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

• Sponsor: Jaeb Center for Health Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT01627249
• Collaborator: National Eye Institute (NEI) (NIH), Genentech, Inc. (Industry), Regeneron Pharmaceuticals (Industry)
• Enrollment: 660
• Locations: 90
• Arms: 3
• Duration (Months): 80.5
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: 2.0 mg intravitreal aflibercept; Drug: 1.25 mg intravitreal bevacizumab; Drug: 0.3 mg intravitreal ranibizumab	Phase 3

Detailed Description

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 660 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: A Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for Diabetic Macular Edema
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Apr 18, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ranibizumab	Drug: 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.
Experimental: Aflibercept	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.
Experimental: Bevacizumab	Drug: 1.25 mg intravitreal bevacizumab; Intravitreal injection of 1.25 mg bevacizumab at baseline and up to every 4 weeks using defined retreatment criteria.

Outcome Measures

Primary Outcome Measures

1. Overall Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year [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.

2. Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score <69 [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.

3. Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score 78-69 [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.

Secondary Outcome Measures

1. Overall Change in Optical Coherence Tomography Central Subfield Thickness [baseline to 1-year]

   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.

2. Change in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score <69 [baseline to 1-year]

   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.

3. Change in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score 78-69 [baseline to 1-year]

   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.

4. Overall Change in Retinal Volume [Baseline to 1-year]

   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.

5. Total Number of Injections Prior to 1 Year [Baseline to 1-year]

   Only includes participants that completed the 1 year visit

6. Total Number of Laser Treatments [between 24 weeks and 1 year]

   Only includes participants that completed the 1 year visit.

