Treat-and-extend Regimen of Aflibercept in Diabetic Macular Edema (VIBIM Study)

Study Overview
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Brief Summary
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Efficacy of Treat-and-extend regimen (TER) using aflibercept in diabetic macular edema (DME) will be evaluated.

Detailed Description
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Efficacy of aflibercept for diabetic macular edema was demonstrated in the phase III, VIVID and VISTA studies. In these studies, aflibercept was injected using the fixed dosing regimen that an intravitreal injection was performed 5 times every 4 weeks and then every 8 weeks. Although the efficacy was comparable to that of ranibizumab injected every 4 weeks, continuous visits and treatments account for quite a burden. TER is regarded as a alternative regimen that may reduce visit and treatment numbers for age-related macular degeneration. TER is a variable dosing regimen that an injection interval is adjusted based on the treatment response. The aim of this study is to evaluate efficacy of TER using aflibercept for DME, by assessing changes of visual acuity at 104 weeks compared to baseline.

Official Title
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Single Arm, Single Dose Clinical Study to Investigate Efficacy of Treat-and-Extend Regimen of Intravitreal Aflibercept Injection in Diabetic Macular Edema

Conditions
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Macular Edema, Diabetic

Intervention / Treatment
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* Drug: aflibercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type I or II diabetes older than 18 years old Patients with DME secondary to diabetes mellitus involving the center of the macula (defined as CSMT >= 300μm measured using OCT) in the study eye. Decreased visual acuity to 20/40 - 20/300 to be primarily the results of DME in the study eye. Willing and able to comply with clinic visits and study-related procedures, and provide a signed informed consent form. Exclusion Criteria: History of vitreoretinal surgery including scleral buckling in the study eye. Laser photocoagulation (panretinal or macular) in the study eye within 90 days of day 1. More than two previous macular laser treatments in the study eye. Previous use of intraocular or periocular corticosteroids in the study eye within 120 days of day 1. Previous treatment with anti-angiogenic drugs in the study eye within 90 days of day 1. Active proliferative diabetic retinopathy in the study eye. History of idiopathic or autoimmune uveitis in the study eye. Cataract surgery within 90 days before day 1 in the study eye. Aphakia in the study eye. Yttrium-aluminium-garnet capsulotomy in the study eye within 30 days before day 1. Vitreomacular traction or epiretinal membrane in the study eye evident biomicroscopically or on OCT that is thought to affect central vision. Current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment in the study eye. Structural damage to the center of the macula in the study eye that is likely to preclude improvement in best-corrected visual acuity (BCVA) following the resolution of macular edema including atrophy of the retinal pigment epithelium, subretinal fibrosis or scar, significant macular ischemia or organized hard exudates. Evidence of infection including infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye. Uncontrolled glaucoma in the study eye (>25mmHg) or filtration surgery and/or valve surgery for glaucoma in the past on the study eye. Myopia of a spherical equivalent prior to any possible refractive or cataract surgery of ≥ -8 diopters. Concurrent disease in the study eye, other than DME, that could compromise VA, require medical or surgical intervention during the study period, or could confound interpretation of the results (including retinal vascular occlusion retinal detachment, macular hole, or choroidal neovascularization of any cause). Ocular media of insufficient quality to obtain fundus and OCT images. Current treatment for a serious systemic infection. Administration of systemic anti-angiogenic agents within 180 days before day 1. Uncontrolled diabetes mellitus in the opinion of the investigator (VISTA) or as defined by hemoglobin A1c >12%. Uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic > 95 mmHg while patient is sitting). History of either cerebral vascular accident and/or myocardial infarction within 180 days prior to day 1. Renal failure requiring dialysis or renal transplant. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, might affect interpretation of the results of the study, or renders the patient at high risk for treatment complications. Pregnant or breast-feeding women. Sexually active men or women of childbearing potential who are unwilling to practice adequate contraception during the study. Allergy to fluorescein. Patients with hypersensitivity to study drug or excipients. Participation in an investigational study within 30 days prior to screening visit that involved treatment with any drug (excluding vitamins and minerals) or device.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treat-and-extend<br>Aflibercept 2mg is injected into the vitreous cavity. An injection is given every 4 weeks five times and then the Treat-and-Extend process begins. If 1mm central subfield macular thickness (CSMT) improved (10% or more reduction) compared to the previous visit, the next treatment will be performed at the same interval. If CSMT is maintained (less than 10% changes), the next interval will be extended by two weeks (up to 12 weeks). If CSMT is worsened (10% or more increase), the next interval will be shortened by two weeks (minimum 4 weeks). If CSMT is stable two times at 12 weeks-interval, the injection will be deferred, and the next visit will be 8 weeks later. These process will be continued for 2 years. | Drug: aflibercept<br>* Aflibercept 2mg is injected into the vitreous cavity through the pars plana using 30 gauge needle-attached syringe.<br>* Other names: Eylea, VEGF Trap-Eye;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in visual acuity from baseline to 104 weeks | Visual acuity is assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The ETDRS chart includes 100 letters as the maximum possible score, and 0 letters read as the minimum possible score. Visual acuity of 85 letters is equivalent to 20/20. Higher scores represents better functioning. | baseline and 104 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in visual acuity from baseline to 52 weeks | Visual acuity is assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The ETDRS chart includes 100 letters as the maximum possible score, and 0 letters read as the minimum possible score. Visual acuity of 85 letters is equivalent to 20/20. Higher scores represents better functioning. | baseline and 52 weeks | 
| Changes in CSMT from baseline to 104 weeks | CSMT is central 1mm thickness of the macula measured using spectral-domain optical coherence tomography (OCT). Normal thickness is around 250μm. Increased CSMT is regarded as presence of macular edema. | baseline and 104 weeks | 
| Number of injections for 52 and 104 weeks | How many injections are performed from baseline to 52 and 104 weeks. | 52 and 104 weeks | 
| Injection interval | The interval is calculated for the next visit based on the treatment response. The range is between 4 and 12 weeks. | 52 and 104 weeks. | 
| Percentage of patients with injection interval of 12 weeks or more | Patients whose injection interval is extended to 12 weeks more include the patients that the next visit was calculated as 12 weeks and those that the injection was deferred in the previous visit. | 104 weeks. | 
| Percentage of patients that visual acuity increased 15 letters or more | Visual acuity was assessed using ETDRS chart. The ETDRS chart includes 100 letters as the maximum possible score, and 0 letters read as the minimum possible score. Higher scores represents better functioning. Percentage of patients whose visual acuity increased 15 letters or more compared to baseline will be calculated. | baseline, 52 and 104 weeks. | 
| Percentage of Patients With Visual Acuity >=20/40 | Visual acuity was assessed using ETDRS chart. The ETDRS chart includes 100 letters as the maximum possible score, and 0 letters read as the minimum possible score. Higher scores represents better functioning. Percentage of patients with visual acuity 70 ETDRS letters (equivalent to 20/40) or better was calculated. | 52 and 104 weeks |