Prospective Observational Study to Assess Effectiveness of Intravitreal Aflibercept in Patients With Wet Macular Degeneration in Greece
Condition: Choroidal Neovascularization; Macular Degeneration
MeSH terms: Macular Degeneration; Choroidal Neovascularization; Neovascularization, Pathologic
Study type: Observational

Summary: 
      This is a prospective, observational, multi-center, study. The study will be conducted in
      approximately 12 ophthalmological clinics and practices throughout Greece. It is planned to
      collect data on treatment of wet Age related Macular Degeneration (wAMD) from about 120
      patients for which the decision to treat with intravitreal aflibercept injections is made at
      the discretion of the attending physician, according to his/her medical practice. Visits will
      be performed at baseline, aflibercept first injection (if different from enrollment) and at
      12 and 24 months. The 12 and 24 month comprise the data collection visits during which any
      data generated in the period preceding these visits will be recorded.

      All required information for the purposes of this study will be collected using electronic
      Case Record Form (eCRF). The web-based electronic data capture (EDC) application will be
      specifically designed for the needs of the study and will adhere to all applicable data
      protection regulations and requirements with regard to electronic records.

      The study observation period for each patient enrolled in this study is the time from the
      beginning of treatment with intravitreal aflibercept injection up to two years or until
      discontinuation of intravitreal aflibercept injection-treatment due to any reason including
      withdrawal of consent or patient loss from follow-up.
    

Detailed description: 
      Rationale and background Age-related macular degeneration (AMD) is the most common
      degenerative disease of the macula and the most common cause of legal blindness in the
      Western world. AMD is a disease of the elderly affecting 10% of individuals aged 65 to 74
      years and 30% of those aged 75 to 85 years. Two forms of AMD can be distinguished. The dry
      form is more benign accounting for 90% of all AMD cases, but only for 10% of cases of
      blindness due to AMD. On the other hand wet AMD affects only 10% of AMD patients. However, it
      is more aggressive and rapidly progresses. Wet AMD (wAMD) accounts for 80% of cases of severe
      visual impairment and represents the majority of cases of legal blindness. Thus, wet or
      neovascular AMD is a disease with a great impact on both visual acuity and patients' quality
      of life.

      About 1% of the population is affected by wAMD between 65-74 years of age, 5% between 75-84
      years of age and 13% in people 85+ years. Given that wAMD is a strongly age-dependent disease
      its prevalence is expected to significantly increase in western countries (including Greece)
      in the near future. Therefore, early diagnosis and proper treatment will be a major public
      health concern.

      AMD is diagnosed by stereoscopic biomicroscopy and additional examinations of the macula,
      such as fluorescein angiography (FA), indocyanine green angiography (ICGA) and optical
      coherence tomography (OCT). The patient's visual status can be monitored with the Snellen
      chart and Early Treatment Diabetic Retinopathy Study (ETDRS) chart, the Snellen chart being
      most often used in Greece.

      Wet AMD is caused by choroidal neovascularization (CNV) whereby new abnormal blood vessels
      spread beneath the retina. These vessels may rupture and cause retinal damage. In addition,
      vascular leakage may cause thickening and oedema of the retina, which is thought to
      contribute to vision loss. Vascular endothelial growth factor (VEGF) and placental growth
      factor (PlGF) play a pivotal role in this scenario. VEGF-A and PlGF are members of the VEGF
      family of angiogenic factors that act as potent mitogenic, chemotactic, and vascular
      permeability factors for endothelial cells. VEGF acts via two receptor tyrosine
      kinases-VEGFR-1 and VEGFR-2-which are located on the surface of endothelial cells. PlGF binds
      only to VEGFR-1, which is also present on the surface of leukocytes. Excessive activation of
      these receptors by VEGF-A can induce pathological neovascularization and excessive vascular
      permeability. PlGF can synergize with VEGF-A in these processes, and is also known to promote
      leukocyte infiltration and vascular inflammation.

