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

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ClinicalTrials.gov Identifier: NCT01627249

Recruitment Status : Completed

First Posted : June 25, 2012

Results First Posted : December 16, 2015

Last Update Posted : August 10, 2020

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborators:

National Eye Institute (NEI)

Genentech, Inc.

Regeneron Pharmaceuticals

Information provided by (Responsible Party):

Jaeb Center for Health Research

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Treatment
Condition	Diabetic Macular Edema
Interventions	Drug: 2.0 mg intravitreal aflibercept Drug: 1.25 mg intravitreal bevacizumab Drug: 0.3 mg intravitreal ranibizumab
Enrollment	660

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description	2.0 mg intravitreal aflibercept: In...	1.25 mg intravitreal bevacizumab: I...	0.3 mg intravitreal ranibizumab: In...
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
Reason Not Completed
Death	3	5	3
Withdrawal by Subject	12	6	9
Missed Visit	1	1	0

Baseline Characteristics

Arm/Group Title		Aflibercept	Bevacizumab	Ranibizumab	Total
Arm/Group Description		2.0 mg intravitreal aflibercept: In...	1.25 mg intravitreal bevacizumab: I...	0.3 mg intravitreal ranibizumab: In...	Total of all reporting groups
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 Number of Baseline Participants		224	218	218	660
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Customized Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	224 participants	218 participants	218 participants	660 participants
		60 (10)	62 (10)	60 (11)	61 (10)
Sex/Gender, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	224 participants	218 participants	218 participants	660 participants
Women		110	103	94	307
Men		114	115	124	353
Race/Ethnicity, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	224 participants	218 participants	218 participants	660 participants
White		145	139	146	430
Black/African American		32	37	36	105
Hispanic		37	36	30	103
Native Hawaiian/other Pacific Islander		2	2	0	4
American Indian/Alaskin Native		1	0	0	1
More than one race		4	1	1	6
Unknown/not reported		1	1	1	3
Asian		2	2	4	8
Diabetes Type Measure Type: Number Unit of measure: Participants	Number Analyzed	224 participants	218 participants	218 participants	660 participants
Type 1		22	12	16	50
Type 2		196	205	196	597
Uncertain		6	1	6	13
Prior Myocardial Infarction Measure Type: Number Unit of measure: Participants
	Number Analyzed	224 participants	218 participants	218 participants	660 participants
		13	14	16	43
Prior Coronary Artery Disease ^[1] Measure Type: Number Unit of measure: Participants
	Number Analyzed	224 participants	218 participants	218 participants	660 participants
		22	27	34	83
		[1] Measure Description: Without myocardial infarction
Prior Stroke Measure Type: Number Unit of measure: Participants
	Number Analyzed	224 participants	218 participants	218 participants	660 participants
		8	13	10	31
Prior Transient Ischemic attacks Measure Type: Number Unit of measure: Participants
	Number Analyzed	224 participants	218 participants	218 participants	660 participants
		6	8	10	24
Prior Hypertension Measure Type: Number Unit of measure: Participants
	Number Analyzed	224 participants	218 participants	218 participants	660 participants
		177	181	175	533
Visual Acuity Letter Score ^[1] Median (Inter-Quartile Range) Unit of measure: Units on a scale
	Number Analyzed	224 participants	218 participants	218 participants	660 participants
		69 (59 to 74)	69 (60 to 72)	68 (58 to 73)	69 (59 to 73)
		[1] Measure Description: Best corrected visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. Best value on the scale 97, worst 0.
OCT Central Subfield ^[1] Median (Inter-Quartile Range) Unit of measure: Microns
	Number Analyzed	224 participants	218 participants	218 participants	660 participants
		387 (310 to 483)	376 (305 to 477)	390 (310 to 493)	387 (308 to 479)
		[1] Measure Description: OCT = Optical Coherence Tomography
Lens Status Measure Type: Number Unit of measure: Participants	Number Analyzed	224 participants	218 participants	218 participants	660 participants
Phakic		166	160	173	499
Pseudophakic		58	58	45	161
Diabetic Retinopathy Severity (ETDRS Level) ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	224 participants	218 participants	218 participants	660 participants
Absent of minimal NPDR		7	6	5	18
Mild to moderately severe NPDR		150	131	145	426
Severe NPDR		17	15	18	50
Prior PRP; without current PDR		17	21	16	54
Mild to moderate PDR		28	31	23	82
High risk PDR		2	7	9	18
Missing		3	7	2	12
		[1] Measure Description: ETDRS = Early Treatment Diabetic Retinopathy Study; DR = diabetic retinopathy; PDR = proliferative diabetic retinopathy, NPDR = non-proliferative diabetic retinopathy, PRP = panretinal photocoagulation Criteria are based on the ETDRS fundus photographic risk factors for the progression of diabetic retinopathy. ETDRS report no. 12. Ophthalmology 1991; 98:823-833
Prior Focal/Grid Laser for DME ^[1] Measure Type: Number Unit of measure: Participants
	Number Analyzed	224 participants	218 participants	218 participants	660 participants
		80	84	80	244
		[1] Measure Description: DME = Diabetic macular edema Number of participants with prior focal/grid laser for DME in the study eye
Prior Anti-VEGF for DME ^[1] Measure Type: Number Unit of measure: Participants
	Number Analyzed	224 participants	218 participants	218 participants	660 participants
		24	31	29	84
		[1] Measure Description: VEGF = anti vascular endothelial growth factor DME = diabetic macular edema
Prior other treatment for DME ^[1] Measure Type: Number Unit of measure: Participants
	Number Analyzed	224 participants	218 participants	218 participants	660 participants
		14	12	11	37
		[1] Measure Description: DME = Diabetic macular edema
Prior PRP ^[1] Measure Type: Number Unit of measure: Participants
	Number Analyzed	224 participants	218 participants	218 participants	660 participants
		32	40	35	107
		[1] Measure Description: PRP = panretinal photocoagulation number of participants with prior panretinal photocoagulation in the study eye

