Proliferative Diabetic Retinopathy
Conditions
Brief summary
The primary objective of the protocol is to determine if visual acuity outcomes at 2 years in eyes with proliferative diabetic retinopathy (PDR) that receive anti-vascular endothelial growth factor (anti-VEGF) therapy with deferred panretinal photocoagulation (PRP) are non-inferior to those in eyes that receive standard prompt PRP therapy. Secondary objectives include: * Comparing other visual function outcomes (including Humphrey visual field testing and study participant self-reports of visual function) in eyes receiving anti-VEGF with deferred PRP with those in eyes receiving prompt PRP. * Determining percent of eyes not requiring PRP when anti-VEGF is given in the absence of prompt PRP. * Comparing safety outcomes between treatment groups. * Comparing associated treatment and follow-up exam costs between treatment groups.
Interventions
Panretinal photocoagulation alone at baseline (full session completed within 56 days).
DRUG0.5-mg Ranibizumab
Intravitreal injection of 0.5 mg ranibizumab (Lucentis™) at baseline and up to every 4 weeks using defined retreatment criteria.
OTHERDeferred panretinal photocoagulation
PRP is deferred until failure/futility criteria for intravitreal injection are met.
Sponsors
National Eye Institute (NEI)
Genentech, Inc.
Jaeb Center for Health Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Age \>= 18 years -Individuals \< 18 years old are not being included because proliferative diabetic retinopathy (PDR) is so rare in this age group that the diagnosis of PDR may be questionable. 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: * Current regular use of insulin for the treatment of diabetes * Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes * Documented diabetes by American Diabetes Association (ADA) and/or World Health Organization (WHO) criteria (see Procedures Manual for definitions) Able and willing to provide informed consent. Meets at least all of the following ocular criteria criteria: * Presence of PDR which the investigator intends to manage with PRP alone but for which PRP can be deferred for at least 4 weeks in the setting of intravitreal ranibizumab, in the investigator's judgment. * Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity letter score \> 24 (approximate Snellen equivalent 20/320) on the day of randomization. * Media clarity, pupillary dilation, and study participant cooperation sufficient to administer PRP and obtain adequate fundus photographs and optical coherence tomography (OCT). * Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality
Exclusion criteria
Significant renal disease, defined as a history of chronic renal failure requiring dialysis or kidney transplant. 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). * Individuals in poor glycemic control who, within the last 4 months, initiated intensive insulin treatment (a pump or multiple daily injections) or plan to do so in the next 4 months should not be enrolled. Participation in an investigational trial within 30 days of randomization that involved treatment with any drug that has not received regulatory approval for the indication being studied. * Study participants cannot receive another investigational drug while participating in the study. Known allergy to any component of the study drug. 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. Myocardial infarction, other acute cardiac event requiring hospitalization, stroke, transient ischemic attack, or treatment for acute congestive heart failure within 4 months prior to randomization. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization. * These drugs should not be used during the study. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 3 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. 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 (DRCR.net) certified clinical center during the 3 years of the study. Individual has any of the following ocular characteristics: * History of prior panretinal photocoagulation (prior PRP is defined as ≥ 100 burns outside of the posterior pole) * Tractional retinal detachment involving the macula. \-- A tractional retinal detachment is not an exclusion if it is outside of the posterior pole (not threatening the macula) and in the investigator's judgment, is not a contraindication to intravitreal ranibizumab treatment and also does not preclude deferring PRP for at least 4 weeks in the setting of intravitreal ranibizumab * Exam evidence of neovascularization of the angle (neovascularization of the iris alone is not an exclusion if it does not preclude deferring PRP for at least 4 weeks in the investigator's