Study of a High-Dose Aflibercept in Participants With Diabetic Eye Disease

Study Overview
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Brief Summary
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The primary objective of the study is to determine if treatment with high-dose aflibercept (HD) at intervals of 12 or 16 weeks provides non-inferior best corrected visual acuity (BCVA) compared to aflibercept dosed every 8 weeks. The secondary objectives of the study are as follows: To determine the effect of HD vs. aflibercept on anatomic and other visual measures of response To evaluate the safety, immunogenicity, and pharmacokinetics (PK) of aflibercept

Official Title
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A Randomized, Double-Masked, Active-Controlled Phase 2/3 Study of the Efficacy and Safety of High-Dose Aflibercept in Patients With Diabetic Macular Edema

Conditions
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Diabetic Macular Edema, Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: aflibercept
* Drug: High-dose aflibercept


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diabetic macular edema (DME) with central involvement in the study eye Best corrected visual acuity (BCVA) early treatment diabetic retinopathy study (ETDRS) letter score of 78 to 24 (approximate Snellen equivalent of 20/32 to 20/320) in the study eye with decreased vision determined to be primarily the result of DME Willing and able to comply with clinic visits and study-related procedures Provide informed consent signed by study participant or legally acceptable representative Extension Phase: All randomized patients that complete visit 26, week 96, as long as the patient 1) provides informed consent and 2) no treatment for DME has been given in the study eye other than the randomized study treatment. Key Exclusion Criteria: Evidence of macular edema due to any cause other than diabetes mellitus in either eye Active proliferative diabetic retinopathy in the study eye IVT anti-VEGF treatment (aflibercept, ranibizumab, bevacizumab, brolucizumab, pegaptanib sodium) or panretinal laser photocoagulation (PRP) /macular laser photocoagulation within 12 weeks (84 days) or intraocular or periocular corticosteroids within 16 weeks (112 days) of the screening visit in the study eye Prior IVT investigational agents in either eye (eg, anti-ang-2/anti-VEGF bispecific monoclonal antibodies, gene therapy, etc.) at any time Treatment with ocriplasmin (JETREA®) in the study eye at any time NOTE: Other Protocol Defined 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 |
| --- | --- |
| Active Comparator: aflibercept Q8<br>Administered every 8 weeks after a loading phase | Drug: aflibercept<br>* Intravitreally (IVT) administered as a liquid formulation in a vial<br>* Other names: BAY86-5321;|
| Experimental: High-Dose aflibercept Q12<br>Administered every 12 weeks after a loading phase | Drug: High-dose aflibercept<br>* Intravitreally (IVT) administered as a liquid formulation in a vial<br>|
| Experimental: High-Dose aflibercept Q16<br>Administered every 16 weeks after a loading phase | Drug: High-dose aflibercept<br>* Intravitreally (IVT) administered as a liquid formulation in a vial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Best Corrected Visual Acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] Letter Score) in the Study Eye at Week 48 | 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). | Baseline, Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a ≥2 Step Improvement From Baseline in Diabetic Retinopathy Severity Scale (DRSS) Score at Week 48 | The DRSS was assessed according to the following scale: 10 = Diabetic retinopathy (DR) absent, 14 = DR questionable, 15 = DR questionable, 20 = Micro-aneurysms only, 35 = Mild Non-proliferative diabetic retinopathy (NPDR), 43 = Moderate NPDR, 47 = Moderately severe NPDR, 53 = Severe NPDR, 61 = Mild Proliferative diabetic retinopathy (PDR), 65 = Moderate PDR, 71 = High-risk PDR, 75 = High-risk PDR, 81 = Advanced PDR: fundus partially obscured, center of macula attached, 85 = Advanced PDR: posterior fundus obscured, or center of macula detached, 90 = cannot grade, even sufficiently for level 81 or 85. | Baseline, Week 48 | 
| Percentage of Participants Gaining ≥15 Letters in BCVA From Baseline at Week 48 | 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). Only one study eye per participant was analyzed within the study | Baseline, Week 48 | 
| Percentage of Participants With BCVA ≥69 Letters at Week 48 | 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 48 | 
| Percentage of Participants Without Fluid at Foveal Center at Week 48 | Retinal fluid status was evaluated using spectral domain optical coherence tomography (SD-OCT) on the study eye. | At Week 48 | 
| Change From Baseline in Central Retinal Thickness (CRT) in the Study Eye at Week 48 | Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT). | Baseline, Week 48 | 
| Percentage of Participants Without Leakage on Fluorescein Angiography (FA) at Week 48 | Leakage is the release of fluorescein dye from diseased retinal vessels. | At Week 48 | 
| Change From Baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) Total Score at Week 48 | Vision-specific quality of life is assessed with the NEI VFQ-25 (National Eye Institute Visual Function Questionnaire), i.e. a 25-item questionnaire that gives a score on a scale from 0 (worst) to 100 (best = no vision problems). | Baseline, Week 48 | 
| Systemic Pharmacokinetics (PK) of Aflibercept as Assessed by Plasma Concentrations Through Week 48 | Concentrations of Free Aflibercept in Plasma by Time and Treatment Group | Through Week 48 | 
| Change From Baseline in BCVA in the Study Eye in Participants With Both Baseline and Week 48 BCVA | 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). (Per Statistical Analysis Plan (SAP) Version 2.0 Appendix 10.9 for US Only) | Baseline, Week 48 | 
| Change From 8-weeks Post Initial Treatment Phase in BCVA in the Study Eye in Participants With Both 8-weeks Post Initial Treatment Phase BCVA and Week 48 BCVA | 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). (Per SAP Version 2.0 Appendix 10.9 for US Only) | Baseline, Week 48 | 
| Change From Baseline in BCVA (Region-specific Analysis) in the Study Eye at Week 60 | 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). | Baseline, Week 60 | 
| Assessment of Immunogenicity to Aflibercept by Measuring the Incidence of Treatment-emergent Anti-drug Antibodies (ADA) Response Through Week 96 |  | Through Week 96 | 
| Safety Assessed by Adverse Events (AEs) Through Week 156 |  | Through Week 156 | 
| Safety Assessed by Serious Adverse Events (SAEs) Through Week 156 |  | Through Week 156 |