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 (...
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: In...	1.25 mg intravitreal bevacizumab: I...	0.3 mg intravitreal ranibizumab: In...
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.
Overall Number of Participants Analyzed	208	206	206
Mean (Standard Deviation) Unit of Measure: 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	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.5
	Confidence Interval	(2-Sided) 95% 1.4 to 5.7
	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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.034
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.1
	Confidence Interval	(2-Sided) 95% 0.1 to 4.2
	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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.12
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95% -0.4 to 3.2
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

2.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 (...
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


Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description:	2.0 mg intravitreal aflibercept: In...	1.25 mg intravitreal bevacizumab: I...	0.3 mg intravitreal ranibizumab: In...
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.
Overall Number of Participants Analyzed	102	102	101
Mean (Standard Deviation) Unit of Measure: 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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.5
	Confidence Interval	(2-Sided) 95% 2.9 to 10.1
	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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0031
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.7
	Confidence Interval	(2-Sided) 95% 1.4 to 8.0
	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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.21
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 95% -1.1 to 4.8
	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 78-69
Description	Visual Acuity was measured with the Electronic Early Treatment Study (...
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


Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description:	2.0 mg intravitreal aflibercept: In...	1.25 mg intravitreal bevacizumab: I...	0.3 mg intravitreal ranibizumab: In...
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.
Overall Number of Participants Analyzed	106	104	105
Mean (Standard Deviation) Unit of Measure: 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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.69
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95% -1.3 to 2.7
	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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.69
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95% -2.3 to 1.5
	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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.69
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95% -0.9 to 3.1
	Estimation Comments	Reported P-values have been adjusted for multiple treatment group comparisons.

