Intravitreous Anti-Vascular Endothelial Growth Factor Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk
Overview
- Phase
- Phase 3
- Intervention
- Prompt Sham
- Conditions
- Diabetic Retinopathy
- Sponsor
- Jaeb Center for Health Research
- Enrollment
- 399
- Locations
- 85
- Primary Endpoint
- Development of PDR and/or DME (Whichever Came First)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
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
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age \>= 18 years
- •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 and/or World Health Organization criteria
- •Able and willing to provide informed consent.
- •Meets all of the following ocular criteria in at least one eye:
- •Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity letter score ≥79 (approximate Snellen equivalent 20/25 or better)
- •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.
Exclusion Criteria
- •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).
- •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.
- •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.
- •Known allergy to any component of the study drug or any drug used in the injection prep (including povidone iodine prep).
- •Known allergy to fluorescein dye.
- •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.
- •Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization.
- •These drugs should not be used during the study.
Arms & Interventions
Observation (Prompt 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.
Intervention: Prompt Sham
Observation (Prompt 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.
Intervention: Deferred laser
Observation (Prompt 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.
Intervention: Deferred aflibercept
Prompt 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.
Intervention: Prompt aflibercept
Prompt 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.
Intervention: Deferred laser
Prompt 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.
Intervention: Deferred aflibercept
Outcomes
Primary Outcomes
Development of PDR and/or DME (Whichever Came First)
Time Frame: 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
Time Frame: 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 Outcomes
- Change in Visual Acuity From Baseline(4 years)
- Development of PDR and/or DME (Whichever Came First)(4 years)