judgment). * If macular edema is present, it is considered to be primarily due to a cause other than diabetic macular edema. \-- An eye should not be considered eligible if: * macular edema is present that is considered to be related to ocular surgery such as cataract extraction or * clinical exam and/or OCT suggest that vitreoretinal interface abnormalities disease (e.g., a taut posterior hyaloid or epiretinal membrane) is the primary cause of any macular edema. * 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, neovascular glaucoma, etc.). \-- A vitreous or preretinal hemorrhage is not an exclusion if it is out of the visual axis and in the investigator's judgment is not having any affect on visual acuity. * Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye were otherwise normal). * History of intravitreal anti-VEGF treatment at any time in the past 2 months. * History of corticosteroid treatment (intravitreal or peribulbar) at any time in the past 4 months. --If the investigator believes that there may still be a substantial effect 4 months after prior treatment (e.g., dose of intravitreal triamcinolone higher than 4 mg), the eye should not be included. * History of major ocular surgery (including vitrectomy, cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization. * History of (yttrium-aluminum-garnet) YAG capsulotomy performed within 2 months prior to randomization. * Aphakia. * Uncontrolled glaucoma (in investigator's judgment). * Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean 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 |
|---|---|---|
| Number of Eyes With Greater Than or Equal to 10 Letter Vision Gain | 2-years | — |
| Humphrey Visual Field Test Cumulative Score Change From Baseline | 2-years | Visual fields, collected using the Humphrey Visual Field analyzer, measured the total point score (sum of retinal sensitivities of all points) tested on 30-2 and 60-4 patterns, which included the mid-peripheral and peripheral visual fields. A lower score indicates greater visual field loss.The cumulative score is the sum of all visual field sensitivity values for each of the four individual quadrants of the visual field (the quadrants are divided by the horizontal and vertical lines). The range can be from 0 to about 600 for the 30-2 test \[for each quadrant\], and from 0 to about 400 or 450 for the peripheral test. |
| Frequency of Vitrectomy | 2-years | — |
| Mean Change in OCT Central Subfield Thickness From Baseline | 2-years | All baseline and 2-year optical coherence tomography (OCT) scans were evaluated by the OCT reading center. |
| Mean Visual Acuity | 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. |
| Number of Eyes With Vitreous Hemorrhage | 2-years | — |
| Number of Eyes Without Active or Regressed Neovascularization on Fundus Photography at 2-years | 2-years | — |
| Number of Eyes With Greater Than or Equal to 10 Letter Vision Loss | 2-year | — |
| Development of Central DME With Vision Impairment by 2-years | 2-years | — |
Countries
United States
Participant flow
Recruitment details
Participants with 2 eyes in the study had 1 eye randomly assigned to receive ranibizumab and 1 eye to receive panretinal photocoagulation. Two-year completed visits include those that occurred between 644 and 812 days (between 92 and 116 weeks).
Participants by arm
| Arm | Count |
|---|---|
| Anti-VEGF+Deferred PRP Anti-VEGF= Anti vascular endothelial growth factor. PRP= Panretinal photocoagulation. Intravitreal anti-VEGF with PRP only if indicated.
0.5-mg Ranibizumab: Intravitreal injection of 0.5 mg ranibizumab (Lucentis™) at baseline and up to every 4 weeks using defined retreatment criteria.
Deferred panretinal photocoagulation: PRP is deferred until failure/futility criteria for intravitreal injection are met. | 191 |
| Prompt PRP PRP= Panretinal Photocoagulation. PRP alone.
Prompt Panretinal Photocoagulation: Panretinal photocoagulation alone at baseline (full session completed within 56 days). | 203 |
| Total | 394 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 10 | 8 |
| Overall Study | Missed Visit | 1 | 4 |
| Overall Study | Withdrawal by Subject | 20 | 23 |
Baseline characteristics
| Characteristic | Prompt PRP | Total | Anti-VEGF+Deferred PRP |
|---|---|---|---|
| Age, Customized | 51 years | 51 years | 52 years |
| Arterial Blood Pressure | 99 mmHg | 99 mmHg | 99 mmHg |
| Diabetes Type Type 1 | 41 eyes | 84 eyes | 43 eyes |
| Diabetes Type Type 2 | 155 eyes | 295 eyes | 140 eyes |
| Diabetes Type Uncertain | 7 eyes | 15 eyes | 8 eyes |
| Diabetic Retinopathy Severity Advanced PDR, macular center attached (level 81) | 0 eyes | 2 eyes | 2 eyes |
