Diabetic Macular Edema, Diabetic Retinopathy
Conditions
Keywords
anti-vascular endothelial growth factor, nonproliferative diabetic retinopathy
Brief summary
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
Interventions
PROCEDUREPrompt Sham
A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
PROCEDUREDeferred laser
Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
Sponsors
Regeneron Pharmaceuticals
Juvenile Diabetes Research Foundation
National Eye Institute (NEI)
National Institutes of Health (NIH)
Jaeb Center for Health Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Development of PDR and/or DME (Whichever Came First) | 2 years | CI-DME = center-involved diabetic macular edema, PDR = proliferative diabetic macular edema. First development of criteria meeting end point. Eyes that met any criteria are then censored from contributing to the next criteria. Eyes that did not meet the outcome were censored at the time of the last completed visit. Each outcome appears only once under First PDR and/or DME criteria met. Outcomes appear under Development of PDR if PDR developed at any time in the study (regardless of if or when DME developed) and outcomes appear under Development of DME if DME developed at any time in the study (regardless of if or when PDR developed) |
| Change in Visual Acuity From Baseline | 2 years | Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Visual Acuity From Baseline | 4 years | Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart. |
| Development of PDR and/or DME (Whichever Came First) | 4 years | CI-DME = center-involved diabetic macular edema, PDR = proliferative diabetic macular edema. First development of criteria meeting end point. Eyes that met any criteria are then censored from contributing to the next criteria. Eyes that did not meet the outcome were censored at the time of the last completed visit. Each outcome appears only once under First PDR and/or DME criteria met. Outcomes appear under Development of PDR if PDR developed at any time in the study (regardless of if or when DME developed) and outcomes appear under Development of DME if DME developed at any time in the study (regardless of if or when PDR developed) |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aflibercept Aflibercept injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. More frequent aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.
Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria. | 200 |
| Aflibercept Aflibercept injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. More frequent aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.
Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria. | 200 |
| Sham Sham injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.
Prompt Sham: A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria. | 199 |
| Sham Sham injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.
Prompt Sham: A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria. | 199 |
| Total | 798 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Completed out of Window | 3 | 2 |
| Overall Study | Death | 11 | 8 |
| Overall Study | Lost to Follow-up | 12 | 7 |
| Overall Study | Missed Visit | 5 | 2 |
| Overall Study | Withdrawal by Subject | 9 | 13 |
Baseline characteristics
| Characteristic | Aflibercept | Sham | Total |
|---|---|---|---|
| Age, Continuous | 57 years | 56 years | 57 years |
| Body mass index | 31 kg/m^2 | 31 kg/m^2 | 31 kg/m^2 |
| Diabetes Type Type 1 | 12 Eyes | 23 Eyes | 35 Eyes |
| Diabetes Type Type 2 | 188 Eyes | 176 Eyes | 364 Eyes |
| Diabetic retinopathy severity scale level Moderately severe NPDR (level 47A) | 65 Eyes | 61 Eyes | 126 Eyes |
| Diabetic retinopathy severity scale level Moderately severe NPDR (level 47B-D) | 54 Eyes | 55 Eyes | 109 Eyes |
| Diabetic retinopathy severity scale level Moderate NPDR (level 43) | 33 Eyes | 35 Eyes | 68 Eyes |
| Diabetic retinopathy severity scale level Severe NPDR (level 53) | 48 Eyes | 48 Eyes | 96 Eyes |
| Duration of Diabetes | 17 years | 16 years | 16 years |
| Hemoglobin A1c | 8.6 Percent | 8.3 Percent | 8.4 Percent |
| Intraocular pressure | 15 mmHg | 15 mmHg | 15 mmHg |
| Lens status Phakic | 166 Eyes | 167 Eyes | 333 Eyes |
| Lens status Posterior chamber Intraocular lens | 34 Eyes | 32 Eyes | 66 Eyes |
| Mean arterial blood pressure | 100 mmHg | 98 mmHg | 99 mmHg |
| Non-central diabetic macular edema | 75 Eyes | 83 Eyes | 158 Eyes |
| Optical coherence tomography central subfield thickness | 283 Microns | 283 Microns | 283 Microns |
| Pre-existing renal disease | 6 Participant | 6 Participant | 11 Participant |