7. Eyes Receiving 1 or More Alternative Treatments for DME Other Than Laser [Baseline to 1-year]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Retina Associates	Tucson	Arizona	United States	85710
2	Retina-Vitreous Associates Medical Group	Beverly Hills	California	United States	90211
3	Loma Linda University Health Care, Dept. of Ophthalmology	Loma Linda	California	United States	92354
4	Southern California Desert Retina Consultants, MC	Palm Desert	California	United States	92211
5	California Retina Consultants	Santa Barbara	California	United States	93103
6	Bay Area Retina Associates	Walnut Creek	California	United States	94598
7	Retinal Consultants of Southern California Medical Group, Inc.	Westlake Village	California	United States	91361
8	New England Retina Associates	Norwich	Connecticut	United States	06360
9	Gulf Coast Retina Center	Clearwater	Florida	United States	33761
10	Retina Group of Florida	Fort Lauderdale	Florida	United States	33334
11	National Ophthalmic Research Institute	Fort Myers	Florida	United States	33912
12	Central Florida Retina Institute	Lakeland	Florida	United States	33805
13	Ocala Eye Retina Consultants	Ocala	Florida	United States	34474
14	Magruder Eye Institute	Orlando	Florida	United States	32803
15	Fort Lauderdale Eye Institute	Plantation	Florida	United States	33324
16	Sarasota Retina Institute	Sarasota	Florida	United States	34239
17	Retina Associates of Florida, P.A.	Tampa	Florida	United States	33609
18	Emory Eye Center	Atlanta	Georgia	United States	30322
19	Georgia Retina, P.C.	Atlanta	Georgia	United States	30342
20	Thomas Eye Group	Atlanta	Georgia	United States	30342
21	Southeast Retina Center, P.C.	Augusta	Georgia	United States	30909
22	Retina Consultants of Hawaii, Inc.	Honolulu	Hawaii	United States	96701
23	Northwestern Medical Faculty Foundation	Chicago	Illinois	United States	60611
24	University of Illinois at Chicago Medical Center	Chicago	Illinois	United States	60612
25	NorthShore University HealthSystem	Glenview	Illinois	United States	60026
26	Raj K. Maturi, M.D., P.C.	Indianapolis	Indiana	United States	46280
27	John-Kenyon American Eye Institute	New Albany	Indiana	United States	47150
28	Medical Associates Clinic, P.C.	Dubuque	Iowa	United States	52002
29	Wolfe Eye Clinic	West Des Moines	Iowa	United States	50266
30	Retina Associates, P.A.	Shawnee Mission	Kansas	United States	66204
31	Retina and Vitreous Associates of Kentucky	Lexington	Kentucky	United States	40509-1802
32	Paducah Retinal Center	Paducah	Kentucky	United States	42001
33	Elman Retina Group, P.A.	Baltimore	Maryland	United States	21237
34	Wilmer Eye Institute at Johns Hopkins	Baltimore	Maryland	United States	21287-9277
35	Ophthalmic Consultants of Boston	Boston	Massachusetts	United States	02114
36	Joslin Diabetes Center	Boston	Massachusetts	United States	02215
37	Vitreo-Retinal Associates, PC	Worcester	Massachusetts	United States	01605
38	Henry Ford Health System, Dept of Ophthalmology and Eye Care Services	Detroit	Michigan	United States	48202
39	Retina Vitrous Center	Grand Blanc	Michigan	United States	48439
40	Retina Specialists of Michigan	Grand Rapids	Michigan	United States	49525
41	Vitreo-Retinal Associates	Grand Rapids	Michigan	United States	49525
42	Retina Center, PA	Minneapolis	Minnesota	United States	55404
43	Mayo Clinic Department of Ophthalmology	Rochester	Minnesota	United States	55905
44	Barnes Retina Institute	Saint Louis	Missouri	United States	63110
45	Eyesight Ophthalmic Services, PA	Portsmouth	New Hampshire	United States	03801
46	The Institute of Ophthalmology and Visual Science (IOVS)	Newark	New Jersey	United States	07103
47	Eye Associates of New Mexico	Albuquerque	New Mexico	United States	87102
48	University of New Mexico Health Sciences Center	Albuquerque	New Mexico	United States	871310001
49	Montefiore Medical Center	Bronx	New York	United States	10467-2401
50	The New York Eye and Ear Infirmary/Faculty Eye Practice	New York	New York	United States	10003
51	MaculaCare	New York	New York	United States	10021
52	Mount Sinai School of Medicine, Dept. of Ophthalmology	New York	New York	United States	10029
53	Retina Associates of Western New York	Rochester	New York	United States	14618
54	University of Rochester	Rochester	New York	United States	14642
55	Retina-Vitreous Surgeons of Central New York, PC	Syracuse	New York	United States	13224
56	Western Carolina Retinal Associates, PA	Asheville	North Carolina	United States	28803
57	University of North Carolina	Chapel Hill	North Carolina	United States	27599-7040
58	Charlotte Eye, Ear, Nose and Throat Assoc., PA	Charlotte	North Carolina	United States	28210
59	Wake Forest University Eye Center	Winston-Salem	North Carolina	United States	27157
60	Retina Associates of Cleveland, Inc.	Beachwood	Ohio	United States	44122
61	Case Western Reserve University	Cleveland	Ohio	United States	44106
62	OSU Eye Physicians and Surgeons, LLC.	Columbus	Ohio	United States	43212
63	Retina Vitreous Center	Edmond	Oklahoma	United States	73013
64	Dean A. McGee Eye Institute	Oklahoma City	Oklahoma	United States	73104
65	Retina Northwest, PC	Portland	Oregon	United States	97210
66	Casey Eye Institute	Portland	Oregon	United States	97239
67	Family Eye Group	Lancaster	Pennsylvania	United States	17601-2644
68	University of Pennsylvania Scheie Eye Institute	Philadelphia	Pennsylvania	United States	19104
69	Retina Vitrous Consultants	Pittsburgh	Pennsylvania	United States	15213
70	Storm Eye Institute, Medical University of South Carolina	Charleston	South Carolina	United States	29425
71	Palmetto Retina Center	Columbia	South Carolina	United States	29169
72	Carolina Retina Center	Columbia	South Carolina	United States	29223
73	Southeastern Retina Associates, PC	Kingsport	Tennessee	United States	37660
74	Southeastern Retina Associates, P.C.	Knoxville	Tennessee	United States	37909
75	Southwest Retina Specialists	Amarillo	Texas	United States	79106
76	Austin Retina Associates	Austin	Texas	United States	78705
77	Retina Research Center	Austin	Texas	United States	78705
78	Retina and Vitreous of Texas	Houston	Texas	United States	77025
79	Baylor Eye Physicians and Surgeons	Houston	Texas	United States	77030
80	Retina Consultants of Houston, PA	Houston	Texas	United States	77030
81	Texas Retina Associates	Lubbock	Texas	United States	79424
82	Valley Retina Institute	McAllen	Texas	United States	78503
83	Retinal Consultants of San Antonio	San Antonio	Texas	United States	78240
84	Retina Associates of Utah, P.C.	Salt Lake City	Utah	United States	84107
85	Virginia Retina Center	Leesburg	Virginia	United States	20176
86	Retina Institute of Virginia	Richmond	Virginia	United States	23235
87	University of Washington Medical Center	Seattle	Washington	United States	98195
88	Spokane Eye Clinic	Spokane	Washington	United States	99204
89	University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service	Madison	Wisconsin	United States	53705
90	Medical College of Wiconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

