Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema

Diabetic Macular Edema Clinical Trial

— Protocol T  

Official title:

A Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for Diabetic Macular Edema

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01627249
• Other study ID #: DRCR.net Protocol T
• Secondary ID: EY14231EY23207EY
• Status: Completed
• Phase: Phase 3
• Start date: August 2012
• Est. completion date: April 18, 2019

Study information

• Verified date: July 2020
• Source: Jaeb Center for Health Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Although multiple studies have suggested that treatment with ranibizumab is safe and efficacious and superior to focal/grid laser alone for patients with center-involved diabetic macular edema (DME), there may be barriers in place to widespread adoption of ranibizumab use given its high cost per dose and the need for multiple treatments over time. Prioritizing resources from a public health policy perspective could be easier if more precise estimates regarding the risks and benefits of other anti-vascular endothelial growth factor (anti-VEGF) therapies were available, especially when the difference in costs could be billions of dollars over just a few years. Thus, there is a clear rationale at this time to explore potential anti-VEGF alternatives to ranibizumab that might prove to be as or more efficacious, might deliver equally lasting or longer-lasting treatment effects, and cost substantially less. Of the potentially available alternative anti-VEGF agents for this trial, bevacizumab and aflibercept are the best candidates for a direct comparison study. Bevacizumab shares the most similar molecular structure, costs far less, and is widely available. Furthermore, there is already preliminary evidence to suggest that it may be efficacious in the treatment of DME and it is already being widely used for this indication. Although aflibercept has a similar cost per unit dose to ranibizumab, it has the potential to decrease treatment burden and associated cost. If results from a comparative trial demonstrate improved efficacy or suggest similar efficacy of bevacizumab or aflibercept over ranibizumab, this information might give clinicians scientific rationale to substitute either one of these drugs for ranibizumab in the treatment of DME, and might thereby have substantial implications for public policy in terms of future estimates of health care dollars and possibly number of treatments necessary for anti-VEGF treatment of diabetic macular disease.

Because of its availability and lower cost, bevacizumab is already currently in widespread clinical use for treatment of DME despite the lack of FDA approval for this indication. Thus, a clinical trial that suggested whether bevacizumab could be used as a safe and efficacious alternative to ranibizumab could substantially impact nationwide practice patterns for treatment of DME by either validating the current use of bevacizumab or by demonstrating improved outcomes with ranibizumab or aflibercept treatment for DME.

Study Objective The primary objective of the proposed research is to compare the efficacy and safety of (1) intravitreal aflibercept, (2) intravitreal bevacizumab, and (3) intravitreal ranibizumab when given to treat central-involved DME in eyes with visual acuity of 20/32 to 20/320.

Description:

A five year follow-up visit is being conducted to gather information on long term outcomes

Recruitment information / eligibility

• Status: Completed
• Enrollment: 660
• Est. completion date: April 18, 2019
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age = 18 years

• Individuals <18 years old are not being included because DME is so rare in this age group that the diagnosis of DME 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 and/or World Health Organization criteria (see Procedures Manual for definitions)

• At least one eye meets the following study eye criteria:

• Best corrected Electronic-Early Treatment Diabetic Retinopathy Study visual acuity letter score = 78 (i.e., 20/32 or worse) and = 24 (i.e., 20/320 or better) within eight days of randomization.

• On clinical exam, definite retinal thickening due to diabetic macular edema involving the center of the macula.

• Diabetic macular edema present on optical coherence tomography (OCT) (central subfield thickness on OCT >250 µm on Zeiss Stratus or the equivalent on spectral domain OCTs based on gender specific cutoffs), within eight days of randomization.

• Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality (for Zeiss Stratus, standard deviation of center point thickness should be = 10% of the center point thickness and signal strength should be = 6)

• Media clarity, pupillary dilation, and individual cooperation sufficient for adequate fundus photographs

• Able and willing to provide informed consent.

