Study of the Efficacy and Safety of Intravitreal (IVT) Aflibercept for the Improvement of Moderately Severe to Severe Nonproliferative Diabetic Retinopathy (NPDR)

Study Overview
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Brief Summary
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The primary objective of the study is to assess the efficacy of intravitreal (IVT) aflibercept compared to sham treatment in the improvement of moderately severe to severe nonproliferative diabetic retinopathy (NPDR). The secondary objectives of the study are: To characterize the safety of IVT aflibercept in patients with moderately severe to severe NPDR To determine if IVT aflibercept will prevent the worsening of diabetic retinopathy and reduce the incidence of DME To determine the anatomic effects of IVT aflibercept in patients with moderately severe to severe NPDR

Official Title
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A Phase 3, Double-Masked, Randomized Study of the Efficacy and Safety of Intravitreal Aflibercept Injection in Patients With Moderately Severe to Severe Nonproliferative Diabetic Retinopathy

Conditions
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Nonproliferative Diabetic Retinopathy

Intervention / Treatment
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* Drug: Intravitreal aflibercept injection [IAI]
* Drug: Sham


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Men or women ≥18 years of age with type 1 or 2 diabetes mellitus who have moderately severe to severe nonproliferative diabetic retinopathy (NPDR) [(diabetic retinopathy severity scale (DRSS) levels 47 or 53)], confirmed by the central reading center, in whom panretinal photocoagulation (PRP) can be safely deferred for at least 6 months per the investigator Best corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in the study eye of ≥69 letters (approximate Snellen equivalent of 20/40 or better) Key Exclusion Criteria: Presence of diabetic macular edema (DME) threatening the center of the macula in the study eye Evidence of retinal neovascularization on clinical examination or Fluorescein Angiography (FA) Any prior focal or grid laser photocoagulation or any prior PRP in the study eye Any prior systemic anti-vascular endothelial growth factor (VEGF) treatment or intravitreal (IVT) anti-VEGF treatment in the study eye Any prior intraocular steroid injection in the study eye Current anterior segment neovascularization (ASNV), vitreous hemorrhage, or tractional retinal detachment visible at the screening assessments in the study eye Note: Other inclusion/ exclusion criteria apply

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dosing regimen 1<br>Participants will receive IVT aflibercept dosing regimen 1 | Drug: Intravitreal aflibercept injection [IAI]<br> <br> * Other names: BAY86-5321;|
| Experimental: Dosing regimen 2<br>Participants will receive IVT aflibercept dosing regimen 2 | Drug: Intravitreal aflibercept injection [IAI]<br> <br> * Other names: BAY86-5321;|
| Sham Comparator: Dosing regimen 3<br>Participants will receive matching sham injections | Drug: Sham<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Improved by ≥2 Steps From Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups | The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 24 from baseline. | At Week 24 | 
| Percentage of Participants With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline | The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 52 from baseline. | At Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Developed a Vision-Threatening Complication Due to Diabetic Retinopathy at Week 52 | Vision-threatening complications are defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle). | At Week 52 | 
| Percentage of Participants Who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52 | The percentage of participants who developed CI-DME at week 52 were reported. | At Week 52 | 
| Time to Development of Any Neovascular Vision Threatening Complication (PDR/ASNV) Through Week 52 | Vision-threatening complication (VTC) is defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle). Vision Threatening Complications include PDR/ASNV identified by investigators and Diabetic Retinopathy Scale Score (DRSS) >61. | Baseline through week 52 (day 365) | 
| Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) Through Week 52 | Time to develop Central Involved-Diabetic Macular Edema (CI-DME) through week 52 reported. | Baseline through week 52 (day 365) | 
| Percentage of Participants Who Received Panretinal Photocoagulation (PRP), Inclusive of Participants Undergoing Vitrectomy With Endolaser, at Week 52 | The percentage of participants who received panretinal photocoagulation (PRP), inclusive of participants undergoing vitrectomy with endolaser, at week 52 were reported. | At Week 52 | 
| Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | The area under the curve (AUC) is the area under the best corrected visual acuity (BCVA) versus time curve from baseline to week 52. Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). | At week 52 |