Efficacy and Safety of Three Different Aflibercept Regimens in Subjects With Diabetic Macular Edema (DME)

Study Overview
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Brief Summary
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To evaluate the efficacy of long-term treatment with 2 mg aflibercept via different intravitreal (IVT) treatment regimens to participants with DME pretreated with 2 mg aflibercept every 8 weeks after 5 initial monthly injections for approximately 1 year or more (according to the EU label for the first year of treatment)

Official Title
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An Open-label, Randomized, Active-controlled, Parallel-group, Phase-3b Study of the Efficacy, Safety, and Tolerability of Three Different Treatment Regimens of 2 mg Aflibercept Administered by Intravitreal Injections to Subjects With Diabetic Macular Edema (DME)

Conditions
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Macular Edema

Intervention / Treatment
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* Drug: Aflibercept (Eylea, VEGF Trap-Eye, BAY86-5321)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject's history of aflibercept treatment met all of the following: Treatment in the study eye was initiated with five monthly (-1 week /+2 weeks) doses of 2 mg aflibercept and improvements of visual and anatomic outcomes were observed and documented. Following the above initiation phase, the intervals between treatments were between 6 weeks and 12 weeks (one exception was allowed). The interval between the last 2 pre-study injections was ≥ 8 weeks, and visual and anatomic outcomes had been stable over this interval. The subject received the last intravitreal (IVT) injection of aflibercept in the study eye 8 weeks (±10 days) before the first planned treatment /randomization in this study. Total prior treatment duration with aflibercept (i.e. from first aflibercept treatment ever to enrollment into this study) was 1 year or longer. To be met at initiation of pre-study aflibercept treatment: Type 1 or 2 diabetes mellitus (DM) Diagnosis of diabetic macular edema (DME) secondary to DM involving the center of the macula (defined as the area of the center subfield on optical coherence tomography [OCT]) in the study eye Decrease in vision determined to be primarily the result of DME in the study eye Best corrected visual acuity (BCVA) in the study eye of Early Treatment Diabetic Retinopathy Study (ETDRS) letter score 73 to 24 Exclusion Criteria: At initiation of pre-study aflibercept treatment: - Previous treatment with anti-angiogenic drugs in study eye (e.g., pegaptanib sodium, bevacizumab, ranibizumab, or aflibercept) within the last 12 weeks before initiation of aflibercept pre-study treatment At initiation of pre-study aflibercept treatment, screening for this study, and baseline for this study: Prior treatment of the study eye with long acting steroids, either periocular or intraocular, in the preceding 120 days or Iluvien intravitreal implant at any time Active proliferative diabetic retinopathy, current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment in the study eye Cataract surgery or any other intraocular surgery within 90 days of aflibercept treatment in the study eye Ocular inflammation (including trace or above) or history of uveitis in the study eye Structural damage to the center of the macula in the study eye that was likely to preclude improvement in 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 Concurrent disease in the study eye, other than DME, that could compromise visual acuity, require medical or surgical intervention during the study period, or could confound interpretation of the results (including advanced glaucoma, retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause) Uncontrolled DM as defined by hemoglobin (Hb) A1c > 12.0% at screening and baseline for this study Any ocular or periocular infection in the preceding 4 weeks in either eye History of either cerebral vascular accident and/or myocardial infarction within 180 days before aflibercept treatment

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aflibercept 2 mg fixed<br>Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks | Drug: Aflibercept (Eylea, VEGF Trap-Eye, BAY86-5321)<br> <br> |
| Experimental: Aflibercept 2 mg flexible<br>Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥8 week | Drug: Aflibercept (Eylea, VEGF Trap-Eye, BAY86-5321)<br> <br> |
| Experimental: Aflibercept 2 mg PRN<br>Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed) | Drug: Aflibercept (Eylea, VEGF Trap-Eye, BAY86-5321)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity. | From baseline to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 52 | Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT). | From baseline to week 52 | 
| Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity | From baseline to week 52 | 
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity. | From baseline to Week 100 | 
| Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 100 | Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT). | From baseline to Week 100 | 
| Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity | From baseline to Week 100 | 
| Number of Participants With Treatment-emergent Adverse Event (TEAE) | AEs that started after the first application of aflibercept under this protocol until 30 days after the last dose of study drug administration | Up to Week 100 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DME, Diabetic macular edema