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 four months, initiated intensive insulin treatment (a pump or multiple daily injections) or plan to do so in the next four 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 at the time of study entry.

• Note: 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 four months prior to randomization or anticipated use during the study.

• These drugs cannot be used during the study.

• For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 24 months.

• 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 clinical center during the first 12 months of the study.

The following exclusions apply to the study eye only (i.e., they may be present for the nonstudy eye):

• Macular edema is considered to be due to a cause other than diabetic macular edema.

• An eye should not be considered eligible if: (1) the macular edema is considered to be related to ocular surgery such as cataract extraction or (2) clinical exam and/or OCT suggest that vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid or epiretinal membrane) are the primary cause of the macular edema.

• An ocular condition is present such that, in the opinion of the investigator, visual acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, nonretinal condition).

• 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, etc.).

• Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by three lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye was otherwise normal).

• History of an anti-VEGF treatment for DME in the past 12 months or history of any other treatment for DME at any time in the past four months (such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids).

• Enrollment will be limited to a maximum of 25% of the planned sample size with any history of anti-VEGF treatment for DME. Once this number of eyes has been enrolled, any history of anti-VEGF treatment for DME will be an exclusion criterion.

• History of pan-retinal photocoagulation within four months prior to randomization or anticipated need for pan-retinal photocoagulation in the six months following randomization.

• History of anti-VEGF treatment for a disease other than DME in the past 12 months.

• History of major ocular surgery (including vitrectomy, cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior four months or anticipated within the next six months following randomization.

• History of YAG capsulotomy performed within two months prior to randomization.

• Aphakia.

• Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

Related Conditions & MeSH terms

• Diabetic Macular Edema
• Edema
• Macular Edema

Intervention

Drug:
• 2.0 mg intravitreal aflibercept
Intravitreal injection of 2.0 mg aflibercept at baseline and up to every 4 weeks using defined retreatment criteria.
• 1.25 mg intravitreal bevacizumab
Intravitreal injection of 1.25 mg bevacizumab at baseline and up to every 4 weeks using defined retreatment criteria.
• 0.3 mg intravitreal ranibizumab
Intravitreal injection of 0.3 mg ranibizumab (Lucentis™) at baseline and up to every 4 weeks using defined retreatment criteria.