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

Investigators

• Study Chair: John A Wells, MD, Palmetto Retina Center

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.
• 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.
• 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 Sep 1;137(9):977-985. doi: 10.1001/jamaophthalmol.2019.1963.
• 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.
• 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.
• Glassman AR, Duh EJ, Liu D, Jampol LM. Reply. Ophthalmology. 2018 Nov;125(11):e82. doi: 10.1016/j.ophtha.2018.05.004.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Wells JA, Glassman AR, Ayala AR, Jampol LM. Reply. Ophthalmology. 2017 Jan;124(1):e5-e6. doi: 10.1016/j.ophtha.2016.04.032.
• 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.
• 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.
• 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.

• Responsible Party: Jaeb Center for Health Research
• ClinicalTrials.gov Identifier: NCT01627249
• Other Study ID Numbers: DRCR.net Protocol T; EY14231; EY23207; EY18817
• First Posted: Jun 25, 2012
• Last Update Posted: Aug 10, 2020
• Last Verified: Jul 1, 2020

• Keywords provided by Jaeb Center for Health Research: Diabetic Macular Edema; anti-vascular endothelial growth factor
• Additional relevant MeSH terms: Macular Edema; Edema; Bevacizumab; Ranibizumab; Aflibercept

Study Results

Participant Flow

Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description	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 at baseline and up to every 4 weeks using defined retreatment criteria.
Period Title: Overall Study
STARTED	224	218	218
COMPLETED	208	206	206
NOT COMPLETED	16	12	12