4.Secondary Outcome


Title	Overall Change in Optical Coherence Tomography Central Subfield Thickness
Description	All baseline and 1-year optical coherence tomography (OCT) scans were ...
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: In...	1.25 mg intravitreal bevacizumab: I...	0.3 mg intravitreal ranibizumab: In...
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.
Overall Number of Participants Analyzed	205	203	201
Mean (Standard Deviation) Unit of Measure: 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	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-69.9
	Confidence Interval	(2-Sided) 95% -91.1 to -48.6
	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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.036
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-18.6
	Confidence Interval	(2-Sided) 95% -36 to -1.2
	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	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-51.2
	Confidence Interval	(2-Sided) 95% -71.2 to -31.3
	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 ...
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


Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description:	2.0 mg intravitreal aflibercept: In...	1.25 mg intravitreal bevacizumab: I...	0.3 mg intravitreal ranibizumab: In...
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.
Overall Number of Participants Analyzed	101	100	99
Mean (Standard Deviation) Unit of Measure: 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 ...
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


Arm/Group Title	Aflibercept	Bevacizumab	Ranibizumab
Arm/Group Description:	2.0 mg intravitreal aflibercept: In...	1.25 mg intravitreal bevacizumab: I...	0.3 mg intravitreal ranibizumab: In...
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.
Overall Number of Participants Analyzed	104	103	102
Mean (Standard Deviation) Unit of Measure: 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 measure...
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: In...	1.25 mg intravitreal bevacizumab: I...	0.3 mg intravitreal ranibizumab: In...
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.
Overall Number of Participants Analyzed	162	153	162
Mean (Standard Deviation) Unit of Measure: 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
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: In...	1.25 mg intravitreal bevacizumab: I...	0.3 mg intravitreal ranibizumab: In...
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.
Overall Number of Participants Analyzed	208	206	206
Mean (Standard Deviation) Unit of Measure: 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.
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: In...	1.25 mg intravitreal bevacizumab: I...	0.3 mg intravitreal ranibizumab: In...
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.
Overall Number of Participants Analyzed	208	206	206
Measure Type: Number Unit of Measure: participants
0	132	91	111
1	57	85	77
2	19	30	18

10.Secondary Outcome


Title	Eyes Receiving 1 or More Alternative Treatments for DME Other Than Laser
Description	[Not Specified]
Description	[Not Specified]
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: In...	1.25 mg intravitreal bevacizumab: I...	0.3 mg intravitreal ranibizumab: In...
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.
Overall Number of Participants Analyzed	208	206	206
Measure Type: Number Unit of Measure: Eyes
	2	4	1