Locations

Country	Name	City	State
United States	Eye Associates of New Mexico	Albuquerque	New Mexico
United States	University of New Mexico Health Sciences Center	Albuquerque	New Mexico
United States	Southwest Retina Specialists	Amarillo	Texas
United States	Western Carolina Retinal Associates, PA	Asheville	North Carolina
United States	Emory Eye Center	Atlanta	Georgia
United States	Georgia Retina, P.C.	Atlanta	Georgia
United States	Thomas Eye Group	Atlanta	Georgia
United States	Southeast Retina Center, P.C.	Augusta	Georgia
United States	Austin Retina Associates	Austin	Texas
United States	Retina Research Center	Austin	Texas
United States	Elman Retina Group, P.A.	Baltimore	Maryland
United States	Wilmer Eye Institute at Johns Hopkins	Baltimore	Maryland
United States	Retina Associates of Cleveland, Inc.	Beachwood	Ohio
United States	Retina-Vitreous Associates Medical Group	Beverly Hills	California
United States	Joslin Diabetes Center	Boston	Massachusetts
United States	Ophthalmic Consultants of Boston	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Storm Eye Institute, Medical University of South Carolina	Charleston	South Carolina
United States	Charlotte Eye, Ear, Nose and Throat Assoc., PA	Charlotte	North Carolina
United States	Northwestern Medical Faculty Foundation	Chicago	Illinois
United States	University of Illinois at Chicago Medical Center	Chicago	Illinois
United States	Gulf Coast Retina Center	Clearwater	Florida
United States	Case Western Reserve University	Cleveland	Ohio
United States	Carolina Retina Center	Columbia	South Carolina
United States	Palmetto Retina Center	Columbia	South Carolina
United States	OSU Eye Physicians and Surgeons, LLC.	Columbus	Ohio
United States	Henry Ford Health System, Dept of Ophthalmology and Eye Care Services	Detroit	Michigan
United States	Medical Associates Clinic, P.C.	Dubuque	Iowa
United States	Retina Vitreous Center	Edmond	Oklahoma
United States	Retina Group of Florida	Fort Lauderdale	Florida
United States	National Ophthalmic Research Institute	Fort Myers	Florida
United States	NorthShore University HealthSystem	Glenview	Illinois
United States	Retina Vitrous Center	Grand Blanc	Michigan
United States	Retina Specialists of Michigan	Grand Rapids	Michigan
United States	Vitreo-Retinal Associates	Grand Rapids	Michigan
United States	Retina Consultants of Hawaii, Inc.	Honolulu	Hawaii
United States	Baylor Eye Physicians and Surgeons	Houston	Texas
United States	Retina and Vitreous of Texas	Houston	Texas
United States	Retina Consultants of Houston, PA	Houston	Texas
United States	Raj K. Maturi, M.D., P.C.	Indianapolis	Indiana
United States	Southeastern Retina Associates, PC	Kingsport	Tennessee
United States	Southeastern Retina Associates, P.C.	Knoxville	Tennessee
United States	Central Florida Retina Institute	Lakeland	Florida
United States	Family Eye Group	Lancaster	Pennsylvania
United States	Virginia Retina Center	Leesburg	Virginia
United States	Retina and Vitreous Associates of Kentucky	Lexington	Kentucky
United States	Loma Linda University Health Care, Dept. of Ophthalmology	Loma Linda	California
United States	Texas Retina Associates	Lubbock	Texas
United States	University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service	Madison	Wisconsin
United States	Valley Retina Institute	McAllen	Texas
United States	Medical College of Wiconsin	Milwaukee	Wisconsin
United States	Retina Center, PA	Minneapolis	Minnesota
United States	John-Kenyon American Eye Institute	New Albany	Indiana
United States	MaculaCare	New York	New York
United States	Mount Sinai School of Medicine, Dept. of Ophthalmology	New York	New York
United States	The New York Eye and Ear Infirmary/Faculty Eye Practice	New York	New York
United States	The Institute of Ophthalmology and Visual Science (IOVS)	Newark	New Jersey
United States	New England Retina Associates	Norwich	Connecticut
United States	Ocala Eye Retina Consultants	Ocala	Florida
United States	Dean A. McGee Eye Institute	Oklahoma City	Oklahoma
United States	Magruder Eye Institute	Orlando	Florida
United States	Paducah Retinal Center	Paducah	Kentucky
United States	Southern California Desert Retina Consultants, MC	Palm Desert	California
United States	University of Pennsylvania Scheie Eye Institute	Philadelphia	Pennsylvania
United States	Retina Vitrous Consultants	Pittsburgh	Pennsylvania
United States	Fort Lauderdale Eye Institute	Plantation	Florida
United States	Casey Eye Institute	Portland	Oregon
United States	Retina Northwest, PC	Portland	Oregon
United States	Eyesight Ophthalmic Services, PA	Portsmouth	New Hampshire
United States	Retina Institute of Virginia	Richmond	Virginia
United States	Mayo Clinic Department of Ophthalmology	Rochester	Minnesota
United States	Retina Associates of Western New York	Rochester	New York
United States	University of Rochester	Rochester	New York
United States	Barnes Retina Institute	Saint Louis	Missouri
United States	Retina Associates of Utah, P.C.	Salt Lake City	Utah
United States	Retinal Consultants of San Antonio	San Antonio	Texas
United States	California Retina Consultants	Santa Barbara	California
United States	Sarasota Retina Institute	Sarasota	Florida
United States	University of Washington Medical Center	Seattle	Washington
United States	Retina Associates, P.A.	Shawnee Mission	Kansas
United States	Spokane Eye Clinic	Spokane	Washington
United States	Retina-Vitreous Surgeons of Central New York, PC	Syracuse	New York
United States	Retina Associates of Florida, P.A.	Tampa	Florida
United States	Retina Associates	Tucson	Arizona
United States	Bay Area Retina Associates	Walnut Creek	California
United States	Wolfe Eye Clinic	West Des Moines	Iowa
United States	Retinal Consultants of Southern California Medical Group, Inc.	Westlake Village	California
United States	Wake Forest University Eye Center	Winston-Salem	North Carolina
United States	Vitreo-Retinal Associates, PC	Worcester	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
Jaeb Center for Health Research	Genentech, Inc., National Eye Institute (NEI), Regeneron Pharmaceuticals

