A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema: Bevacizumab (Avastin)
- Conditions
- Diabetic Retinopathy
- Interventions
- Procedure: Laser Photocoagulation
- Registration Number
- NCT00336323
- Lead Sponsor
- Jaeb Center for Health Research
- Brief Summary
This study will provide preliminary data on the dose and dose interval related effects of intravitreally administered Avastin on retinal thickness and visual acuity in subjects with Diabetic Macular Edema (DME) to aid in planning a phase 3 trial.
In addition, this study will provide preliminary data on the safety of intravitreally administered Avastin in subjects with DME.
- Detailed Description
Diabetic retinopathy is a major cause of visual impairment in the United States. Diabetic macular edema (DME) is a manifestation of diabetic retinopathy that produces loss of central vision. Data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) estimate that after 15 years of known diabetes, the prevalence of diabetic macular edema is approximately 20% in patients with type 1 diabetes mellitus (DM), 25% in patients with type 2 DM who are taking insulin, and 14% in patients with type 2 DM who do not take insulin.
In a review of three early studies concerning the natural history of diabetic macular edema, Ferris and Patz found that 53% of 135 eyes with diabetic macular edema, presumably all involving the center of the macula, lost two or more lines of visual acuity over a two year period. In the Early Treatment Diabetic Retinopathy Study (ETDRS), 33% of 221 untreated eyes available for follow-up at the 3-year visit, all with edema involving the center of the macula at baseline, had experienced a 15 or more letter decrease in visual acuity score (equivalent to a doubling of the visual angle, e.g., 20/25 to 20/50, and termed "moderate visual loss").
In the ETDRS, focal photocoagulation (direct treatment to microaneurysms and grid treatment to diffuse edema) of eyes with clinically significant macular edema (CSME) reduced the risk of moderate visual loss by approximately 50% (from 24% to 12%, three years after initiation of treatment). Therefore, 12% of treated eyes developed moderate visual loss in spite of treatment. Furthermore, approximately 40% of treated eyes that had retinal thickening involving the center of the macula at baseline still had thickening involving the center at 12 months, as did 25% of treated eyes at 36 months.
Although several treatment modalities are currently under investigation, the only demonstrated means to reduce the risk of vision loss from diabetic macular edema are laser photocoagulation, as demonstrated by the ETDRS, intensive glycemic control, as demonstrated by the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) and blood pressure control, as demonstrated by the UKPDS. In the DCCT, intensive glucose control reduced the risk of onset of diabetic macular edema by 23% compared with conventional treatment. Long-term follow-up of patients in the DCCT show a sustained effect of intensive glucose control, with a 58% risk reduction in the development of diabetic macular edema for the DCCT patients followed in the Epidemiology of Diabetes Interventions and Complications Study.
The frequency of an unsatisfactory outcome with respect to proportion with vision improvement following laser photocoagulation in some eyes with diabetic macular edema has prompted interest in other treatment modalities. One such treatment is pars plana vitrectomy. These studies suggest that vitreomacular traction, or the vitreous itself, may play a role in increased retinal vascular permeability. Removal of the vitreous or relief of mechanical traction with vitrectomy and membrane stripping may be followed by substantial resolution of macular edema and corresponding improvement in visual acuity. However, this treatment may be applicable only to a specific subset of eyes with diabetic macular edema that have a component of vitreomacular traction contributing to the edema. It also requires a complex surgical intervention with its inherent risks, recovery time, and expense. Other treatment modalities such as pharmacologic therapy with oral protein kinase C inhibitors and use of intravitreal corticosteroids are under investigation. The use of antibodies targeted at vascular endothelial growth factor (VEGF), such as in the current study, is another treatment modality that has generated considerable interest, and is currently being investigated in phase 3 trials of choroidal neovascularization in age-related macular degeneration (with pegaptanib or ranibizumab) or diabetic macular edema (with pegaptanib).