| Diabetic Retinopathy Severity Advanced PDR, macular center detached (level 85) | 1 eyes | 2 eyes | 1 eyes |
| Diabetic Retinopathy Severity High-risk PDR (levels 71 and 75) | 73 eyes | 142 eyes | 69 eyes |
| Diabetic Retinopathy Severity Microaneurysms only (level 20) | 1 eyes | 1 eyes | 0 eyes |
| Diabetic Retinopathy Severity Mild NPDR (level 35) | 4 eyes | 10 eyes | 6 eyes |
| Diabetic Retinopathy Severity Mild PDR (level 61) | 31 eyes | 61 eyes | 30 eyes |
| Diabetic Retinopathy Severity Moderately severe NPDR (level 47) | 15 eyes | 25 eyes | 10 eyes |
| Diabetic Retinopathy Severity Moderate NPDR (level 43) | 5 eyes | 7 eyes | 2 eyes |
| Diabetic Retinopathy Severity Moderate PDR (level 65) | 67 eyes | 135 eyes | 68 eyes |
| Diabetic Retinopathy Severity Prior PRP without active PDR (level 60) | 1 eyes | 1 eyes | 0 eyes |
| Diabetic Retinopathy Severity Severe NPDR (level 53) | 1 eyes | 2 eyes | 1 eyes |
| Duration of Diabetes | 17 years | 18 years | 18 years |
| Hemoglobin A1c | 8.9 percent | 8.7 percent | 8.6 percent |
| Neovascularization on Clinical Examination Elsewhere | 174 eyes | 340 eyes | 166 eyes |
| Neovascularization on Clinical Examination Of the disc | 103 eyes | 199 eyes | 96 eyes |
| Number of study eyes One | 114 eyes | 216 eyes | 102 eyes |
| Number of study eyes Two (one in each group) | 89 eyes | 178 eyes | 89 eyes |
| Optical Coherence Tomography Central Subfield Thickness | 230 µm | 229 µm | 223 µm |
| Phakic Lens Status on Clinical Exam | 187 eyes | 357 eyes | 170 eyes |
| Presence of Center-Involved Diabetic Macular Edema Regardless of Visual Acuity | 62 eyes | 117 eyes | 55 eyes |
| Presence of Center-Involved Diabetic Macular Edema with Visual Acuity Impairment | 46 eyes | 88 eyes | 42 eyes |
| Prior anti-VEGF treatment for DME | 13 eyes | 34 eyes | 21 eyes |
| Prior focal/grid laser treatment for DME | 29 eyes | 59 eyes | 30 eyes |
| Prior Myocardial Infarction | 4 eyes | 7 eyes | 3 eyes |
| Prior Stroke | 3 eyes | 7 eyes | 4 eyes |
| Prior treatment for diabetic macular edema (DME) | 36 eyes | 79 eyes | 43 eyes |
| Race/Ethnicity, Customized American Indian/Alaskan Native | 0 eyes | 1 eyes | 1 eyes |
| Race/Ethnicity, Customized Asian | 3 eyes | 5 eyes | 2 eyes |
| Race/Ethnicity, Customized Black/African American | 43 eyes | 81 eyes | 38 eyes |
| Race/Ethnicity, Customized Hispanic | 51 eyes | 99 eyes | 48 eyes |
| Race/Ethnicity, Customized More than 1 race | 2 eyes | 2 eyes | 0 eyes |
| Race/Ethnicity, Customized Unknown/not reported | 3 eyes | 5 eyes | 2 eyes |
| Race/Ethnicity, Customized White | 101 eyes | 201 eyes | 100 eyes |
| Sex/Gender, Customized Female | 92 eyes | 175 eyes | 83 eyes |
| Sex/Gender, Customized Male | 111 eyes | 219 eyes | 108 eyes |
| Visual Acuity | 75.2 letters STANDARD_DEVIATION 12.5 | 75.1 letters STANDARD_DEVIATION 12.6 | 75 letters STANDARD_DEVIATION 12.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 85 / 89 | 96 / 102 | 105 / 114 |
| serious Total, serious adverse events | 36 / 89 | 50 / 102 | 43 / 114 |
Outcome results
Primary
Mean 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
Population: Participants that completed the 2-year visit.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Anti-VEGF+Deferred PRP | Mean Change in Visual Acuity From Baseline | 2.8 letters |
| Prompt PRP | Mean Change in Visual Acuity From Baseline | 0.2 letters |
Secondary
Development of Central DME With Vision Impairment by 2-years
Time frame: 2-years
Population: Excludes that did not have central DME with vision impairment (20/32 or worse) at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anti-VEGF+Deferred PRP | Development of Central DME With Vision Impairment by 2-years | 15 eyes |
| Prompt PRP | Development of Central DME With Vision Impairment by 2-years | 42 eyes |
Secondary
Frequency of Vitrectomy
Time frame: 2-years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anti-VEGF+Deferred PRP | Frequency of Vitrectomy | 8 eyes |
| Prompt PRP | Frequency of Vitrectomy | 30 eyes |
Secondary
Humphrey Visual Field Test Cumulative Score Change From Baseline
Visual fields, collected using the Humphrey Visual Field analyzer, measured the total point score (sum of retinal sensitivities of all points) tested on 30-2 and 60-4 patterns, which included the mid-peripheral and peripheral visual fields. A lower score indicates greater visual field loss.The cumulative score is the sum of all visual field sensitivity values for each of the four individual quadrants of the visual field (the quadrants are divided by the horizontal and vertical lines). The range can be from 0 to about 600 for the 30-2 test \[for each quadrant\], and from 0 to about 400 or 450 for the peripheral test.