Country where clinical trial is conducted

United States, 

References & Publications (19)

Bressler NM, Beaulieu WT, Glassman AR, Blinder KJ, Bressler SB, Jampol LM, Melia M, Wells JA 3rd; Diabetic Retinopathy Clinical Research Network. Persistent Macular Thickening Following Intravitreous Aflibercept, Bevacizumab, or Ranibizumab for Central-Involved Diabetic Macular Edema With Vision Impairment: A Secondary Analysis of a Randomized Clinical Trial. JAMA Ophthalmol. 2018 Mar 1;136(3):257-269. doi: 10.1001/jamaophthalmol.2017.6565. Erratum in: JAMA Ophthalmol. 2018 May 1;136(5):601. — View Citation

Bressler NM, Beaulieu WT, Maguire MG, Glassman AR, Blinder KJ, Bressler SB, Gonzalez VH, Jampol LM, Melia M, Sun JK, Wells JA 3rd; Diabetic Retinopathy Clinical Research Network. Early Response to Anti-Vascular Endothelial Growth Factor and Two-Year Outcomes Among Eyes With Diabetic Macular Edema in Protocol T. Am J Ophthalmol. 2018 Nov;195:93-100. doi: 10.1016/j.ajo.2018.07.030. Epub 2018 Aug 2. — View Citation

Bressler NM, Glassman AR, Hutton DW. Controversies in Using Off-Label Intravitreous Bevacizumab for Patients With Diabetic Macular Edema-Reply. JAMA Ophthalmol. 2017 Mar 1;135(3):291-292. doi: 10.1001/jamaophthalmol.2016.5686. — View Citation

Bressler NM, Odia I, Maguire M, Glassman AR, Jampol LM, MacCumber MW, Shah C, Rosberger D, Sun JK; DRCR Retina Network. Association Between Change in Visual Acuity and Change in Central Subfield Thickness During Treatment of Diabetic Macular Edema in Participants Randomized to Aflibercept, Bevacizumab, or Ranibizumab: A Post Hoc Analysis of the Protocol T Randomized Clinical Trial. JAMA Ophthalmol. 2019 Jun 27. doi: 10.1001/jamaophthalmol.2019.1963. [Epub ahead of print] — View Citation

Bressler SB, Liu D, Glassman AR, Blodi BA, Castellarin AA, Jampol LM, Kaufman PL, Melia M, Singh H, Wells JA; Diabetic Retinopathy Clinical Research Network. Change in Diabetic Retinopathy Through 2 Years: Secondary Analysis of a Randomized Clinical Trial Comparing Aflibercept, Bevacizumab, and Ranibizumab. JAMA Ophthalmol. 2017 Jun 1;135(6):558-568. doi: 10.1001/jamaophthalmol.2017.0821. — View Citation

Bressler SB, Odia I, Maguire MG, Dhoot DS, Glassman AR, Jampol LM, Marcus DM, Solomon SD, Sun JK; Diabetic Retinopathy Clinical Research Network. Factors Associated With Visual Acuity and Central Subfield Thickness Changes When Treating Diabetic Macular Edema With Anti-Vascular Endothelial Growth Factor Therapy: An Exploratory Analysis of the Protocol T Randomized Clinical Trial. JAMA Ophthalmol. 2019 Apr 1;137(4):382-389. doi: 10.1001/jamaophthalmol.2018.6786. — View Citation

Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, Antoszyk AN, Arnold-Bush B, Baker CW, Bressler NM, Browning DJ, Elman MJ, Ferris FL, Friedman SM, Melia M, Pieramici DJ, Sun JK, Beck RW. Aflibercept, b — View Citation

Glassman AR, Duh EJ, Liu D, Jampol LM. Reply. Ophthalmology. 2018 Nov;125(11):e82. doi: 10.1016/j.ophtha.2018.05.004. — View Citation

Glassman AR, Liu D, Jampol LM, Sun JK; Diabetic Retinopathy Clinical Research Network. Changes in Blood Pressure and Urine Albumin-Creatinine Ratio in a Randomized Clinical Trial Comparing Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema. Invest Ophthalmol Vis Sci. 2018 Mar 1;59(3):1199-1205. doi: 10.1167/iovs.17-22853. — View Citation

Jampol LM, Glassman AR, Bressler NM, Wells JA, Ayala AR; Diabetic Retinopathy Clinical Research Network. Anti-Vascular Endothelial Growth Factor Comparative Effectiveness Trial for Diabetic Macular Edema: Additional Efficacy Post Hoc Analyses of a Randomized Clinical Trial. JAMA Ophthalmol. 2016 Dec 1;134(12). doi: 10.1001/jamaophthalmol.2016.3698. — View Citation

Jampol LM, Glassman AR, Bressler NM. Comparative Effectiveness Trial for Diabetic Macular Edema: Three Comparisons for the Price of 1 Study From the Diabetic Retinopathy Clinical Research Network. JAMA Ophthalmol. 2015 Sep;133(9):983-4. doi: 10.1001/jamaophthalmol.2015.1880. — View Citation

Jampol LM, Glassman AR, Liu D, Aiello LP, Bressler NM, Duh EJ, Quaggin S, Wells JA, Wykoff CC; Diabetic Retinopathy Clinical Research Network. Plasma Vascular Endothelial Growth Factor Concentrations after Intravitreous Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema. Ophthalmology. 2018 Jul;125(7):1054-1063. doi: 10.1016/j.ophtha.2018.01.019. Epub 2018 Mar 7. — View Citation

Ross EL, Hutton DW, Stein JD, Bressler NM, Jampol LM, Glassman AR; Diabetic Retinopathy Clinical Research Network. Cost-effectiveness of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema Treatment: Analysis From the Diabetic Retinopathy Clinical Research Network Comparative Effectiveness Trial. JAMA Ophthalmol. 2016 Aug 1;134(8):888-96. doi: 10.1001/jamaophthalmol.2016.1669. — View Citation

Wells JA 3rd, Glassman AR, Jampol LM. Targeting the Effect of VEGF in Diabetic Macular Edema. N Engl J Med. 2015 Jul 30;373(5):481-2. doi: 10.1056/NEJMc1505684. — View Citation

Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, Brucker AJ, Ferris FL, Hampton GR, Jhaveri C, Melia M, Beck RW; Diabetic Retinopathy Clinical Research Network. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016 Jun;123(6):1351-9. doi: 10.1016/j.ophtha.2016.02.022. Epub 2016 Feb 27. — View Citation

Wells JA, Glassman AR, Ayala AR, Jampol LM. Reply. Ophthalmology. 2017 Jan;124(1):e5-e6. doi: 10.1016/j.ophtha.2016.04.032. — View Citation

Wells JA, Glassman AR, Bressler NM, Ayala AR, Jampol LM. Reply. Ophthalmology. 2017 Apr;124(4):e38-e39. doi: 10.1016/j.ophtha.2016.08.032. — View Citation

