A Study to Learn How Well a Higher Amount of Aflibercept Given as an Injection Into the Eye Works and How Safe it is in People With Reduced Vision Due to Swelling in the Macula, Central Part of the Retina Caused by a Blocked Vein in the Retina (Macula Edema Secondary to Retinal Vein Occlusion)

Study Overview
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Brief Summary
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Researchers are looking for a better way to treat people who have macular edema secondary to retinal vein occlusion (RVO). In people with RVO, a blood vessel that carries blood away from the retina (vein) becomes blocked. The retina is the very back part of the eye. The blocked vein causes fluid and blood to leak into the retina and thereby causes a swelling of the macula (the center of the retina responsible for fine vision). This swelling is called macular edema. When a vein in the retina is blocked, the levels of a protein called vascular endothelial growth factor (VEGF) rises. VEGF helps the growth of new blood vessels. This can lead to macular edema and may cause the vision to become blurry. The study treatment intravitreal (IVT) aflibercept is given as an injection into the eye. It works by blocking VEGF and this can help repair vision problems related to RVO. IVT aflibercept is already available and is prescribed by doctors as the standard of care treatment for macula edema secondary to RVO. Standard of care is a treatment that medical experts consider most appropriate for a disease. Standard of care is given every 4 weeks in people with macula edema secondary to RVO. While repeated injections of aflibercept may prevent worsening of vision, it may place a burden on the patient. However, a higher amount (8 mg) compared to the standard of care (2 mg) of IVT aflibercept is being tested in studies. This higher amount could be given less often. The amount of IVT aflibercept given is measured in milligrams, also known as mg. The main purpose of this study is to learn how well a higher amount of the study treatment aflibercept works in people with macular edema secondary to RVO. To answer this, researchers will measure changes in vision called best corrected visual acuity (BCVA) in the study participants between study start and after 36 weeks of treatment. Changes will then be compared between those participants who received the higher amount of IVT aflibercept and those that received standard of care. To learn how safe the study treatment is in the participants, the researchers will count the number of participants from study start and up to 64 weeks later that have: adverse events serious adverse events Adverse events are any medical problems that the participants have during a study. Doctors keep track of all adverse events that happen in studies, even if they do not think they might be related to the study treatments. An adverse event is considered serious when it leads to death, puts the participants' lives at risk, requires hospitalization, causes disability, causes a baby being born with medical problems or is otherwise medically important. Dependent on the treatment group, the participants will either receive the higher amount of aflibercept or standard of care as an intravitreal injection for up to 60 weeks. The study will consist of a test (screening) phase, a treatment phase and an end of study phase. Each participant will be in the study for up to 64 weeks. One visit to the study site is planned during the screening phase, followed by visits approximately every 4 weeks (16 in total) during treatment and one visit at the end of the study. During the study, the study doctors and their team will: check patients' eye health using various eye examination techniques measure patients' eye vision (BCVA) take blood and urine samples do physical examinations check vital signs examine heart health using electrocardiogram (ECG) do pregnancy tests in women of childbearing age In addition, participants will be asked to fill a questionnaire on vision-related quality of life.

Official Title
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Randomized, Double-Masked, Active-Controlled, Phase 3 Study of the Efficacy and Safety of Aflibercept 8 mg in Macular Edema Secondary to Retinal Vein Occlusion

Conditions
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Macular Edema Secondary to Retinal Vein Occlusion

Intervention / Treatment
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* Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_higher dose
* Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_2 mg
* Drug: Sham
* Diagnostic Test: Fluorescein