Time frame: 2-years
Population: Humphrey visual fields were obtained at a subset of sites. Fields with excessive false positive response, excessive false negative response, or excessive fixation loss were excluded from analysis. Twenty-two eyes in the anti-VEGF+deferred PRP group and 25 eyes in the prompt PRP group were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anti-VEGF+Deferred PRP | Humphrey Visual Field Test Cumulative Score Change From Baseline | -25 decibels |
| Prompt PRP | Humphrey Visual Field Test Cumulative Score Change From Baseline | -379 decibels |
Secondary
Mean Change in OCT Central Subfield Thickness From Baseline
All baseline and 2-year optical coherence tomography (OCT) scans were evaluated by the OCT reading center.
Time frame: 2-years
Population: Eyes with optical coherence tomography (OCT) data at baseline and 2-years.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Anti-VEGF+Deferred PRP | Mean Change in OCT Central Subfield Thickness From Baseline | -47 µm |
| Prompt PRP | Mean Change in OCT Central Subfield Thickness From Baseline | -3 µm |
Secondary
Mean Visual Acuity
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
Population: Participants that completed the 2-year visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-VEGF+Deferred PRP | Mean Visual Acuity | 78.7 letters | Standard Deviation 16.3 |
| Prompt PRP | Mean Visual Acuity | 76.2 letters | Standard Deviation 14.1 |
Secondary
Number of Eyes With Greater Than or Equal to 10 Letter Vision Gain
Time frame: 2-years
Population: Eyes with a baseline letter score of 78 or less (approximate Snellen equivalent 20/32 or worse) from participants that completed the 2-year visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anti-VEGF+Deferred PRP | Number of Eyes With Greater Than or Equal to 10 Letter Vision Gain | 35 eyes |
| Prompt PRP | Number of Eyes With Greater Than or Equal to 10 Letter Vision Gain | 31 eyes |
Secondary
Number of Eyes With Greater Than or Equal to 10 Letter Vision Loss
Time frame: 2-year
Population: Participants that completed the 2-year visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anti-VEGF+Deferred PRP | Number of Eyes With Greater Than or Equal to 10 Letter Vision Loss | 15 eyes |
| Prompt PRP | Number of Eyes With Greater Than or Equal to 10 Letter Vision Loss | 23 eyes |
Secondary
Number of Eyes Without Active or Regressed Neovascularization on Fundus Photography at 2-years
Time frame: 2-years
Population: Eyes with baseline diabetic retinopathy level 61B or worse (active neovascularization). Last-observation-carried-forward was used for 23 eyes in the anti-VEGF+Deferred PRP group and 25 eyes in the Prompt PRP group missing photographs at 2 years if 1-year fundus photographs were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anti-VEGF+Deferred PRP | Number of Eyes Without Active or Regressed Neovascularization on Fundus Photography at 2-years | 49 eyes |
| Prompt PRP | Number of Eyes Without Active or Regressed Neovascularization on Fundus Photography at 2-years | 44 eyes |
Secondary
Number of Eyes With Vitreous Hemorrhage
Time frame: 2-years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anti-VEGF+Deferred PRP | Number of Eyes With Vitreous Hemorrhage | 52 Eyes |
| Prompt PRP | Number of Eyes With Vitreous Hemorrhage | 69 Eyes |