes than PCV 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., diabetic macula edema (DME), vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.) 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). Any intraocular surgery within 3 months of enrollment Treatment with intra vitreal corticosteroids History of retinal detachment or surgery for retinal detachment History of vitrectomy History of macular hole Evidence of vitreomacular traction that may preclude resolution of macular edema > 4 disc areas of intra/sub retinal hemorrhage Aphakia Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis Other Eye Active intraocular inflammation History of uveitis

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, 2-arm, Non-inferiority, interventional study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fixed dosing group (2Q8)<br>Fixed Dosing with Aflibercept 2mg will be administered at a fixed regime at 8 week intervals through to week 52. | Drug: Fixed Dosing with Aflibercept 2mg<br>* Fixed 8 weekly dosing regime throughout the study duration<br>* Other names: 2Q8;|
| Experimental: Treat and Extend group (T&E)<br>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. | Drug: Treat and Extend with Aflibercept 2mg<br>* Drug treatment regime which allows extension of treatment interval based on disease activity<br>* Other names: T&E;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Best Corrected Visual Acuity (BCVA) | Mean Change in Best corrected visual acuity (BCVA) from baseline to week 52 for personalized and fixed regimen. it is a Non-inferiority of personalized to fixed regimen for mean change in BCVA from baseline to week 52 (Non-inferiority is considered as -5 ETDRS Letters difference ) | From Baseline to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Central Sub Field Thickness | central sub field thickness (CSFT) was defined as the average thickness of the macula in the central 1 mm ETDRS grid. Defined as the thickness from the inner retinal boundary at the location of the inner limiting membrane (ILM) to the outer retinal boundary at Bruch's membrane (BM). Change in the central sub field thickness (CSFT) after the treatment was assessed , the measurement was done by optical coherence tomography (OCT). the measures were taken at baseline and week 52, the change between the two measurements ( baseline to week 52) were assessed in both groups to understand the effect of treatment on CSFT | From Baseline to Week 52 | 
| Number of Participants With Complete Polypoidal Lesion Closure | This measure reports the Number of participants with complete polypoidal lesion closure defined as those showing no late leakage on Indocyanine green angiography (ICGA). | At Week 52 | 
| Number of Injections | number of aflibercept injections administered in personalised and fixed groups | From Baseline to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti vegf, aflibercept, treat and extend