A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema: Bevacizumab (Avastin) (Bevacizumab)

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.

Study Overview

• Status: Completed
• Conditions: Diabetic Retinopathy
• Intervention / Treatment: Procedure: Laser Photocoagulation; Drug: Bevacizumab; Drug: Bevacizumab; Drug: Bevacizumab; Drug: Bevacizumab

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.

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Health Care, Dept. of Ophthalmology
    • Palm Springs, California, United States, 92262
      • Southern California Desert Retina Consultants, MC
    • Santa Barbara, California, United States, 93103
      • California Retina Consultants
    • Walnut Creek, California, United States, 94598
      • Bay Area Retina Associates
  • Florida
    • Ft. Lauderdale, Florida, United States, 33334
      • Retina Vitreous Consultants
    • Lakeland, Florida, United States, 33805
      • Central Florida Retina Institute
  • Georgia
    • Augusta, Georgia, United States, 30909
      • Southeast Retina Center, P.C.
  • Illinois
    • Joliet, Illinois, United States, 60435
      • Illinois Retina Associates
  • Indiana
    • Indianapolis, Indiana, United States, 46280
      • Raj K. Maturi, M.D., P.C.
    • New Albany, Indiana, United States, 47150
      • American Eye Institute
  • Kentucky
    • Lexington, Kentucky, United States
      • Retina and Vitreous Associates of Kentucky
    • Paducah, Kentucky, United States, 42001
      • Paducah Retinal Center
  • Maine
    • Bangor, Maine, United States, 04401
      • Maine Vitreoretinal Consultants
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • Elman Retina Group, P.A.
    • Salisbury, Maryland, United States, 21801
      • Retina Consultants of Delmarva, P.A.
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
    • Boston, Massachusetts, United States, 02114
      • Ophthalmic Consultants of Boston
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Retina Center, PA
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Charlotte Eye, Ear, Nose and Throat Assoc., PA
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Eye Center
  • Ohio
    • Beachwood, Ohio, United States, 44122
      • Retina Associates of Cleveland, Inc.
  • Oregon
    • Portland, Oregon, United States, 97239
      • Casey Eye Institute
    • Portland, Oregon, United States, 97210
      • Retina Northwest, PC
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State College of Medicine
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Retina Consultants
  • South Carolina
    • Columbia, South Carolina, United States, 29223
      • Carolina Retina Center
    • Columbia, South Carolina, United States, 29169
      • Palmetto Retina Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37909
      • Southeastern Retina Associates, P.C.
  • Texas
    • Abilene, Texas, United States, 79605
      • West Texas Retina Consultants P.A.
    • Austin, Texas, United States, 78705
      • Retina Research Center
    • Dallas, Texas, United States, 75231
      • Texas Retina Associates
    • Houston, Texas, United States, 77002
      • Charles A. Garcia, PA & Associates
    • Lubbock, Texas, United States, 79424
      • Texas Retina Associates
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

   EXCLUSION

   A subject is not eligible if any of the following exclusion criteria (4-13) are present:

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:

INCLUSION

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 fundus photographs.

5. If prior macular photocoagulation has been performed, the investigator believes that the study eye may possibly benefit from additional photocoagulation.