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult ≥18 years of age (or country's legal age of adulthood if the legal age is >18 years) at the time of signing the informed consent. Treatment-naïve macular edema involving the foveal center secondary to RVO (BRVO, HRVO, or CRVO) diagnosed within 16 weeks (112 days) before the screening visit in the study eye. Early Treatment Diabetic Retinopathy Study BCVA letter score of 73 to 24 (20/40 to 20/320) at screening and baseline visits in the study eye. Decrease in BCVA determined to be primarily the result of RVO in the study eye. Mean CST ≥300 μm on optical coherence tomography (OCT) if excluding Bruch's membrane (e.g., Cirrus or Topcon) or ≥320 μm if including Bruch's membrane (e.g., Heidelberg Spectralis), confirmed by the reading center at the screening visit and by the site at baseline visit in the study eye. Capable of giving signed informed consent form (ICF) by study participant or legally acceptable representative, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. US participants will be required to have a Health Insurance Portability and Accountability Act (HIPAA) authorization; in other countries, as applicable according to national laws. Women of childbearing potential (WOCBP) or men who are sexually active with partners of childbearing potential must agree to use highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 4 months after the last administration of study intervention. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for participation in clinical studies and fulfil the conditions set on Section 10.4.2. Exclusion Criteria: Concurrent disease that causes substantial decrease of BCVA, is expected to limit BCVA recovery or is likely to require medical or surgical intervention during the study in the study eye. Presence or history of the following ocular conditions: Advanced age-related macular degeneration (neovascular AMD or geographic atrophy) in the study eye. Diabetic macular edema or diabetic retinopathy, defined in diabetic participants as diabetic retinopathy lesions outside the area of the vein occlusion in the study eye and anywhere in the retina in the fellow eye. Anterior segment neovascularization, vitreous hemorrhage, retinal detachment in the study eye. Vitreomacular traction, epiretinal membrane or structural damage to the macula that is considered by the Investigator to significantly affect central vision or preclude improvement in vision in the study eye. Macular hole of stage 2 and above in the study eye. Myopia of a spherical equivalent of at least 8 diopters prior to any refractive or cataract surgery in the study eye. Corneal transplant or corneal dystrophy in the study eye. Idiopathic or autoimmune uveitis in the study or in the fellow eye. Presence of the following ocular conditions at screening or baseline visit: Significant media opacities, including cataract, that interfere with BCVA, or imaging assessments (e.g., fundus photography [FP], OCT) in the study eye. Aphakia, or pseudophakia with absence of posterior capsule (unless it occurred as a result of a yttrium-aluminum-garnet [YAG] posterior capsulotomy performed more than 30 days before the screening visit), in the study eye. Uncontrolled glaucoma (defined as IOP >25 mmHg despite treatment with anti-glaucoma medication); or history or likely future need of glaucoma surgery in the study eye. Intraocular inflammation/infection (including trace, or above, cells in the anterior chamber and/or vitreous) within 12 weeks (84 days) of the screening visit in the study or in the fellow eye. Extraocular or periocular infection or inflammation (including infectious blepharitis, keratitis, scleritis, or conjunctivitis) in the study or in the fellow eye. Uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic >95 mmHg) at the screening visit or baseline visit. Uncontrolled diabetes mellitus, defined by hemoglobin A1c (HbA1c) >12% at the screening visit. History of cerebrovascular accident or myocardial infarction within 24 weeks (168 days) before the screening visit or between screening and baseline visits. Renal failure requiring dialysis, or renal transplant at screening or potentially during the study. Any prior or concomitant ocular or systemic treatment (with an investigational or approved, anti-VEGF or other agent) or surgery for RVO in the study eye. Previous administration of systemic anti-angiogenic medications for any condition. Prior treatment of the study eye with any of the following drugs (any route of ophthalmic administration) or procedures: Anti-angiogenic drugs at any time including investigational therapy (e.g., with anti-angiopoietin/anti-VEGF bispecific monoclonal antibodies). Previous use topical steroids within 4 weeks (28 days) from the screening visit, or intraocular or periocular steroids within 16 weeks (112 days) from the screening visit, or steroid implants at any time. Previous treatment with intraocular or periocular implant, gene therapy, or cell therapy at any time. Treatment with ocriplasmin at any time. Vitreoretinal surgery (including scleral buckling) at any time. Any intraocular surgery, including cataract surgery, within 12 weeks (84 days) before the screening visit. Previous treatment with retinal laser photocoagulation. Prior treatment of the fellow eye with any of the following: a. Gene therapy, or cell therapy in the fellow eye at any time. Participation in other clinical studies requiring administration of investigational treatments (other than vitamins and minerals) at the time of screening visit, or within 30 days or 5 half-lives of administration of the previous study intervention, whichever is longer.