Baseline Characteristics

Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab	Total
Arm/Group Description	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 at baseline and up to every 4 weeks using defined retreatment criteria.	Total of all reporting groups
Overall Participants	224	218	218	660
Age, Customized (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60 (10)	62 (10)	60 (11)	61 (10)
Sex/Gender, Customized (participants) [Number]
Women	110 49.1%	103 47.2%	94 43.1%	307 46.5%
Men	114 50.9%	115 52.8%	124 56.9%	353 53.5%
Race/Ethnicity, Customized (participants) [Number]
White	145 64.7%	139 63.8%	146 67%	430 65.2%
Black/African American	32 14.3%	37 17%	36 16.5%	105 15.9%
Hispanic	37 16.5%	36 16.5%	30 13.8%	103 15.6%
Native Hawaiian/other Pacific Islander	2 0.9%	2 0.9%	0 0%	4 0.6%
American Indian/Alaskin Native	1 0.4%	0 0%	0 0%	1 0.2%
More than one race	4 1.8%	1 0.5%	1 0.5%	6 0.9%
Unknown/not reported	1 0.4%	1 0.5%	1 0.5%	3 0.5%
Asian	2 0.9%	2 0.9%	4 1.8%	8 1.2%
Diabetes Type (participants) [Number]
Type 1	22 9.8%	12 5.5%	16 7.3%	50 7.6%
Type 2	196 87.5%	205 94%	196 89.9%	597 90.5%
Uncertain	6 2.7%	1 0.5%	6 2.8%	13 2%
Prior Myocardial Infarction (participants) [Number]
Number [participants]	13 5.8%	14 6.4%	16 7.3%	43 6.5%
Prior Coronary Artery Disease (participants) [Number]
Number [participants]	22 9.8%	27 12.4%	34 15.6%	83 12.6%
Prior Stroke (participants) [Number]
Number [participants]	8 3.6%	13 6%	10 4.6%	31 4.7%
Prior Transient Ischemic attacks (participants) [Number]
Number [participants]	6 2.7%	8 3.7%	10 4.6%	24 3.6%
Prior Hypertension (participants) [Number]
Number [participants]	177 79%	181 83%	175 80.3%	533 80.8%
Visual Acuity Letter Score (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	69	69	68	69
OCT Central Subfield (Microns) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Microns]	387	376	390	387
Lens Status (participants) [Number]
Phakic	166 74.1%	160 73.4%	173 79.4%	499 75.6%
Pseudophakic	58 25.9%	58 26.6%	45 20.6%	161 24.4%
Diabetic Retinopathy Severity (ETDRS Level) (participants) [Number]
Absent of minimal NPDR	7 3.1%	6 2.8%	5 2.3%	18 2.7%
Mild to moderately severe NPDR	150 67%	131 60.1%	145 66.5%	426 64.5%
Severe NPDR	17 7.6%	15 6.9%	18 8.3%	50 7.6%
Prior PRP; without current PDR	17 7.6%	21 9.6%	16 7.3%	54 8.2%
Mild to moderate PDR	28 12.5%	31 14.2%	23 10.6%	82 12.4%
High risk PDR	2 0.9%	7 3.2%	9 4.1%	18 2.7%
Missing	3 1.3%	7 3.2%	2 0.9%	12 1.8%
Prior Focal/Grid Laser for DME (participants) [Number]
Number [participants]	80 35.7%	84 38.5%	80 36.7%	244 37%
Prior Anti-VEGF for DME (participants) [Number]
Number [participants]	24 10.7%	31 14.2%	29 13.3%	84 12.7%
Prior other treatment for DME (participants) [Number]
Number [participants]	14 6.3%	12 5.5%	11 5%	37 5.6%
Prior PRP (participants) [Number]
Number [participants]	32 14.3%	40 18.3%	35 16.1%	107 16.2%

Outcome Measures

1. Primary Outcome

Title	Overall Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year
Description	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.
Time Frame	Baseline to 1-year

Outcome Measure Data

Analysis Population Description

Visual acuity change truncated to +/- 3SD (-22 and +44) to minimize the effects of outliers for 6 eyes in the aflibercept group (4 on the positive end, 2 on the negative end) and 2 eyes in the bevacizumab group (both on the negative end).

Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description	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.
Measure Participants	208	206	206
Mean (Standard Deviation) [units on a scale]	13.3 (11.1)	9.7 (10.1)	11.2 (9.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aflibercept, Bevacizumab
	Comments	Aflibercept vs. Bevacizumab
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.5
	Confidence Interval	(2-Sided) 95%; 1.4 to 5.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aflibercept, Ranibizumab
	Comments	Aflibercept vs. Ranibizumab
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.1
	Confidence Interval	(2-Sided) 95%; 0.1 to 4.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab, Ranibizumab
	Comments	Ranibizumab vs. Bevacizumab
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.12
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; -0.4 to 3.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

2. Secondary Outcome

Title	Overall Change in Optical Coherence Tomography Central Subfield Thickness
Description	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.
Time Frame	baseline to 1-year

Outcome Measure Data

Analysis Population Description

In addition to participants missing the 1-year visit, 3 in the aflibercept group, 3 in the bevacizumab group, and 5 in the ranibizumab group had 1-year visits but unusable OCT data to compute change due to the scan being missing or ungradable at either baseline or 1 year.

Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description	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.
Measure Participants	205	203	201
Mean (Standard Deviation) [microns]	-169 (138)	-101 (121)	-147 (137)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aflibercept, Bevacizumab
	Comments	Aflibercept vs Bevacizumab
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-69.9
	Confidence Interval	(2-Sided) 95%; -91.1 to -48.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aflibercept, Ranibizumab
	Comments	Aflibercept vs Ranibizumab
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-18.6
	Confidence Interval	(2-Sided) 95%; -36 to -1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab, Ranibizumab
	Comments	Ranibizumab vs Bevacizumab
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-51.2
	Confidence Interval	(2-Sided) 95%; -71.2 to -31.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

3. Primary Outcome

Title	Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score <69
Description	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.
Time Frame	Baseline to 1-year

Outcome Measure Data

Analysis Population Description

Visual acuity change truncated to +/- 3SD (-22 and +44) to minimize the effects of outliers for 6 eyes in the aflibercept group (4 on the positive end, 2 on the negative end) and 2 eyes in the bevacizumab group (both on the negative end).

Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description	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.
Measure Participants	102	102	101
Mean (Standard Deviation) [units on a scale]	18.9 (11.5)	11.8 (12.0)	14.2 (10.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aflibercept, Bevacizumab
	Comments	Aflibercept vs. Bevacizumab
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.5
	Confidence Interval	(2-Sided) 95%; 2.9 to 10.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aflibercept, Ranibizumab
	Comments	Aflibercept vs. Ranibizumab
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0031
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.7
	Confidence Interval	(2-Sided) 95%; 1.4 to 8.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab, Ranibizumab
	Comments	Ranibizumab vs Bevacizumab
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.21
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 95%; -1.1 to 4.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

4. Primary Outcome

Title	Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score 78-69
Description	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.
Time Frame	Baseline to 1-year

Outcome Measure Data

Analysis Population Description

Visual acuity change truncated to +/- 3SD (-22 and +44) to minimize the effects of outliers for 6 eyes in the aflibercept group (4 on the positive end, 2 on the negative end) and 2 eyes in the bevacizumab group (both on the negative end).

Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description	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.
Measure Participants	106	104	105
Mean (Standard Deviation) [units on a scale]	8.0 (7.6)	7.5 (7.4)	8.3 (6.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aflibercept, Bevacizumab
	Comments	Aflibercept vs Bevacizumab
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -1.3 to 2.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aflibercept, Ranibizumab
	Comments	Aflibercept vs Ranibizumab
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -2.3 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab, Ranibizumab
	Comments	Ranibizumab vs Bevacizumab
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; -0.9 to 3.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

5. Secondary Outcome

Title	Change in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score <69
Description	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.
Time Frame	baseline to 1-year

Outcome Measure Data

Analysis Population Description

In addition to participants missing the 1-year visit, 3 in the aflibercept group, 3 in the bevacizumab group, and 5 in the ranibizumab group had 1-year visits but unusable OCT data to compute change due to the scan being missing or ungradable at either baseline or 1 year.

Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description	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.
Measure Participants	101	100	99
Mean (Standard Deviation) [microns]	-210 (151)	-135 (152)	-176 (151)

6. Secondary Outcome

Title	Change in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score 78-69
Description	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.
Time Frame	baseline to 1-year

Outcome Measure Data

Analysis Population Description

In addition to participants missing the 1-year visit, 3 in the aflibercept group, 3 in the bevacizumab group, and 5 in the ranibizumab group had 1-year visits but unusable OCT data to compute change due to the scan being missing or ungradable at either baseline or 1 year.

Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description	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.
Measure Participants	104	103	102
Mean (Standard Deviation) [microns]	-129 (110)	-67 (65)	-119 (109)

7. Secondary Outcome

Title	Overall Change in Retinal Volume
Description	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.
Time Frame	Baseline to 1-year

Outcome Measure Data

Analysis Population Description

In addition to participants missing the 1-year visit, 46 in the aflibercept group, 53 in the bevacizumab group, and 44 in the ranibizumab group had 1-year visits but unusable OCT data to compute change due to the scan being missing or ungradable at either baseline or 1 year.

Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description	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.
Measure Participants	162	153	162
Mean (Standard Deviation) [mm^3]	-1.7 (1.6)	-1.0 (1.2)	-1.7 (1.5)

8. Secondary Outcome

Title	Total Number of Injections Prior to 1 Year
Description	Only includes participants that completed the 1 year visit
Time Frame	Baseline to 1-year

Outcome Measure Data

Analysis Population Description

Seven study eyes received 1 injection and 2 eyes received 2 injections of 0.5 mg of ranibizumab prior to the FDA approving a 0.3 mg dosage of ranibizumab for diabetic macular edema treatment.

Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description	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.
Measure Participants	208	206	206
Mean (Standard Deviation) [Injections]	9.2 (2.0)	9.7 (2.3)	9.4 (2.1)

9. Secondary Outcome

Title	Total Number of Laser Treatments
Description	Only includes participants that completed the 1 year visit.
Time Frame	between 24 weeks and 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description	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.
Measure Participants	208	206	206
0	132 58.9%	91 41.7%	111 50.9%
1	57 25.4%	85 39%	77 35.3%
2	19 8.5%	30 13.8%	18 8.3%

10. Secondary Outcome

Title	Eyes Receiving 1 or More Alternative Treatments for DME Other Than Laser
Time Frame	Baseline to 1-year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description	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.
Measure Participants	208	206	206
Number [Eyes]	2	4	1

Adverse Events

Arm/Group Title	Aflibercept		Bevacizumab		Ranibizumab
Arm/Group Description	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 at baseline and up to every 4 weeks using defined retreatment criteria.
All Cause Mortality
	Aflibercept		Bevacizumab		Ranibizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Aflibercept		Bevacizumab		Ranibizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/224 (27.2%)		46/218 (21.1%)		57/218 (26.1%)
Blood and lymphatic system disorders
anaemia	3/224 (1.3%)		0/218 (0%)		1/218 (0.5%)
anaemia of chronic disease	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Cardiac disorders
arrhythmia	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
arteriosclerosis coronary artery	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Atrial Fibrillation	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Atrioventricular block second degree	0/224 (0%)		0/218 (0%)		2/218 (0.9%)
Cardiac arrest	1/224 (0.4%)		1/218 (0.5%)		0/218 (0%)
cardiac failure	0/224 (0%)		1/218 (0.5%)		2/218 (0.9%)
cardiac failure congestive	1/224 (0.4%)		3/218 (1.4%)		6/218 (2.8%)
cardiomegaly	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
coronary artery disease	2/224 (0.9%)		2/218 (0.9%)		3/218 (1.4%)
diastolic dysfunction	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
hypertensive heart disease	2/224 (0.9%)		0/218 (0%)		1/218 (0.5%)
myocardial infarction	3/224 (1.3%)		1/218 (0.5%)		3/218 (1.4%)
palpitations	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
pericardial effusion	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
ventricular tachycardia	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Endocrine disorders
Diabetic ketoacidosis	2/224 (0.9%)		1/218 (0.5%)		1/218 (0.5%)
Glucocorticoid deficiency	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Hyperglycaemia	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Hypoglycaemia	2/224 (0.9%)		0/218 (0%)		1/218 (0.5%)
Eye disorders
Cataract	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Endophthalmitis	1/224 (0.4%)		0/218 (0%)		1/218 (0.5%)
Glaucoma	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Visual acuity reduced	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Gastrointestinal disorders
Abdominal pain	0/224 (0%)		3/218 (1.4%)		1/218 (0.5%)
Clostridium difficile colitis	1/224 (0.4%)		0/218 (0%)		1/218 (0.5%)
Colon cancer	0/224 (0%)		1/218 (0.5%)		1/218 (0.5%)
Diabetic gastroparesis	2/224 (0.9%)		0/218 (0%)		1/218 (0.5%)
Gastric cancer stage I	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Gastritis	0/224 (0%)		2/218 (0.9%)		0/218 (0%)
Gastroenteritis	0/224 (0%)		1/218 (0.5%)		1/218 (0.5%)
Gastroenteritis viral	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Gastrointestinal haemorrhage	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Gastrointestinal stoma complication	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Impaired gastric emptying	0/224 (0%)		0/218 (0%)		3/218 (1.4%)
Intestinal perforation	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Nausea	1/224 (0.4%)		1/218 (0.5%)		0/218 (0%)
Pancreatitis	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Peptic ulcer	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Rectal haemorrhage	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Vomiting	5/224 (2.2%)		4/218 (1.8%)		1/218 (0.5%)