      Treatment paradigms for wet AMD have changed tremendously since anti-VEGF treatment
      (inhibition of all VEGF-A Isoforms) was introduced. As a consequence, most previous therapy
      approaches lost significance and are applied in rare cases only. The pan-anti-angiogenesis
      treatment with ranibizumab was the first to show significant improvements in visual acuity of
      patients suffering from wAMD, thus becoming the first-choice therapy for most patients. The
      phase III clinical trials MARINA and ANCHOR have shown that ranibizumab applied every month
      is highly effective in improving visual impairment. However, in addition to the small risk of
      endophthalmitis associated with intravitreal injections, monthly treatment, which may
      continue for a patient's lifetime, is extremely burdensome to patients, their caregivers,
      ophthalmologists and the healthcare system. As a consequence, in clinical practice the
      monthly treatment regimen of ranibizumab is often altered to less frequent dosing intervals
      to reduce the associated treatment burden, although this may result in notably reduced
      efficacy.

      Results from observational studies such as WAVE and AURA, which investigated wAMD patients
      treated with Lucentis (ranibizumab) in a real life setting in western countries, suggest that
      these patients are not treated according to a continuous treatment pattern and are also
      undertreated resulting in suboptimal treatment effects. In the WAVE Study (n=2587) patients
      received 4.3 injections during the first treatment year and the visual acuity returned to the
      baseline visual acuity at the end of the year. In the AURA study (n=420), German cohort,
      patients received 4.3 injections in the first year and only 2.1 injections during the second
      year. The visual acuity declined during year 1 to -1.4 letters and further declined to -2.4
      letters during year 2 compared to baseline. In the AURA study (n =365), Italian cohort,
      patients received 3.9 injections in the first year and only 1.4 injections during the second
      year. The visual acuity declined during year 1 to 0 letters and further declined to -2.9
      letters during year 2 compared to baseline .

      Intravitreal aflibercept is the next generation of anti-angiogenesis treatments which also
      introduces a new proactive every-other-month treatment regimen (after 3 monthly injections)
      in the first year, followed by individually extended treatment intervals afterwards.
      Aflibercept is a fusion protein consisting of portions of human VEGF receptors 1 and 2
      extracellular domains fused to the Fc portion of human IgG1. It is purified and formulated as
      a solution for intravitreal use. As such, aflibercept acts as a soluble decoy receptor that
      binds VEGF-A and PlGF with higher affinity than naturally occurring VEGF receptors. Thus
      aflibercept competitively inhibits VEGF-A and PIGF binding to the cognate VEGF receptors and
      their activation.

      Intravitreal aflibercept was recently approved by the European Medicines Agency (EMA) in
      November 2012. The aims of this study are to collect data on the effectiveness of
      intravitreal aflibercept and to evaluate follow-up as well as treatment patterns in treatment
      naive patients with wAMD in routine clinical practice in Greece treated with intravitreal
      aflibercept injection.

      Research questions and objectives The main objectives of this observational study are to
      evaluate the effectiveness of intravitreal aflibercept injection and to describe routine
      clinical practice monitoring and treatment patterns in treatment-naïve wAMD patients in
      Greece.

      Primary objective

      The primary objective in this study is:

        -  To evaluate the effectiveness of intravitreal aflibercept injection by assessing the
           change in best corrected visual acuity (BCVA; defined as visual acuity with manifest
           refraction) from baseline at the 12-month timepoint, in treatment naive patients with
           wAMD in routine clinical practice in Greece.

      Secondary objective(s)

      The secondary objectives in this study are:

        -  To evaluate the effectiveness of intravitreal aflibercept injection by assessing the
           change in BCVA (with manifest refraction) from baseline at the 24-month timepoint

        -  To evaluate the effectiveness of intravitreal aflibercept injection by assessing the
           change in visual acuity with glasses from baseline to the 24-month timepoint

        -  To assess the change in central retinal thickness at 12 and 24 months

        -  To assess the proportion of patients with no fluid at 12 and 24 months

        -  To assess the disease activity monitoring patterns and the treatment patterns used in
           routine clinical practice (e.g. number of evaluation visits, injection visits, combined
           visits, OCT tests, visual acuity tests, fundoscopy tests, Fluorescein Angiography (FA)
           and Indocyanine Green Angiograpy (ICGA tests).
    

Intervention name(s): Aflibercept (Eylea, BAY86-5321)
Intervention type(s): Drug
Intervention description(s): Intravitreal injection; should comply with the recommendations written in the local Summary of Product Characteristics (SPC) of the product
Other intervention name(s): VEGF Trap-Eye
Intervention MeSH terms: Aflibercept
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        The study population consisted of patients treated with Aphlibercept as first treatment for
        wAMD ( Treatment Naïve Patients).
      
Keywords: Treatment Naïve Patients