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: Higher Dose Regimen 1<br>Higher dose of aflibercept is administered with initial initiation doses intervals, followed by extension of treatment intervals and further adjustment of intervals according to treatment response. | Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_higher dose<br>* Intravitreally (IVT) injection.<br>Drug: Sham<br>* Sham procedure will be given on visits when an active injection is not planned.<br>Diagnostic Test: Fluorescein<br>* Fluorescein 100 mg/mL solution for injection is a dye that makes the retinal vessels visible during FA examinations, and as such, it will be used as an auxiliary medicinal product (AxMP) in this periodic ophthalmic examination. This medicine is for diagnostic use only. It is not used to treat any condition.<br>|
| Experimental: Higher Dose Regimen 2<br>Higher dose of aflibercept is administered with initial initiation doses intervals, followed by extension of treatment intervals and further adjustment of intervals according to treatment response. | Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_higher dose<br>* Intravitreally (IVT) injection.<br>Drug: Sham<br>* Sham procedure will be given on visits when an active injection is not planned.<br>Diagnostic Test: Fluorescein<br>* Fluorescein 100 mg/mL solution for injection is a dye that makes the retinal vessels visible during FA examinations, and as such, it will be used as an auxiliary medicinal product (AxMP) in this periodic ophthalmic examination. This medicine is for diagnostic use only. It is not used to treat any condition.<br>|
| Active Comparator: Standard of care<br>Aflibercept 2 mg is administered by standard treatment intervals, followed by adjustment of treatment intervals according to treatment response. | Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_2 mg<br>* Intravitreally (IVT) injection.<br>Diagnostic Test: Fluorescein<br>* Fluorescein 100 mg/mL solution for injection is a dye that makes the retinal vessels visible during FA examinations, and as such, it will be used as an auxiliary medicinal product (AxMP) in this periodic ophthalmic examination. This medicine is for diagnostic use only. It is not used to treat any condition.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in BCVA measured by the ETDRS letter score at Week 36 | BCVA: Best-Corrected Visual Acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; ETDRS letter score (ranging from 0 to 100 letters). A higher letter score means a better outcome (better visual acuity) | At Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of active injections from baseline to Week 64 |  | From baseline to Week 64 | 
| Number of active injections from baseline to Week 36 |  | From baseline to Week 36 | 
| Change from baseline in BCVA measured by the ETDRS letter score at Week 44 | ETDRS letter score (ranging from 0 to 100 letters). A higher letter score means a better outcome (better visual acuity) | At baseline, week 44 | 
| Change from baseline in BCVA measured by the ETDRS letter score at Week 64 | ETDRS letter score (ranging from 0 to 100 letters). A higher letter score means a better outcome (better visual acuity) | At baseline, week 64 | 
| Number of participants gaining at least 15 letters in BCVA from baseline at Weeks 36 and 64 |  | From baseline at week 36 and week 64 | 
| Number of participant achieving an ETDRS letter score of at least 69 (approximate 20/40 Snellen equivalent) at Weeks 36 and 64 | ETDRS letter score (ranging from 0 to 100 letters). A higher letter score means a better outcome (better visual acuity) | At week 36 and week 64 | 
| Participant having no IRF and no SRF in the center subfield at Weeks 36 and 64 (yes/no) |  | At week 36 and week 64 | 
| Change from baseline in CST at Weeks 36 and 64 | CST: Central Sub-field Thickness; | At baseline, week 36 and week 64 | 
| Change from baseline in NEI VFQ 25 total score at Weeks 36 and 64 | NEI-VFQ-25: National Eye Institute Visual Functioning Questionnaire-25; The NEI VFQ-25 total score ranges from 0 to 100. A higher score means a better outcome (better patient-reported visual function). | At baseline, week 36 and week 64 | 
| Number of participant with TEAEs and SAEs through Weeks 36 and 64 |  | Through weeks 36 and 64 | 
| Participants dosed only Q8W through Week 36 in the 8 mg Q8W group |  | Through weeks 36 | 
| Participants having last treatment intervals ≥12 or of 16 weeks at Week 64 |  | At week 64 | 
| Participants having next intended interval ≥12 or of 16 weeks at Week 64 |  | At week 64 | 
| Systemic exposure to aflibercept as assessed by plasma concentrations of free, adjusted bound and total aflibercept from baseline through Weeks 36 and 64 |  | From baseline through weeks 36 and 64 |