General disorders
Chest pain	3/224 (1.3%)		4/218 (1.8%)		2/218 (0.9%)
Death	1/224 (0.4%)		1/218 (0.5%)		0/218 (0%)
Device related infection	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Fatigue	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Oedema peripheral	1/224 (0.4%)		1/218 (0.5%)		0/218 (0%)
Pain	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Pyrexia	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Hepatobiliary disorders
Cholecystitis acute	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Cholelithiasis	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Immune system disorders
Drug hypersensitivity	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Infections and infestations
Abscess	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Escherichia infection	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Infection	1/224 (0.4%)		2/218 (0.9%)		1/218 (0.5%)
Influenza	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Localised infection	2/224 (0.9%)		2/218 (0.9%)		3/218 (1.4%)
Sepsis	3/224 (1.3%)		1/218 (0.5%)		1/218 (0.5%)
Septic shock	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Staphylococcal infection	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Injury, poisoning and procedural complications
Fall	1/224 (0.4%)		1/218 (0.5%)		0/218 (0%)
Limb injury	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Subgaleal haematoma	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Investigations
International normalised ratio increased	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Metabolism and nutrition disorders
Dehydration	0/224 (0%)		1/218 (0.5%)		2/218 (0.9%)
Fluid overload	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Hyperkalaemia	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Hyperlipidaemia	0/224 (0%)		0/218 (0%)		2/218 (0.9%)
Hypokalaemia	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Obesity	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Musculoskeletal and connective tissue disorders
Ankle fracture	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Arthritis	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Back pain	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Femur fracture	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Inclusion body myositis	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Intervertebral disc protrusion	0/224 (0%)		2/218 (0.9%)		0/218 (0%)
Lower limb fracture	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Multiple fractures	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Muscular weakness	1/224 (0.4%)		0/218 (0%)		1/218 (0.5%)
Osteoarthritis	0/224 (0%)		2/218 (0.9%)		0/218 (0%)
Osteomyelitis	2/224 (0.9%)		2/218 (0.9%)		2/218 (0.9%)
Pain in extremity	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Pelvic fracture	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Upper limb fracture	0/224 (0%)		1/218 (0.5%)		1/218 (0.5%)
Wrist fracture	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm malignant	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Polyp	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Brain neoplasm	0/224 (0%)		0/218 (0%)		2/218 (0.9%)
Convulsion	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Dizziness	0/224 (0%)		0/218 (0%)		2/218 (0.9%)
Dysarthria	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Encephalopathy	1/224 (0.4%)		0/218 (0%)		1/218 (0.5%)
Headache	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Hypoaesthesia	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Neuropathy peripheral	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Presyncope	1/224 (0.4%)		1/218 (0.5%)		0/218 (0%)
Somnolence	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Syncope	0/224 (0%)		1/218 (0.5%)		2/218 (0.9%)
VIIth nerve paralysis	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Vestibular neuronitis	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Psychiatric disorders
Bipolar disorder	0/224 (0%)		0/218 (0%)		2/218 (0.9%)
Mental disorder	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Psychotic disorder	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Renal and urinary disorders
Bladder prolapse	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Cystitis	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Renal failure	4/224 (1.8%)		6/218 (2.8%)		9/218 (4.1%)
