A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema: Bevacizumab (Avastin)
Information source: Diabetic Retinopathy Clinical Research Network
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Diabetic Retinopathy
Intervention: Laser Photocoagulation (Procedure); Bevacizumab (Drug); Bevacizumab (Drug); Bevacizumab (Drug); Bevacizumab (Drug)
Phase: Phase 2
Sponsored by: Diabetic Retinopathy Clinical Research Network
Official(s) and/or principal investigator(s):
Ingrid U. Scott, M.D., M.P.H., Study Chair, Affiliation: Penn State College of Medicine
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.
Official title: A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema: Bevacizumab (Avastin)
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Treatment
Change in Central Subfield Retinal Thickness From Baseline Over All Study Visits
Percentage of Participants With <250 Microns or ≥ 50% Reduction in Retinal Thickening From Baseline Over All Study Visits
Change in Visual Acuity Letter Score From Baseline Over All All Study Visits
Distribution of Change in Visual Acuity Over All Study Visits
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
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
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.
Minimum age: 18 Years.
Maximum age: N/A.
SUBJECT-LEVEL INCLUSION CRITERIA
To be eligible, the following inclusion criteria (1-3) must be met:
1. Age >= 18 years
2. Diagnosis of diabetes mellitus (type 1 or type 2)
3. Able and willing to provide informed consent.
A subject is not eligible if any of the following exclusion criteria (4-13) are
4. Significant renal disease, defined as a history of chronic renal failure requiring
dialysis or kidney transplant.
5. 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).
6. Participation in an investigational trial within 30 days of randomization that
involved treatment with any drug that has not received regulatory approval at the
time of study entry.
7. Known allergy to any component of the study drug.
8. Blood pressure > 180/110 (systolic above 180 OR diastolic above 110).
9. Major surgery within 28 days prior to randomization or major surgery planned during
the next 6 months.
10. Myocardial infarction, other cardiac event requiring hospitalization, stroke,
transient ischemic attack, or treatment for acute congestive heart failure within 6
months prior to randomization.
11. Systemic anti-VEGF or pro-VEGF treatment within 3 months prior to randomization.
12. For women of child-bearing potential: pregnant or lactating or intending to become
pregnant within the next 6 months.
13. Subject is expecting to move out of the area of the clinical center to an area not
covered by another clinical center during the first 6 months of the study.
STUDY EYE CRITERIA
The subject must have one eye meeting all of the inclusion criteria (a-e) and none of the
exclusion criteria (f-r) listed below.
Subjects can have only one study eye. If both eyes are eligible, the study eye will be
selected by the investigator and subject.
The eligibility criteria for a study eye are as follows:
1. Best corrected E-ETDRS visual acuity letter score of >= 24 (i. e., 20/320 or better)
and <= 78 (i. e., 20/32 or worse) within 8 days of randomization.
2. On clinical exam, definite retinal thickening due to diabetic macular edema involving
the center of the macula.
3. OCT central subfield >=275 microns within 8 days of randomization.
4. Media clarity, pupillary dilation, and subject cooperation sufficient for adequate
5. If prior macular photocoagulation has been performed, the investigator believes that
the study eye may possibly benefit from additional photocoagulation.
The following exclusions apply to the study eye only (i. e., they may be present for
the nonstudy eye):
6. Macular edema is considered to be due to a cause other than diabetic macular edema.
7. An ocular condition is present such that, in the opinion of the investigator, visual
acuity would not improve from resolution of macular edema (e. g., foveal atrophy,
pigmentary changes, dense subfoveal hard exudates, nonretinal condition).
8. An ocular condition is present (other than diabetes) that, in the opinion of the
investigator, might affect macular edema or alter visual acuity during the course of
the study (e. g., vein occlusion, uveitis or other ocular inflammatory disease,
neovascular glaucoma, Irvine-Gass Syndrome, etc.).
9. 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 was otherwise normal).
10. History of treatment for DME at any time in the past 3 months (such as focal/grid
macular photocoagulation, intravitreal or peribulbar corticosteroids, anti-VEGF
drugs, or any other treatment).
11. History of panretinal scatter photocoagulation (PRP) within 4 months prior to
12. Anticipated need for PRP in the 6 months following randomization.
13. History of prior pars plana vitrectomy.
14. History of major ocular surgery (including cataract extraction, scleral buckle, any
intraocular surgery, etc.) within prior 6 months or anticipated within the next 6
months following randomization.
15. History of YAG capsulotomy performed within 2 months prior to randomization.
17. Uncontrolled glaucoma (in investigator's judgment).
18. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or
FELLOW EYE CRITERIA
The fellow eye must meet the following criteria:
1. Best corrected E-ETDRS visual acuity letter score >= 19 (i. e., 20/400 or better).
2. No anti-VEGF treatment within the past 3 months and no expectation of such treatment
in next 3 months.
Locations and Contacts
Loma Linda University Health Care, Dept. of Ophthalmology, Loma Linda, California 92354, United States
Southern California Desert Retina Consultants, MC, Palm Springs, California 92262, United States
California Retina Consultants, Santa Barbara, California 93103, United States
Bay Area Retina Associates, Walnut Creek, California 94598, United States
Retina Vitreous Consultants, Ft. Lauderdale, Florida 33334, United States
Central Florida Retina Institute, Lakeland, Florida 33805, United States
Southeast Retina Center, P.C., Augusta, Georgia 30909, United States
Illinois Retina Associates, Joliet, Illinois 60435, United States
Raj K. Maturi, M.D., P.C., Indianapolis, Indiana 46280, United States
American Eye Institute, New Albany, Indiana 47150, United States
Retina and Vitreous Associates of Kentucky, Lexington, Kentucky, United States
Paducah Retinal Center, Paducah, Kentucky 42001, United States
Maine Vitreoretinal Consultants, Bangor, Maine 04401, United States
Elman Retina Group, P.A., Baltimore, Maryland 21237, United States
Retina Consultants of Delmarva, P.A., Salisbury, Maryland 21801, United States
Joslin Diabetes Center, Boston, Massachusetts 02215, United States
Ophthalmic Consultants of Boston, Boston, Massachusetts 02114, United States
Retina Center, PA, Minneapolis, Minnesota 55404, United States
Charlotte Eye, Ear, Nose and Throat Assoc., PA, Charlotte, North Carolina 28210, United States
Wake Forest University Eye Center, Winston-Salem, North Carolina 27157, United States
Retina Associates of Cleveland, Inc., Beachwood, Ohio 44122, United States
Casey Eye Institute, Portland, Oregon 97239, United States
Retina Northwest, PC, Portland, Oregon 97210, United States
Penn State College of Medicine, Hershey, Pennsylvania 17033, United States
Retina Consultants, Providence, Rhode Island 02903, United States
Carolina Retina Center, Columbia, South Carolina 29223, United States
Palmetto Retina Center, Columbia, South Carolina 29169, United States
Southeastern Retina Associates, P.C., Knoxville, Tennessee 37909, United States
West Texas Retina Consultants P.A., Abilene, Texas 79605, United States
Retina Research Center, Austin, Texas 78705, United States
Texas Retina Associates, Dallas, Texas 75231, United States
Charles A. Garcia, PA & Associates, Houston, Texas 77002, United States
Texas Retina Associates, Lubbock, Texas 79424, United States
University of Washington Medical Center, Seattle, Washington 98195, United States
Starting date: June 2006
Last updated: May 14, 2015