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Aflibercept		Bevacizumab		Ranibizumab
Arm/Group Description	2.0 mg intravitreal aflibercept: In...		1.25 mg intravitreal bevacizumab: I...		0.3 mg intravitreal ranibizumab: In...
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 (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--
Serious Adverse Events Serious Adverse Events
	Aflibercept		Bevacizumab		Ranibizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/224 (27.23%)		46/218 (21.10%)		57/218 (26.15%)
Blood and lymphatic system disorders
anaemia ^* 1	3/224 (1.34%)		0/218 (0.00%)		1/218 (0.46%)
anaemia of chronic disease ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Cardiac disorders
arrhythmia ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
arteriosclerosis coronary artery ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Atrial Fibrillation ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Atrioventricular block second degree ^* 1	0/224 (0.00%)		0/218 (0.00%)		2/218 (0.92%)
Cardiac arrest ^* 1	1/224 (0.45%)		1/218 (0.46%)		0/218 (0.00%)
cardiac failure ^* 1	0/224 (0.00%)		1/218 (0.46%)		2/218 (0.92%)
cardiac failure congestive ^* 1	1/224 (0.45%)		3/218 (1.38%)		6/218 (2.75%)
cardiomegaly ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
coronary artery disease ^* 1	2/224 (0.89%)		2/218 (0.92%)		3/218 (1.38%)
diastolic dysfunction ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
hypertensive heart disease ^* 1	2/224 (0.89%)		0/218 (0.00%)		1/218 (0.46%)
myocardial infarction ^* 1	3/224 (1.34%)		1/218 (0.46%)		3/218 (1.38%)
palpitations ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
pericardial effusion ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
ventricular tachycardia ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Endocrine disorders
Diabetic ketoacidosis ^* 1	2/224 (0.89%)		1/218 (0.46%)		1/218 (0.46%)
Glucocorticoid deficiency ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Hyperglycaemia ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Hypoglycaemia ^* 1	2/224 (0.89%)		0/218 (0.00%)		1/218 (0.46%)
Eye disorders
Cataract ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Endophthalmitis ^* 1	1/224 (0.45%)		0/218 (0.00%)		1/218 (0.46%)
Glaucoma ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Visual acuity reduced ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Gastrointestinal disorders
Abdominal pain ^* 1	0/224 (0.00%)		3/218 (1.38%)		1/218 (0.46%)
Clostridium difficile colitis ^* 1	1/224 (0.45%)		0/218 (0.00%)		1/218 (0.46%)
Colon cancer ^* 1	0/224 (0.00%)		1/218 (0.46%)		1/218 (0.46%)
Diabetic gastroparesis ^* 1	2/224 (0.89%)		0/218 (0.00%)		1/218 (0.46%)
Gastric cancer stage I ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Gastritis ^* 1	0/224 (0.00%)		2/218 (0.92%)		0/218 (0.00%)
Gastroenteritis ^* 1	0/224 (0.00%)		1/218 (0.46%)		1/218 (0.46%)
Gastroenteritis viral ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Gastrointestinal haemorrhage ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Gastrointestinal stoma complication ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Impaired gastric emptying ^* 1	0/224 (0.00%)		0/218 (0.00%)		3/218 (1.38%)
Intestinal perforation ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Nausea ^* 1	1/224 (0.45%)		1/218 (0.46%)		0/218 (0.00%)
Pancreatitis ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Peptic ulcer ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Rectal haemorrhage ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Vomiting ^* 1	5/224 (2.23%)		4/218 (1.83%)		1/218 (0.46%)
General disorders
Chest pain ^* 1	3/224 (1.34%)		4/218 (1.83%)		2/218 (0.92%)
Death ^* 1	1/224 (0.45%)		1/218 (0.46%)		0/218 (0.00%)
Device related infection ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Fatigue ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Oedema peripheral ^* 1	1/224 (0.45%)		1/218 (0.46%)		0/218 (0.00%)
Pain ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Pyrexia ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Hepatobiliary disorders
Cholecystitis acute ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Cholelithiasis ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Immune system disorders
Drug hypersensitivity ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Infections and infestations
Abscess ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Escherichia infection ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Infection ^* 1	1/224 (0.45%)		2/218 (0.92%)		1/218 (0.46%)
Influenza ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Localised infection ^* 1	2/224 (0.89%)		2/218 (0.92%)		3/218 (1.38%)
Sepsis ^* 1	3/224 (1.34%)		1/218 (0.46%)		1/218 (0.46%)