Renal failure acute	1/224 (0.4%)		1/218 (0.5%)		1/218 (0.5%)
Renal failure chronic	5/224 (2.2%)		0/218 (0%)		5/218 (2.3%)
Renal impairment	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Urinary tract infection	3/224 (1.3%)		1/218 (0.5%)		0/218 (0%)
Reproductive system and breast disorders
Breast cancer	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Uterine prolapse	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	2/224 (0.9%)		1/218 (0.5%)		3/218 (1.4%)
Asthma	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Bronchitis	1/224 (0.4%)		1/218 (0.5%)		0/218 (0%)
Cardio-respiratory arrest	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Chronic obstructive pulmonary disease	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Cough	2/224 (0.9%)		0/218 (0%)		0/218 (0%)
Dyspnoea	2/224 (0.9%)		1/218 (0.5%)		1/218 (0.5%)
Nasal congestion	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Pneumonia	3/224 (1.3%)		4/218 (1.8%)		6/218 (2.8%)
Pulmonary embolism	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Skin and subcutaneous tissue disorders
Cellulitis	2/224 (0.9%)		6/218 (2.8%)		2/218 (0.9%)
Cellulitis gangrenous	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Diabetic foot	1/224 (0.4%)		2/218 (0.9%)		3/218 (1.4%)
Furuncle	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Skin ulcer	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Surgical and medical procedures
Cardiac pacemaker insertion	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Foot amputation	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Gastric bypass	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Hip arthroplasty	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Stent placement	0/224 (0%)		2/218 (0.9%)		0/218 (0%)
Surgery	1/224 (0.4%)		0/218 (0%)		2/218 (0.9%)
Vascular disorders
Aortic stenosis	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Arteriovenous fistula	1/224 (0.4%)		0/218 (0%)		1/218 (0.5%)
Basilar artery occlusion	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Cerebrovascular accident	0/224 (0%)		1/218 (0.5%)		3/218 (1.4%)
Deep vein thrombosis	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Haematoma	1/224 (0.4%)		0/218 (0%)		0/218 (0%)
Haemorrhagic stroke	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Hypertension	2/224 (0.9%)		2/218 (0.9%)		3/218 (1.4%)
Hypotension	1/224 (0.4%)		0/218 (0%)		1/218 (0.5%)
Ischaemic stroke	0/224 (0%)		1/218 (0.5%)		3/218 (1.4%)
Orthostatic hypotension	0/224 (0%)		1/218 (0.5%)		0/218 (0%)
Peripheral vascular disorder	2/224 (0.9%)		0/218 (0%)		0/218 (0%)
Transient ischaemic attack	0/224 (0%)		1/218 (0.5%)		2/218 (0.9%)
Venous insufficiency	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Venous stenosis	0/224 (0%)		0/218 (0%)		1/218 (0.5%)
Other (Not Including Serious) Adverse Events
	Aflibercept		Bevacizumab		Ranibizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	152/224 (67.9%)		151/218 (69.3%)		144/218 (66.1%)
Eye disorders
Cataract	14/224 (6.3%)	17	11/218 (5%)	14	14/218 (6.4%)	16
Conjunctival haemorrhage	30/224 (13.4%)	67	42/218 (19.3%)	83	25/218 (11.5%)	55
Dry eye	14/224 (6.3%)	23	9/218 (4.1%)	15	13/218 (6%)	18
Eye irritation	13/224 (5.8%)	28	16/218 (7.3%)	27	14/218 (6.4%)	24
Eye pain	27/224 (12.1%)	45	37/218 (17%)	50	21/218 (9.6%)	27
Eye pruritus	12/224 (5.4%)	15	10/218 (4.6%)	13	11/218 (5%)	20
Lacrimation increased	16/224 (7.1%)	22	7/218 (3.2%)	10	12/218 (5.5%)	14
Vision blurred	38/224 (17%)	55	39/218 (17.9%)	53	45/218 (20.6%)	77
Visual acuity reduced	18/224 (8%)	24	22/218 (10.1%)	27	17/218 (7.8%)	25
Vitreous floaters	41/224 (18.3%)	54	53/218 (24.3%)	70	37/218 (17%)	62
Vitreous haemorrhage	14/224 (6.3%)	17	18/218 (8.3%)	25	13/218 (6%)	15
Nervous system disorders
Headache	15/224 (6.7%)	19	15/218 (6.9%)	19	15/218 (6.9%)	15
Respiratory, thoracic and mediastinal disorders
Nasopharyngitis	27/224 (12.1%)	31	20/218 (9.2%)	22	16/218 (7.3%)	17
Sinusitis	12/224 (5.4%)	13	8/218 (3.7%)	8	13/218 (6%)	20
Vascular disorders
Hypertension	24/224 (10.7%)	26	15/218 (6.9%)	16	23/218 (10.6%)	24

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Trial results can not be discussed until they have been made available to the public.