Increased VEGF levels have been demonstrated in the retina and vitreous of human eyes with diabetic retinopathy. VEGF, also known as vascular permeability factor, has been demonstrated to increase vessel permeability by increasing the phosphorylation of tight junction proteins, and has been shown to increase retinal vascular permeability in in vivo models. Anti-VEGF therapy, therefore, may represent a useful therapeutic modality which targets the underlying pathogenesis of diabetic macular edema.
Bevacizumab is currently approved for the treatment of metastatic colorectal cancer, and published case reports and widespread clinical use have suggested its efficacy in the treatment of neovascular age-related macular degeneration and macular edema associated with diabetes and central retinal vein occlusion. To date, no evidence of ocular inflammation or other adverse events has been noted in association with intravitreal injection of bevacizumab. However, a study has not been conducted to evaluate its efficacy and safety. In view of the widespread use of bevacizumab, such a study is important to conduct.
From a public health perspective, an intravitreal bevacizumab study is also important to conduct because of the relatively low cost of the bevacizumab drug. As noted earlier, bevacizumab is marketed for systemic use for colon cancer. The dose used in the eye is a fraction of the systemic dose and costs $25 to $50 per dose.
The two doses of bevacizumab being evaluated in this study will be 1.25 mg, which is the dose that has most commonly been used in clinical practice, and 2.5 mg, which has also been used though less commonly. A lower dose than 1.25 mg would create difficulties with dilution and the accuracy of injection of a small volume.
The optimal interval for the bevacizumab doses is not known. Six weeks has been selected for this study as it is not believed that the effect will last longer than this. Retinal thickening and visual acuity will be measured at 3 and 6 weeks to provide the requisite information to judge the duration of effect.
There is expected to be a beneficial cumulative effect of multiple doses. A total of two doses, spaced 6 weeks apart, was selected for the study with the primary outcome 3 weeks after the second dose.
The decision as to whether to proceed to a phase 3 trial will be based on the observation of a substantial reduction in retinal thickening in the bevacizumab-treated eyes compared with the laser-treated eyes and at least a suggestion of benefit on visual acuity, plus a safety profile of minimal risk.
Description: The study involves the enrollment of subjects over 18 years of age with diabetic macular edema. Subjects will have one study eye randomly assigned with equal probability (stratified by visual acuity) to one of 5 treatment groups:
Laser photocoagulation at baseline
1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks
2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks
1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks)
1.25 mg intravitreal injection of bevacizumab at baseline, laser photocoagulation at 3 weeks, and intravitreal injection of 1.25 mg bevacizumab at 6 weeks
Follow-up includes 10 visits at 4 days, 3 weeks, 6 weeks, 4 days following 6 weeks, 9 weeks, 12 weeks, 18 weeks, 24 weeks, 41 weeks and 70 weeks. At each visit, visual acuity and ocular exams are completed on both eyes, and an OCT is performed on the study eye (except at the 4-day visits).
During the first 12 weeks, no other treatment for DME is given. During weeks 13-24, treatment depends on the response to the treatment given during the first 12 weeks. After 24 weeks, follow-up is for safety and treatment is at the investigator's discretion.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 121
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 1 Laser Photocoagulation Laser photocoagulation at baseline 4 Bevacizumab 1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks) 2 Bevacizumab 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks 3 Bevacizumab 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks 5 Bevacizumab 1.25 mg intravitreal injection of bevacizumab at baseline, laser photocoagulation at 3 weeks, and intravitreal injection of 1.25 mg bevacizumab at 6 weeks
- Primary Outcome Measures
Name Time Method Change in Central Subfield Retinal Thickness From Baseline Over All Study Visits Baseline to 3,6,9, and 12 weeks Change in central subfield retinal thickness from baseline measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology. The OCT scans were sent to the DRCR.net Reading Center for grading. Negative changes represent a decrease in retinal thickening.
Percentage of Participants With <250 Microns or ≥ 50% Reduction in Retinal Thickening From Baseline Over All Study Visits Baseline to 3,6,9, and 12 Weeks Central subfield retinal thickness measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology. The OCT scans were sent to the DRCR.net Reading Center for grading.