Septic shock ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Staphylococcal infection ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Injury, poisoning and procedural complications
Fall ^* 1	1/224 (0.45%)		1/218 (0.46%)		0/218 (0.00%)
Limb injury ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Subgaleal haematoma ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Investigations
International normalised ratio increased ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Metabolism and nutrition disorders
Dehydration ^* 1	0/224 (0.00%)		1/218 (0.46%)		2/218 (0.92%)
Fluid overload ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Hyperkalaemia ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Hyperlipidaemia ^* 1	0/224 (0.00%)		0/218 (0.00%)		2/218 (0.92%)
Hypokalaemia ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Obesity ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Musculoskeletal and connective tissue disorders
Ankle fracture ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Arthritis ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Back pain ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Femur fracture ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Inclusion body myositis ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Intervertebral disc protrusion ^* 1	0/224 (0.00%)		2/218 (0.92%)		0/218 (0.00%)
Lower limb fracture ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Multiple fractures ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Muscular weakness ^* 1	1/224 (0.45%)		0/218 (0.00%)		1/218 (0.46%)
Osteoarthritis ^* 1	0/224 (0.00%)		2/218 (0.92%)		0/218 (0.00%)
Osteomyelitis ^* 1	2/224 (0.89%)		2/218 (0.92%)		2/218 (0.92%)
Pain in extremity ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Pelvic fracture ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Upper limb fracture ^* 1	0/224 (0.00%)		1/218 (0.46%)		1/218 (0.46%)
Wrist fracture ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm malignant ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Polyp ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Brain neoplasm ^* 1	0/224 (0.00%)		0/218 (0.00%)		2/218 (0.92%)
Convulsion ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Dizziness ^* 1	0/224 (0.00%)		0/218 (0.00%)		2/218 (0.92%)
Dysarthria ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Encephalopathy ^* 1	1/224 (0.45%)		0/218 (0.00%)		1/218 (0.46%)
Headache ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Hypoaesthesia ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Neuropathy peripheral ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Presyncope ^* 1	1/224 (0.45%)		1/218 (0.46%)		0/218 (0.00%)
Somnolence ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Syncope ^* 1	0/224 (0.00%)		1/218 (0.46%)		2/218 (0.92%)
VIIth nerve paralysis ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Vestibular neuronitis ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Psychiatric disorders
Bipolar disorder ^* 1	0/224 (0.00%)		0/218 (0.00%)		2/218 (0.92%)
Mental disorder ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Psychotic disorder ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Renal and urinary disorders
Bladder prolapse ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Cystitis ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Renal failure ^* 1	4/224 (1.79%)		6/218 (2.75%)		9/218 (4.13%)
Renal failure acute ^* 1	1/224 (0.45%)		1/218 (0.46%)		1/218 (0.46%)
Renal failure chronic ^* 1	5/224 (2.23%)		0/218 (0.00%)		5/218 (2.29%)
Renal impairment ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Urinary tract infection ^* 1	3/224 (1.34%)		1/218 (0.46%)		0/218 (0.00%)
Reproductive system and breast disorders
Breast cancer ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Uterine prolapse ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure ^* 1	2/224 (0.89%)		1/218 (0.46%)		3/218 (1.38%)
Asthma ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Bronchitis ^* 1	1/224 (0.45%)		1/218 (0.46%)		0/218 (0.00%)
Cardio-respiratory arrest ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Chronic obstructive pulmonary disease ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Cough ^* 1	2/224 (0.89%)		0/218 (0.00%)		0/218 (0.00%)
Dyspnoea ^* 1	2/224 (0.89%)		1/218 (0.46%)		1/218 (0.46%)
Nasal congestion ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Pneumonia ^* 1	3/224 (1.34%)		4/218 (1.83%)		6/218 (2.75%)
Pulmonary embolism ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Skin and subcutaneous tissue disorders
Cellulitis ^* 1	2/224 (0.89%)		6/218 (2.75%)		2/218 (0.92%)
Cellulitis gangrenous ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Diabetic foot ^* 1	1/224 (0.45%)		2/218 (0.92%)		3/218 (1.38%)
Furuncle ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Skin ulcer ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Surgical and medical procedures
