Experimental medicine treatment for prevention of vision complications of those with diabetic retinopathy

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"Can blocking vascular endothelial growth factor (Anti-VEGF) treatment prevent vision complications for those with diabetic retinopathy?"
18 to 100 years old
Healthy Volunteers:
diabetic retinopathy, eye, diabetes
Procedure study, Phase 3
The purpose of this study is to find out if periodic injections of a drug into the eye can prevent the worsening of diabetic retinopathy. Eyes with non-proliferative diabetic retinopathy like yours are at a high risk of developing two complications that can affect vision: 1) proliferative diabetic retinopathy (PDR) or 2) diabetic macular edema (DME).
PDR means that new blood vessels and scar tissue form on the retina because of poor blood flow to the back part of the eye from diabetes. These new blood vessels can bleed into the middle of the eye, which can cause loss of vision and even blindness.
DME is the term used for swelling in the central part of the retina, which is caused by leaky blood vessels. When the swelling is in the center of the macula, it can reduce vision. This is because the center of the macula is used for sharp vision used for reading or driving or recognizing faces.
Both PDR and DME can be treated with repeated injections of drug into the eye to try to make the abnormal blood vessels or swelling of the retina go away. The drug is used to block or decrease a substance called vascular endothelial growth factor (it is an “anti-VEGF drug”).
There are several anti-VEGF drugs that are used to treat diabetic eye diseases; however, Eylea® (aflibercept) is the anti-VEGF drug being used in this study. Eylea injections into the eye have been approved by the U.S. Food and Drug Administration for treatment of DME and also for treatment of diabetic retinopathy in eyes with DME. Injections of Eylea have not been approved for diabetic eye disease in eyes that do not have DME that will be included in this study. Therefore, injections in this study are considered experimental.
Another anti-VEGF drug, Lucentis (ranibizumab) is approved by the FDA for the treatment of diabetic eye disease either with or without DME. There is no information to suggest that Lucentis works better than Eylea or better than observation for treating this level of diabetic eye disease.
For eyes with poor vision from diabetic retinopathy conditions, we know that repeated injections of anti-VEGF drug can stabilize vision and sometimes improve vision. However, it is possible that treatment will not bring all of the vision back that may have been lost as PDR or DME developed. Starting less frequent injections of anti-VEGF drugs now may keep your eye from having vision loss from PDR or DME. On the other hand, it is possible that these less frequent injections may not prevent the development of PDR or DME or may not help your vision in the long run.
The information from this study will be used to weigh the costs and benefits of two treatment approaches:
1) Starting periodic injections of anti-VEGF drug early OR
2) Observing (or watching) until the diabetic retinopathy has worsened to PDR or DME and then treating with anti-VEGF drug injections
The study will first look at the number of eyes that develop PDR or DME by 2 years to see if there is a difference when periodic injections are started early. However, if an eye develops PDR or DME, this may or may not correspond to a loss of vision. Therefore, the study will also compare the average vision at 4 years to see if there is a difference in vision outcomes when injections are started earlyPDR or DME, this may or may not correspond to a loss of vision. Therefore, the study will also compare the average vision at 4 years to see if there is a difference in vision outcomes when injections are started early.
This study requires
Usual care visual acuity
Electronic visual acuity
OCT (Optical Coherence Tomography )
Eye Exam
Retina Photography
Fluorescein angiography (looks for blood vessel leaks in eyes from Diabetes)
OCT angiography (looks at blood vessels in eyes)
Blood pressure
Injection (anti-VEGF or sham)
Who can participate?
Inclusion Criteria:

1. Age >= 18 years

2. Diagnosis of diabetes mellitus (type 1 or type 2)

• Any one of the following will be considered to be sufficient evidence that diabetes is present:

1. Current regular use of insulin for the treatment of diabetes

2. Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes

3. Documented diabetes by American Diabetes Association and/or World Health Organization criteria

3. Able and willing to provide informed consent.

Meets all of the following ocular criteria in at least one eye:

1. Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity letter score ≥79 (approximate Snellen equivalent 20/25 or better)

2. Severe non-proliferative diabetic retinopathy (NPDR) (based on the 4:2:1 rule) evident on clinical examination and on digital imaging as judged by the investigator, confirmed by central Reading Center grading prior to randomization as ETDRS level 47B to 53E. Severe NPDR is defined as:

1. All 4 midperipheral quadrants show severe hemorrhages or microaneurysms (at least as great as Standard photograph 2A, approximately 20 dot and blot hemorrhages), or

2. At least 2 fields of definite venous beading in the midperipheral quadrants or at least 1 field at least as severe as Standard photograph 6A, or

3. At least 1 field of moderate intraretinal microvascular abnormalities (IRMA) in the midperipheral quadrants, at least as severe as Standard photograph 8A

3. No evidence of neovascularization on clinical exam including active neovascularization of the iris (small iris tufts are not an exclusion) or angle neovascularization (if the angle is assessed).