   EXCLUSION

   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 randomization.
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.
16. Aphakia.
17. Uncontrolled glaucoma (in investigator's judgment).
18. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 1; Laser photocoagulation at baseline	Procedure: Laser Photocoagulation; Laser photocoagulation at baseline; If edema present at 12 weeks, can be treated with 2 intravitreal injections of 1.25 mg bevacizumab spaced 6 weeks apart
EXPERIMENTAL: 2; 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks	Drug: Bevacizumab; 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks; Other Names: Avastin; anti-VEGF drug; Drug: Bevacizumab; 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks; Other Names: Avastin; anti-VEGF drug; Drug: Bevacizumab; 1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks); Other Names: Avastin; anti-VEGF drug; Drug: 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; Other Names: Avastin; anti-VEGF drug
EXPERIMENTAL: 3; 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks	Drug: Bevacizumab; 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks; Other Names: Avastin; anti-VEGF drug; Drug: Bevacizumab; 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks; Other Names: Avastin; anti-VEGF drug; Drug: Bevacizumab; 1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks); Other Names: Avastin; anti-VEGF drug; Drug: 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; Other Names: Avastin; anti-VEGF drug
EXPERIMENTAL: 4; 1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks)	Drug: Bevacizumab; 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks; Other Names: Avastin; anti-VEGF drug; Drug: Bevacizumab; 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks; Other Names: Avastin; anti-VEGF drug; Drug: Bevacizumab; 1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks); Other Names: Avastin; anti-VEGF drug; Drug: 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; Other Names: Avastin; anti-VEGF drug
EXPERIMENTAL: 5; 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	Drug: Bevacizumab; 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks; Other Names: Avastin; anti-VEGF drug; Drug: Bevacizumab; 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks; Other Names: Avastin; anti-VEGF drug; Drug: Bevacizumab; 1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks); Other Names: Avastin; anti-VEGF drug; Drug: 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; Other Names: Avastin; anti-VEGF drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Central Subfield Retinal Thickness From Baseline Over All Study Visits	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.	Baseline to 3,6,9, and 12 weeks
Percentage of Participants With <250 Microns or ≥ 50% Reduction in Retinal Thickening From Baseline Over All Study Visits	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.	Baseline to 3,6,9, and 12 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Visual Acuity Letter Score From Baseline Over All All Study Visits	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.	Baseline to 3,6,9, and 12 weeks
Distribution of Change in Visual Acuity Over All Study Visits	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.	Baseline to 3,6,9, and 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Baseline Central Subfield Thickness	Pooled Bevacizumab groups include the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	Baseline to 3 Weeks
Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Baseline Visual Acuity Letter Score	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	Baseline to 3 Weeks
Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Age at Baseline	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	Baseline to 3 Weeks
Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Gender	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	Baseline to 3 Weeks
Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to History of Treatment for Diabetic Macular Edema at Baseline	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	Baseline to 3 Weeks
Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Retinopathy Severity at Baseline	Pooled Bevacizumab group includes treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks + laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. Retinopathy severity based on investigator discretion on clinical examination.	baseline to 3 Weeks
Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Clinical Diabetic Macular Edema Characterization at Baseline	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	baseline to 3 Weeks
Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Subretinal Fluid Presence at Baseline	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	baseline to 3 Weeks
Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Central Subfield Thickness at Baseline	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.	baseline to 3 Weeks
Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Visual Acuity at Baseline	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.	baseline to 3 Weeks
Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Age at Baseline	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.	baseline to 3 Weeks
Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Gender	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.	baseline to 3 Weeks
Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to History of Treatment for Diabetic Macular Edema	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.	baseline to 3 Weeks
Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Retinopathy Severity at Baseline	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.	baseline to 3 Weeks
Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Clinical Diabetic Macular Edema Characterization at Baseline	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.	baseline to 3 Weeks
Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Subretinal Fluid Presence at Baseline	Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.	baseline to 3 Weeks
Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Injection Only and Had a >11% Decrease in Change of Central Subfield Thickness From Baseline to 3 Weeks	The 1.25mg Bevacizumab groups include the following treatment groups: 1.25mg at baseline and 6 weeks; and 1.25mg at baseline only. Duration of effect of Bevacizumab was based on additional improvement versus maintained improvement versus worsening within 3 to 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in the DRCR.net paper, Reproducibility of macular thickness and volume using Zeiss optical coherence tomography in patients with diabetic macular edema.Ophthalmology 2007;114:1520-25.	3 to 6 Weeks
Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Injection Only and Had Within a ±11% Change of Central Subfield Thickness From Baseline to 3 Weeks	The 1.25mg bevacizumab groups include the following treatment groups: 1.25mg at baseline and 6 weeks; and 1.25mg at baseline only. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The pooled 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	3 to 6 Weeks
Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Injection Only and Had a >11% Increase in Change of Central Subfield Thickness From Baseline to 3 Weeks	The 1.25mg bevacizumab groups include the following treatment groups: 1.25mg at baseline and 6 weeks; and 1.25mg at baseline only. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The pooled 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	3 to 6 Weeks
Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab and Had a >11% Decrease in Change of Central Subfield Thickness From Baseline to 3 Weeks	The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	3 to 6 Weeks
Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab and Had Within a ±11% Change in Central Subfield Thickness From Baseline to 3 Weeks	The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	3 to 6 Weeks
Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab and Had a >11% Increase in Change of Central Subfield Thickness From Baseline to 3 Weeks	The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	3 to 6 Weeks
Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Bevacizumab at 6 Weeks and Had a >11% Decrease in Change of Central Subfield Thickness From 6 Weeks to 9 Weeks	The 1.25mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	3 to 9 weeks
Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Bevacizumab at 6 Weeks and Had Within ±11% Change of Central Subfield Thickness From 6 Weeks to 9 Weeks	The 1.25mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	3 to 9 weeks
Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Bevacizumab at 6 Weeks and Had a >11% Increase in Change of Central Subfield Thickness From 6 Weeks to 9 Weeks	The 1.25mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	3 to 9 weeks
Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab at 6 Weeks and Had a >11% Decrease in Change of Central Subfield Thickness From 6 Weeks to 9 Weeks	The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	3 to 9 weeks
Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab at 6 Weeks and Had Within ±11% Change of Central Subfield Thickness From 6 Weeks to 9 Weeks	The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	3 to 9 weeks
Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab at 6 Weeks and Had Within >11% Increase in Change of Central Subfield Thickness From 6 Weeks to 9 Weeks	The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.	3 to 9 weeks

