Anti-VEGF Treatment for Prevention of PDR/DME



Status:Active, not recruiting
Conditions:Ocular, Ocular, Diabetes
Therapuetic Areas:Endocrinology, Ophthalmology
Healthy:No
Age Range:18 - Any
Updated:8/26/2018
Start Date:January 2016
End Date:January 2022

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Intravitreous Anti-Vascular Endothelial Growth Factor Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk

Multiple studies have implicated vascular endothelial growth factor VEGF as a major causative
factor in human eye diseases characterized by neovascularization including proliferative
diabetic retinopathy (PDR) and vascular permeability including diabetic macular edema (DME).
While there is strong evidence that PDR outcomes are markedly reduced in eyes that are
treated with monthly anti-VEGF therapy (A Study of Ranibizumab Injection in Subjects With
Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes
Mellitus: RIDE/RISE) and moderately reduced in eyes that received fairly frequent dosing
during the 1st year of treatment (Diabetic Retinopathy Clinical Research Network protocol I),
it is unknown whether or not an earlier but less frequent dosing regimen would result in
similar, favorable anatomic outcomes, and whether favorable anatomic outcomes subsequently
would result in favorable visual acuity outcomes.

If this study demonstrates that intravitreous aflibercept treatment is effective and safe for
reducing the onset of PDR or center involved- DME (CI-DME) in eyes that are at high risk for
these complications, a new strategy to prevent vision threatening complications of diabetes
will be available for patients. The application of intravitreous aflibercept earlier in the
course of disease (i.e., at the time when an eye has baseline severe non-proliferative
diabetic retinopathy) could help to reduce future potential treatment burden in patients, at
the same time resulting in similar or better long-term visual outcomes, if PDR and DME are
prevented.

The primary objectives of this protocol are to 1) determine the efficacy and safety of
intravitreous aflibercept injections versus sham injections (observation) for prevention of
PDR or CI-DME in eyes at high risk for development of these complications and 2) compare
long-term visual outcomes in eyes that receive anti-VEGF therapy early in the course of
disease with those that are observed initially, and treated only if high-risk PDR or CI-DME
with vision loss develops.

Secondary objectives include:

- Comparing other visual acuity outcomes between treatment groups, such as proportion of
eyes with at least 10 or at least 15 letter loss from baseline, or gain or loss of at
least 5 letters at the consecutive study visit just before and at the 2- or 4-year visit

- Comparing optical coherence tomography (OCT) outcomes, such as mean change in OCT
central subfield thickness and volume from baseline

- Comparing proportion of eyes with at least 2 and 3-step worsening or improvement of
diabetic retinopathy severity level (scale for individual eyes) by central reading
center from baseline

- Comparing associated treatment and follow-up exam costs between treatment groups

- Comparing safety outcomes between treatment groups


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. Reading
center grading of less than ETDRS level 43 or greater than 53 is an exclusion.

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.
We found this trial at
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