| Prior anti-vascular endothelial growth factor therapy for diabetic macular edema | 8 Eyes | 5 Eyes | 13 Eyes |
| Prior focal or grid laser for diabetic macular edema | 12 Eyes | 19 Eyes | 31 Eyes |
| Prior myocardial infarction | 16 Participant | 19 Participant | 35 Participant |
| Prior stroke | 13 Participant | 11 Participant | 21 Participant |
| Race/Ethnicity, Customized American Indian or Alaskan native | 1 Eyes | 0 Eyes | 1 Eyes |
| Race/Ethnicity, Customized Asian | 10 Eyes | 9 Eyes | 19 Eyes |
| Race/Ethnicity, Customized Black or African American | 29 Eyes | 32 Eyes | 61 Eyes |
| Race/Ethnicity, Customized Hispanic or Latino | 62 Eyes | 67 Eyes | 129 Eyes |
| Race/Ethnicity, Customized More than one race | 3 Eyes | 1 Eyes | 4 Eyes |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 1 Eyes | 1 Eyes | 2 Eyes |
| Race/Ethnicity, Customized Unknown | 2 Eyes | 3 Eyes | 5 Eyes |
| Race/Ethnicity, Customized White | 92 Eyes | 86 Eyes | 178 Eyes |
| Sex/Gender, Customized Female | 83 Eyes | 86 Eyes | 139 Eyes |
| Sex/Gender, Customized Male | 117 Eyes | 113 Eyes | 189 Eyes |
| Visual acuity | 88 letter score | 88 letter score | 88 letter score |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 129 | 10 / 128 | 5 / 71 |
| other Total, other adverse events | 116 / 129 | 112 / 128 | 62 / 71 |
| serious Total, serious adverse events | 52 / 129 | 50 / 128 | 24 / 71 |
Outcome results
Primary
Change in Visual Acuity From Baseline
Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart.
Time frame: 2 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept | Change in Visual Acuity From Baseline | -0.9 Letter Score | Standard Deviation 5.8 |
| Sham | Change in Visual Acuity From Baseline | -2.0 Letter Score | Standard Deviation 6.1 |
Primary
Development of PDR and/or DME (Whichever Came First)
CI-DME = center-involved diabetic macular edema, PDR = proliferative diabetic macular edema. First development of criteria meeting end point. Eyes that met any criteria are then censored from contributing to the next criteria. Eyes that did not meet the outcome were censored at the time of the last completed visit. Each outcome appears only once under First PDR and/or DME criteria met. Outcomes appear under Development of PDR if PDR developed at any time in the study (regardless of if or when DME developed) and outcomes appear under Development of DME if DME developed at any time in the study (regardless of if or when PDR developed)
Time frame: 2 years
Population: Units are in eyes. A participant could have 2 study eyes. For participants with two study eyes the participant was randomly assigned to receive sham in the eye with worse diabetic retinopathy and aflibercept in the other, or aflibercept in the eye with the worse diabetic retinopathy and sham in the other.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept | Development of PDR and/or DME (Whichever Came First) | 27 Eyes |
| Sham | Development of PDR and/or DME (Whichever Came First) | 75 Eyes |
Secondary
Change in Visual Acuity From Baseline
Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart.
Time frame: 4 years
Population: Includes only eyes that completed the 4-year visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept | Change in Visual Acuity From Baseline | -2.7 Letter Score | Standard Deviation 6.5 |
| Sham | Change in Visual Acuity From Baseline | -2.4 Letter Score | Standard Deviation 5.8 |
Secondary
Development of PDR and/or DME (Whichever Came First)
CI-DME = center-involved diabetic macular edema, PDR = proliferative diabetic macular edema. First development of criteria meeting end point. Eyes that met any criteria are then censored from contributing to the next criteria. Eyes that did not meet the outcome were censored at the time of the last completed visit. Each outcome appears only once under First PDR and/or DME criteria met. Outcomes appear under Development of PDR if PDR developed at any time in the study (regardless of if or when DME developed) and outcomes appear under Development of DME if DME developed at any time in the study (regardless of if or when PDR developed)
Time frame: 4 years
Population: Units are in eyes. A participant could have 2 study eyes. For participants with two study eyes the participant was randomly assigned to receive sham in the eye with worse diabetic retinopathy and aflibercept in the other, or aflibercept in the eye with the worse diabetic retinopathy and sham in the other.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept | Development of PDR and/or DME (Whichever Came First) | 54 Eyes |
| Sham | Development of PDR and/or DME (Whichever Came First) | 97 Eyes |