Intravitreal Aflibercept as Indicated by Real-Time Objective Imaging to Achieve Diabetic Retinopathy Improvement

Study Overview
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Brief Summary
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The PRIME trial will assess the safety of 2 mg intravitreal aflibercept injections (IAI) to achieve and maintain DRSS improvements (2 or more steps) in patients with a baseline DRSS level of 47A to 71A inclusive through 104 weeks as determined by reading center determined DRSS gradings on OPTOS fundus photos and leakage index on OPTOS WF-FA.

Detailed Description
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Study eyes will be assigned randomly (1:1 ratio) to one of the following 2 treatment arms. Randomization of PDR subjects will be limited to 50% of each arm. Group 1 Year 1 Subjects will be seen every month, 28 days (+ 7 days), for 52 weeks. All subjects will receive IAI at baseline, after eligibility is confirmed. Week 4 through week 48, subjects will be seen monthly and treated with IAI PRN (pro re nata) according to, same day, central reading center (CRC) determined DRSS level. Monthly treatment with IAI will continue until a greater than or equal to 2 step DRSS level improvement is achieved, relative to screening/baseline DRSS based on CRC assessment OPTOS fundus photos (FP). Subjects who have baseline proliferative diabetic retinopathy (PDR) (DRSS Level 61-71) will continue to receive monthly IAI until a greater than or equal to 2 step DRSS improvement is achieved as determined by CRC assessment of OPTOS fundus photos relative to screening/baseline DRSS, and PDR is quiescent according to the treating investigator. Treatment with IAI will be reinitiated if a 1 step worsening of DRSS occurs compared to best DRSS score achieved, determined by CRC evaluation of OPTOS fundus photos. If such worsening is detected, the subject would resume monthly IAI until best DRSS score or greater is achieved, as determined by CRC assessment of OPTOS fundus photos. In addition, retreatment will also be re-started if new onset neovascularization is identified and is continued until the PDR is quiescent according to the treating investigator. Year 2 Beginning in year 2 (week 52) subjects will be seen every 56 days (+ 14 days) and treated with IAI PRN (pro re nata) utilizing the same criteria from year 1. All subjects will have a mandatory week 104 visit, where treatment will not be given. Group 2 Year 1 Subjects will be seen every month, 28 days (+ 7 days), for 52 weeks. All subjects will receive IAI at baseline, after eligibility is confirmed. Week 4 through week 48, subjects will be seen monthly and treated with IAI PRN (pro re nata) according to, same day, CRC determination of DRSS initially, and subsequently of leakage index. Monthly treatment with IAI will continue until a greater than or equal to 2 step DRSS level improvement is achieved, relative to screening/baseline DRSS based on CRC assessment OPTOS fundus photos (FP). Subjects who have baseline proliferative diabetic retinopathy (PDR) (DRSS Level 61-71) will continue to receive monthly IAI until a greater than or equal to 2 step DRSS improvement is achieved as determined by CRC assessment of OPTOS fundus photos relative to screening/baseline DRSS, and PDR is quiescent according to the treating investigator. Leakage index as determined by CRC assessment of OPTOS WF-FA at the visit at which a greater than or equal to 2 step DRSS level improvement is achieved will be considered the threshold. Treatment with IAI will be reinitiated if the leakage index increases to 33% above the individual subject threshold leakage index level as determined by CRC evaluation of OPTOS WF-FA. If such worsening is detected, the subject would resume monthly IAI until the threshold leakage index as determined by CRC assessment of OPTOS WF-FA is reached. In addition, retreatment will also be re-started if new onset neovascularization is identified and is continued until the PDR is quiescent according to the treating investigator. Year 2 Beginning in year 2 (week 52) subjects will be seen every 56 days (+ 14 days) and treated with IAI PRN (pro re nata) utilizing the same criteria from year 1. All subjects will have a mandatory week 104 visit, where treatment will not be given. If images of insufficient quality are unable to be obtained, in Group 1 or Group 2, subjects will undergo treatment with IAI at principal investigators discretion or designee. Subjects can have both eyes in the study, if eligibility is met. If both eyes are eligible, one eye will be randomized to group 1 while the other is randomized to group 2. If only one eye is eligible IAI will be provided for the fellow eye as needed according to the treating investigator.