- Secondary Outcome Measures
Name Time Method Distribution of Change in Visual Acuity Over All Study Visits Baseline to 3,6,9, and 12 weeks Visual acuity letter score as measured using an electronic visual acuity testing machine based on the electronic Early Treatment for Diabetic Retinopathy Study(E-ETDRS) technique. At baseline and at each follow up visit, best corrected visual acuity was measured at 3 meters by a certified tester using an electronic procedure based on the E-ETDRS method. Letter score best value = 97 and worst value = 0; an increase in a letter score by 10 is considered clinically significant.
Change in Visual Acuity Letter Score From Baseline Over All All Study Visits Baseline to 3,6,9, and 12 weeks Change in visual acuity letter score as measured using an electronic visual acuity testing machine based on the electronic Early Treatment for Diabetic Retinopathy Study(E-ETDRS) technique. At baseline and at each follow up visit, best corrected visual acuity was measured at 3 meters by a certified tester using an electronic procedure based on the E-ETDRS method. Letter score best value = 97 and worst value = 0; positive change represents an improvement in letter score.
Trial Locations
- Locations (33)
Retina Consultants of Delmarva, P.A.
🇺🇸Salisbury, Maryland, United States
Raj K. Maturi, M.D., P.C.
🇺🇸Indianapolis, Indiana, United States
University of Washington Medical Center
🇺🇸Seattle, Washington, United States
Joslin Diabetes Center
🇺🇸Boston, Massachusetts, United States
Retina Center, PA
🇺🇸Minneapolis, Minnesota, United States
Retina Northwest, PC
🇺🇸Portland, Oregon, United States
Charles A. Garcia, PA & Associates
🇺🇸Houston, Texas, United States
Penn State College of Medicine
🇺🇸Hershey, Pennsylvania, United States
Texas Retina Associates
🇺🇸Lubbock, Texas, United States
Palmetto Retina Center
🇺🇸Columbia, South Carolina, United States
Carolina Retina Center
🇺🇸Columbia, South Carolina, United States
California Retina Consultants
🇺🇸Santa Barbara, California, United States
Retina and Vitreous Associates of Kentucky
🇺🇸Lexington, Kentucky, United States
Retina Vitreous Consultants
🇺🇸Ft. Lauderdale, Florida, United States
Loma Linda University Health Care, Dept. of Ophthalmology
🇺🇸Loma Linda, California, United States
Southern California Desert Retina Consultants, MC
🇺🇸Palm Springs, California, United States
Elman Retina Group, P.A.
🇺🇸Baltimore, Maryland, United States
Southeast Retina Center, P.C.
🇺🇸Augusta, Georgia, United States
Bay Area Retina Associates
🇺🇸Walnut Creek, California, United States
Illinois Retina Associates
🇺🇸Joliet, Illinois, United States
Wake Forest University Eye Center
🇺🇸Winston-Salem, North Carolina, United States
Central Florida Retina Institute
🇺🇸Lakeland, Florida, United States
Ophthalmic Consultants of Boston
🇺🇸Boston, Massachusetts, United States
Casey Eye Institute
🇺🇸Portland, Oregon, United States
Retina Associates of Cleveland, Inc.
🇺🇸Beachwood, Ohio, United States
West Texas Retina Consultants P.A.
🇺🇸Abilene, Texas, United States
Southeastern Retina Associates, P.C.
🇺🇸Knoxville, Tennessee, United States
Charlotte Eye, Ear, Nose and Throat Assoc., PA
🇺🇸Charlotte, North Carolina, United States
Retina Research Center
🇺🇸Austin, Texas, United States
Paducah Retinal Center
🇺🇸Paducah, Kentucky, United States
American Eye Institute
🇺🇸New Albany, Indiana, United States
Maine Vitreoretinal Consultants
🇺🇸Bangor, Maine, United States
Retina Consultants
🇺🇸Providence, Rhode Island, United States