Wells JA, Glassman AR, Jampol LM, Aiello LP, Antoszyk AN, Baker CW, Bressler NM, Browning DJ, Connor CG, Elman MJ, Ferris FL, Friedman SM, Melia M, Pieramici DJ, Sun JK, Beck RW; Diabetic Retinopathy Clinical Research Network. Association of Baseline Visual Acuity and Retinal Thickness With 1-Year Efficacy of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema. JAMA Ophthalmol. 2016 Feb;134(2):127-34. doi: 10.1001/jamaophthalmol.2015.4599. Erratum in: JAMA Ophthalmol. 2016 Apr;134(4):469. — View Citation

Wells JA, Glassman AR, Jampol LM, Ayala A, Bressler NM. Reply. Ophthalmology. 2017 Mar;124(3):e26-e27. doi: 10.1016/j.ophtha.2016.07.001. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year	Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.	Baseline to 1-year
Primary	Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score <69	Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.	Baseline to 1-year
Primary	Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score 78-69	Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.	Baseline to 1-year
Secondary	Overall Change in Optical Coherence Tomography Central Subfield Thickness	All baseline and 1-year optical coherence tomography (OCT) scans were graded by Duke Reading Center. In addition, a random sample of OCT images from other visits and images for which the investigator believed central grading was needed also were graded by Duke Reading Center.; Baseline CSF values were converted from the thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 583 scans. One-year CSF values were converted from a thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 604 scans. When calculating change in CSF thickness, measurements taken on the same machine at both visits were not converted, since the conversion equation slope is nearly 1 and the constant difference does not affect the change calculation. Therefore, change in CSF thickness was calculated after converting either the baseline and/or follow-up thickness value from Spectralis or Cirrus to a Stratus equivalent value in 26 eyes.	baseline to 1-year
Secondary	Change in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score <69	All baseline and 1-year optical coherence tomography (OCT) scans were graded by Duke Reading Center. In addition, a random sample of OCT images from other visits and images for which the investigator believed central grading was needed also were graded by Duke Reading Center.; Baseline CSF values were converted from the thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 583 scans. One-year CSF values were converted from a thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 604 scans. When calculating change in CSF thickness, measurements taken on the same machine at both visits were not converted, since the conversion equation slope is nearly 1 and the constant difference does not affect the change calculation. Therefore, change in CSF thickness was calculated after converting either the baseline and/or follow-up thickness value from Spectralis or Cirrus to a Stratus equivalent value in 26 eyes.	baseline to 1-year
Secondary	Change in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score 78-69	All baseline and 1-year optical coherence tomography (OCT) scans were graded by Duke Reading Center. In addition, a random sample of OCT images from other visits and images for which the investigator believed central grading was needed also were graded by Duke Reading Center.; Baseline CSF values were converted from the thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 583 scans. One-year CSF values were converted from a thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 604 scans. When calculating change in CSF thickness, measurements taken on the same machine at both visits were not converted, since the conversion equation slope is nearly 1 and the constant difference does not affect the change calculation. Therefore, change in CSF thickness was calculated after converting either the baseline and/or follow-up thickness value from Spectralis or Cirrus to a Stratus equivalent value in 26 eyes.	baseline to 1-year
Secondary	Overall Change in Retinal Volume	Baseline volume values were converted from the thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 459 scans. One-year volume values were converted from a thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 472 scans. When calculating change in volume, measurements taken on the same machine at both visits were not converted, because the conversion equation slope is nearly 1 and the constant difference does not affect the change calculation. Therefore, change in volume was calculated after converting either the baseline and/or follow-up value from Spectralis or Cirrus to a Stratus equivalent value in 17 eyes.	Baseline to 1-year
Secondary	Total Number of Injections Prior to 1 Year	Only includes participants that completed the 1 year visit	Baseline to 1-year
Secondary	Total Number of Laser Treatments	Only includes participants that completed the 1 year visit.	between 24 weeks and 1 year
Secondary	Eyes Receiving 1 or More Alternative Treatments for DME Other Than Laser		Baseline to 1-year