4. No evidence of neovascularization (NV) on fluorescein angiography within the 7-modified ETDRS fields, confirmed by the central Reading Center prior to randomization.

• The widest method of imaging available at the site must be used to document whether there is NV present in the periphery; however, presence of NV outside of the 7-modified ETDRS fields on ultrawide field imaging will not be an exclusion provided treatment is not planned.

5. No center-involved diabetic macular edema (CI-DME) on clinical exam and optical coherence tomography (OCT) central subfield thickness must be below the following gender and OCT-machine specific thresholds:

1. Zeiss Cirrus: 290 µm in women and 305 µm in men

2. Heidelberg Spectralis: 305 µm in women and 320 µm in men

3. Investigator and potential participant are comfortable withholding treatment for DME until there is at least a 10% increase in OCT central subfield thickness with confirmed visual acuity loss (10 letter loss at a single visit or 5 to 9 at two consecutive visits).

6. Prompt panretinal photocoagulation (PRP) or anti-vascular endothelial growth factor (anti-VEGF) treatment not required AND investigator and potential participant are willing to wait for development of high-risk characteristics (defined in protocol) to treat PDR.

7. Media clarity, pupillary dilation, and study participant cooperation sufficient to obtain adequate fundus photographs, fluorescein angiogram, and OCT.

- Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality (including segmentation line placement)

Exclusion Criteria:

1. History of chronic renal failure requiring dialysis or kidney transplant.

2. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic control).

3. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months.

4. Participation in an investigational trial that involved treatment within 30 days of randomization with any drug that has not received regulatory approval for the indication being studied.

• Note: study participants cannot participate in another investigational trial that involves treatment with an investigational drug while participating in the study.

5. Known allergy to any component of the study drug or any drug used in the injection prep (including povidone iodine prep).

6. Known allergy to fluorescein dye.

7. Blood pressure > 180/110 (systolic above 180 or diastolic above 110). • If blood pressure is brought below 180/110 by anti-hypertensive treatment, individual can become eligible.

8. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization.

• These drugs should not be used during the study.

9. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 2 years.

• Women who are potential study participants should be questioned about the potential for pregnancy. Investigator judgment is used to determine when a pregnancy test is needed.

10. Individual is expecting to move out of the area of the clinical center to an area not covered by another Diabetic Retinopathy Clinical Research Network certified clinical center during the next 2 years.

Individual has any of the following ocular characteristics in the eye(s) being evaluated:

1. Exam or photographic evidence of vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.

2. History of prior vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.

3. History of prior PRP (defined as ≥100 burns outside of the posterior pole).

4. An ocular condition is present (other than diabetic retinopathy) that, in the opinion of the investigator, might alter visual acuity during the course of the study (e.g., retinal vein or artery occlusion, uveitis or other ocular inflammatory disease, vitreomacular traction, etc.).

5. History of DME or diabetic retinopathy treatment with laser or intraocular injections of medication within the prior 12 months and no more than 4 prior intraocular injections at any time in the past.

• Enrollment will be limited to a maximum of 25% of the planned sample size with any history of treatment for DME and/or diabetic retinopathy. Once this number of eyes has been enrolled, any history of treatment for DME and/or diabetic retinopathy will be an exclusion criterion.

6. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization.

7. Any history of vitrectomy.

8. History of yttrium aluminum garnet capsulotomy performed within 2 months prior to randomization.

9. Aphakia.

10. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis.

11. Evidence of uncontrolled glaucoma.

- Intraocular pressure must be <30, with no more than one topical glaucoma medication, and no documented glaucomatous field loss for the eye to be eligible.
Study duration and period
Four years
Recruitment period
From Aug. 23, 2016
UC Davis Eye Center
4860 Y Street
Sacramento, CA 95817
Angela Beliveau
Research Topic
  • Diabetic Retinopathy
  • Diabetic Macular Edema

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