Official Title
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Intravitreal Aflibercept as Indicated by Real-Time Objective Imaging to Achieve Diabetic Retinopathy Improvement

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: Men or Women > 18 years of age with type 1 or II diabetes mellitus Diabetic Retinopathy, DRSS Level 47A to 71A, as assessed by CRC (enrollment of PDR levels will be limited to 50% of the total population) BCVA in the study eye better than 20/800 Exclusion Criteria: Any prior systemic anti-VEGF treatment or IVT anti-search vascular endothelial growth factor (VEGF) treatment in the study eye within 24 weeks of screening/baseline Any intravitreal or peribulbar corticosteroids in the study eye within 12 weeks of screening/baseline Any prior treatment with Ozurdex or Iluvien in the study eye SD-OCT central subfield thickness (CST) > 320 µm in the study eye Central DME causing visual acuity loss, in which treatment can not be safely deferred for at least 6 months, in the investigator's judgment Current visually significant vitreous hemorrhage in the study eye. Vitreous hemorrhage is allowed as long as DRSS level is 71A or lower. History of panretinal photocoagulation (PRP) in the study eye History of vitrectomy surgery in the study eye Cataract surgery in the study eye within 8 weeks of screening/baseline Pregnant or breast-feeding women Sexually active men* or women of childbearing potential** who are unwilling to practiceadequate 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 amenorrheic for at least 52 weeks in order not to be considered of childbearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation. If currently receiving diaylisis, must have started treatment more than 12 weeks prior to screening/baseline Uncontrolled blood pressure (defined as > 190/110 mm Hg systolic/diastolic, while seated)

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>Treatment based on central reading center reading evaluation of DRSS (diabetic retinopathy severity scale) level based on OPTOS funds photos. | Drug: Aflibercept Injection<br>* intravitreal 2mg aflibercept injection<br>* Other names: Eyela;|
| Experimental: Group 2<br>Treatment based on central reading center reading evaluation of DRSS (diabetic retinopathy severity scale) level based leakage index of OPTOS wide field fluorescein angiography. | Drug: Aflibercept Injection<br>* intravitreal 2mg aflibercept injection<br>* Other names: Eyela;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events for diabetic retinopathy subjects who receive intravitreal Aflibercept | Assess the safety of 2 mg intravitreal aflibercept injections (IAI) to achieve and maintain DRSS improvements (2 or more steps) in patients with a baseline DRSS level of 47A to 71A inclusive as determined by reading center determined DRSS gradings on OPTOS fundus photos and leakage index on OPTOS WF-FA | 104 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of DRSS and leakage index | Correlation of reading-center determined DRSS level and leakage index to determine change in DR severity | 104 weeks | 
| Correlation between Reading Center DRSS Level and Physician determined DR severity | Correlation of reading-center determined DRSS level and investigator-determined DR severity level based on ophthalmoscopic fundus examination (Physician determined DR severity level will be based on AAO (American Academy of Ophthalmology) simplified grading system: mild NPDR, moderate NPDR, Severe NPDR, low risk PDR, high risk PDR) | 104 weeks | 
| Number of IAI | Mean and Median number of IVT aflibercept Injections (with and without IAI given for DME) | 104 weeks | 
| Mean number of IAI (NPDR VS PDR) | Mean number of IVT aflibercept Injections in eyes with baseline NPDR vs PDR through week 52 | 104 weeks | 
| ETDRS-BCVA change | Mean change in Early Treatment Diabetic Retinopathy Study best corrected visual acuity (ETDRS-BCVA) | 104 weeks | 
| Changes in Visual Function | Changes in visual function outcomes as measured by National Eye Institute Visual Functioning Questionnaire (NEI-VFQ) | 104 weeks | 
| DRSS Change | Changes in DRSS | 104 weeks | 
| Change in Non-Perfusion | Change in area of retinal non-perfusion within the macula and periphery | 104 weeks | 
| Change in Vascular Leakage | Change in relative area of vascular leakage on wide-field fluorescein angiography | 104 weeks | 
| Change in microaneurysms | Change in number of microaneurysms, assessed by wide-field fluorescein angiography | 104 weeks | 
| Change in CST | Mean change in central subfield thickness (CST), as assessed by spectral Domain Optical coherence tomography (SD-OCT) | 104 weeks | 
| DME development | Percentage of subjects, who develop center-involving diabetic macular edema necessitating treatment compared to baseline | 104 weeks | 
| PDR Development | Percentage of subjects, who develop a new PDR event compared to baseline | 104 weeks | 
| Cytokine Levels | Corelation of cytokine levels in aqueous humor samples to clinical and imaging outcomes | 104 weeks |