Long-Term Efficacy and Safety of Intravitreal Aflibercept Injections for the Treatment of Diabetic Retinopathy for Subjects Who Completed the 2-Year PANORAMA Trial

Study Overview
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Brief Summary
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The VOYAGE trial will assess diabetic retinopathy severity scale (DRSS) levels, through 112 weeks, while being managed with aflibercept as needed, among subjects who completed the 2-year PANORAMA trial (VGFTe-OD-1411) and were treated in a clinical setting prior to joining the VOYAGE study.

Detailed Description
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This phase 4 study is designed to assess the need for ongoing 2 mg intravitreal aflibercept injections (IAI) for subjects who completed the 2-year PANORAMA (VGFTe-OD-1411) trial for the management of diabetic retinopathy (DR). Sites will be considered for VOYAGE if they have 4 or more subjects from PANORAMA able to participate. Relevant data from all participating subjects will be collected and reported retrospectively for the period between PANORAMA study exit and VOYAGE study enrollment. For the prospective portion of the study, eyes will be assigned to 1 of 2 groups, eyes without panretinal photocoagulation (PRP) and eyes with PRP. Group 1: Subjects with study eyes without PRP will be seen every 16 weeks (Q16W) and treated with IAI on a flexible treatment regimen based on their DRSS level. An injection will be given at each 16-week visit when the DRSS level is 47 or worse. If the DRSS level is better than 47, for example level 43 or 35, the study eye will not be treated. DRSS level will be determined by the investigator, based on ophthalmic exam and fundus photography (FP) compared to prior imaging when available. Every 8 week visits can be performed under specific circumstances: If a subject has a 2-step DRSS level worsening compared to the last protocol-scheduled 16-week visit (for example the week-16 or week-32 visit) and/or the DRSS level is 53 or worse OR If a subject has active proliferative DR (PDR) Under both of these circumstances, IAI will be administered as scheduled and the subject can be seen and treated every 8 weeks (Q8W) with IAI. Under both of these circumstances, Q8W visits and Q8W IAI treatments can be continued until there is no active PDR and the DRSS improves to the level observed at the visit before the subject began being seen at 8-week intervals. Group 2: Subjects with study eyes with PRP will be seen Q16W and treated with IAI on a flexible treatment regimen based on activity of the neovascular disease process as assessed by the treating investigator based on ophthalmic exam and/or FP compared to prior imaging when available. If the neovascular disease is inactive, no treatment will be given. If the neovascular disease is active and stable (not new or worse), the subject will be treated with intravitreal (IVT) IAI at the Q16W interval. If new or worsening neovascular disease develops, subjects may be seen and treated Q8W until the neovascular disease is stable or inactive at which time the interval between visits will increase to 16 weeks. Subjects in both groups will be evaluated for efficacy, using best corrected visual acuity (BCVA) using the 4-meter ETDRS protocol with normal-luminance, Humphrey Visual Field (HVF), National Eye Institute (NEI) Visual Function Questionnaire (VFQ) 25, spectral domain optical coherence tomography (SD-OCT), optical coherence tomography angiography (OCT-A), FP, and fluorescein angiography (FA), and for ocular and systemic safety (including ophthalmic exams and laboratory assessments) through week 112. Subjects who develop new or worsening PDR, including anterior segment neovascularization (ASNV), or center-involved DME may qualify for rescue treatment.

Official Title
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Long-Term Efficacy and Safety of Intravitreal Aflibercept Injections for the Treatment of Diabetic Retinopathy for Subjects Who Completed the 2-Year PANORAMA Trial

Conditions
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Diabetic Retinopathy

Intervention / Treatment
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* Drug: Aflibercept Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Enrolled and completed PANORAMA (VGFTe-OD-1411) clinical trial Willing and able to comply with clinic visits and study-related procedures Provide signed informed consent Exclusion Criteria: Any prior systemic anti-vascular endothelial growth factor (VEGF) treatment or IVT anti-VEGF treatment in the study eye within 21 days of baseline Any intra- or periocular corticosteroid treatment in the study eye within 3 months of baseline Any intraocular sustained-release treatment, implantable device, or gene therapy in the study eye Pregnant or breastfeeding women Sexually active men* or women of childbearing potential** who are unwilling to practice adequate contraception during the study (adequate contraceptive measures include stable use of oral contraceptives or other prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to screening/baseline; intrauterine device (IUD); bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly). Contraception is not required for men with documented vasectomy. **Postmenopausal women must be amenorrhoeic for at least 12 months in order not to be considered of childbearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.

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: Group 1<br>Study eyes without PRP from the PANORAMA trial. Subjects will be evaluated every 16 weeks and treated if DRSS level is 47 or worse as determined by the treating investigator. Subjects may be evaluated every 8 weeks if a 2-step DRSS level worsening compared to the last protocol-scheduled 16-week visit occurs, the DRSS level is 53 or worse, or if a subject has active PDR. Visits can continue every 8 weeks until there is no active PDR, and the DRSS improves to the level observed at the visit before the subject began being seen at 8-week intervals. Thereafter, visits will continue at 16 week intervals. | Drug: Aflibercept Injection<br>* Intravitreal 2mg aflibercept injection<br>* Other names: Eylea;|
| Experimental: Group 2<br>Study eyes with PRP from the PANORAMA trial. Subjects will be evaluated every 16 weeks and treated if the neovascular disease process is active and stable (not new or worse) as determined by the treating investigator. If the neovascular disease is inactive, no treatment will be given. If new or worsening neovascularization develops, subjects may be seen and treated every 8 weeks until the neovascular disease is stable or inactive, at which time the interval between visits will increase to 16 weeks. | Drug: Aflibercept Injection<br>* Intravitreal 2mg aflibercept injection<br>* Other names: Eylea;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DRSS Level Achievement in the VOYAGE study | Proportion of subjects achieving a DRSS level of 43 or less in the VOYAGE study. | 112 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DRSS Level Achievement in the PANORAMA study | Proportion of subjects achieving a DRSS level of 43 or less from the completion of the PANORAMA study | 112 weeks | 
| DRSS Level Improvement | Proportion of subjects with stable, worsened, or improved DRSS level from baseline to week 48 and baseline to week 112 compared to the DRSS at the baseline of the VOYAGE trial and the DRSS at the last visit of the PANORAMA trial. | 112 weeks | 
| Injection Frequency | Mean and median number of IVT aflibercept injections (with and without IAI given for DME) | 112 weeks | 
| Subjects without Treatment | Proportion of subjects receiving 0 injections | 112 weeks | 
| PDR Events | Percentage of subjects over time who develop a new PDR event | 112 weeks | 
| Center-Involved Diabetic Macular Edema Development | Percentage of subjects over time who develop center-involved (CI) DME | 112 weeks | 
| Change in Visual Acuity | Mean change in ETDRS BCVA from baseline | 112 weeks | 
| Change in Central Retinal Thickness | Mean change in central retinal thickness from baseline | 112 weeks | 
| Change in Area of Nonperfusion | Change in total area of retinal capillary non-perfusion from baseline | 112 weeks | 
| Changes in Visual Function (HVF) | Changes in visual function outcomes from Humphrey Visual Field from baseline | 112 weeks | 
| Changes in Visual Function | Changes in visual function outcomes NEI VFQ-25 from baseline | 112 weeks | 
| Incidence of Adverse Events | Incidence and severity of ocular and systemic adverse events from baseline | 112 weeks |