An Open Label-study to Compare the Efficacy of Aflibercept Monotherapy for Polypoidal Choroidal Vasculopathy
Condition: Age Related Macular Degeneration; Polypoidal Choroidal Vasculopathy
MeSH terms: Macular Degeneration; Polypoidal Choroidal Vasculopathy; Vascular Diseases
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Treat and Extend with Aflibercept 2mg; Fixed Dosing with Aflibercept 2mg
Intervention type(s): Drug; Drug
Intervention description(s): Drug treatment regime which allows extension of treatment interval based on disease activity; Fixed 8 weekly dosing regime throughout the study duration
Other intervention name(s): T&E; 2Q8
Intervention MeSH terms: Aflibercept
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Prospective, 2-arm, Non-inferiority, interventional study
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: anti vegf; aflibercept; treat and extend