Collaborators and Investigators

• Sponsor: Jaeb Center for Health Research
• Collaborators: National Eye Institute (NEI)
• Investigators: Study Chair: Ingrid U. Scott, M.D., M.P.H., Penn State College of Medicine

Publications and helpful links

General Publications

• Diabetic Retinopathy Clinical Research Network; Scott IU, Edwards AR, Beck RW, Bressler NM, Chan CK, Elman MJ, Friedman SM, Greven CM, Maturi RK, Pieramici DJ, Shami M, Singerman LJ, Stockdale CR. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology. 2007 Oct;114(10):1860-7. doi: 10.1016/j.ophtha.2007.05.062. Epub 2007 Aug 15.
• Scott IU, Bressler NM, Bressler SB, Browning DJ, Chan CK, Danis RP, Davis MD, Kollman C, Qin H; Diabetic Retinopathy Clinical Research Network Study Group. Agreement between clinician and reading center gradings of diabetic retinopathy severity level at baseline in a phase 2 study of intravitreal bevacizumab for diabetic macular edema. Retina. 2008 Jan;28(1):36-40. doi: 10.1097/IAE.0b013e31815e9385.
• Bhavsar AR, Ip MS, Glassman AR; DRCRnet and the SCORE Study Groups. The risk of endophthalmitis following intravitreal triamcinolone injection in the DRCRnet and SCORE clinical trials. Am J Ophthalmol. 2007 Sep;144(3):454-6. doi: 10.1016/j.ajo.2007.04.011.

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (ACTUAL): November 1, 2006
• Study Completion (ACTUAL): February 1, 2008

Study Registration Dates

• First Submitted: June 9, 2006
• First Submitted That Met QC Criteria: June 9, 2006
• First Posted (ESTIMATE): June 13, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): August 26, 2016
• Last Update Submitted That Met QC Criteria: August 25, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: bevacizumab; avastin; edema; anti-VEGF; visual acuity; macular; DME; diabetic; retinal thickness
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Eye Diseases; Endocrine System Diseases; Diabetic Angiopathies; Diabetes Complications; Diabetes Mellitus; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Diabetic Retinopathy; Macular Edema; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: NEI-129; U10EY018817-03 (U.S. NIH Grant/Contract); U10EY014231-09 (U.S. NIH Grant/Contract); U10EY014229-07 (U.S. NIH Grant/Contract); EY14231, EY14269, EY14229