Cardiac pacemaker insertion ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Foot amputation ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Gastric bypass ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Hip arthroplasty ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Stent placement ^* 1	0/224 (0.00%)		2/218 (0.92%)		0/218 (0.00%)
Surgery ^* 1	1/224 (0.45%)		0/218 (0.00%)		2/218 (0.92%)
Vascular disorders
Aortic stenosis ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Arteriovenous fistula ^* 1	1/224 (0.45%)		0/218 (0.00%)		1/218 (0.46%)
Basilar artery occlusion ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Cerebrovascular accident ^* 1	0/224 (0.00%)		1/218 (0.46%)		3/218 (1.38%)
Deep vein thrombosis ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Haematoma ^* 1	1/224 (0.45%)		0/218 (0.00%)		0/218 (0.00%)
Haemorrhagic stroke ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Hypertension ^* 1	2/224 (0.89%)		2/218 (0.92%)		3/218 (1.38%)
Hypotension ^* 1	1/224 (0.45%)		0/218 (0.00%)		1/218 (0.46%)
Ischaemic stroke ^* 1	0/224 (0.00%)		1/218 (0.46%)		3/218 (1.38%)
Orthostatic hypotension ^* 1	0/224 (0.00%)		1/218 (0.46%)		0/218 (0.00%)
Peripheral vascular disorder ^* 1	2/224 (0.89%)		0/218 (0.00%)		0/218 (0.00%)
Transient ischaemic attack ^* 1	0/224 (0.00%)		1/218 (0.46%)		2/218 (0.92%)
Venous insufficiency ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
Venous stenosis ^* 1	0/224 (0.00%)		0/218 (0.00%)		1/218 (0.46%)
* Indicates events were collected by non-systematic assessment 1 Term from vocabulary, MedDRA
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Aflibercept		Bevacizumab		Ranibizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	152/224 (67.86%)		151/218 (69.27%)		144/218 (66.06%)
Eye disorders
Cataract ^* 1	14/224 (6.25%)	17	11/218 (5.05%)	14	14/218 (6.42%)	16
Conjunctival haemorrhage ^* 1	30/224 (13.39%)	67	42/218 (19.27%)	83	25/218 (11.47%)	55
Dry eye ^* 1	14/224 (6.25%)	23	9/218 (4.13%)	15	13/218 (5.96%)	18
Eye irritation ^* 1	13/224 (5.80%)	28	16/218 (7.34%)	27	14/218 (6.42%)	24
Eye pain ^* 1	27/224 (12.05%)	45	37/218 (16.97%)	50	21/218 (9.63%)	27
Eye pruritus ^* 1	12/224 (5.36%)	15	10/218 (4.59%)	13	11/218 (5.05%)	20
Lacrimation increased ^* 1	16/224 (7.14%)	22	7/218 (3.21%)	10	12/218 (5.50%)	14
Vision blurred ^* 1	38/224 (16.96%)	55	39/218 (17.89%)	53	45/218 (20.64%)	77
Visual acuity reduced ^* 1	18/224 (8.04%)	24	22/218 (10.09%)	27	17/218 (7.80%)	25
Vitreous floaters ^* 1	41/224 (18.30%)	54	53/218 (24.31%)	70	37/218 (16.97%)	62
Vitreous haemorrhage ^* 1	14/224 (6.25%)	17	18/218 (8.26%)	25	13/218 (5.96%)	15
Nervous system disorders
Headache ^* 1	15/224 (6.70%)	19	15/218 (6.88%)	19	15/218 (6.88%)	15
Respiratory, thoracic and mediastinal disorders
Nasopharyngitis ^* 1	27/224 (12.05%)	31	20/218 (9.17%)	22	16/218 (7.34%)	17
Sinusitis ^* 1	12/224 (5.36%)	13	8/218 (3.67%)	8	13/218 (5.96%)	20
Vascular disorders
Hypertension ^* 1	24/224 (10.71%)	26	15/218 (6.88%)	16	23/218 (10.55%)	24
* Indicates events were collected by non-systematic assessment 1 Term from vocabulary, MedDRA

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Adam Glassman
Organization:	Jaeb Center for Health Research
Phone:	813-975-8690
EMail:	drcrstat2@jaeb.org

Publications of Results:

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, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015 Mar 26;372(13):1193-203. doi: 10.1056/NEJMoa1414264. Epub 2015 Feb 18.

Other Publications:

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, 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.

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. No abstract available.

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):10.1001/jamaophthalmol.2016.3698. doi: 10.1001/jamaophthalmol.2016.3698.

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. No abstract available.

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. No abstract available.

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 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.

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, 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.

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 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. Erratum In: JAMA Ophthalmol. 2022 Oct 1;140(10):1030.

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.

Wells JA, Glassman AR, Ayala AR, Jampol LM. Reply. Ophthalmology. 2017 Jan;124(1):e5-e6. doi: 10.1016/j.ophtha.2016.04.032. No abstract available.

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. No abstract available.

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. No abstract available.

Glassman AR, Duh EJ, Liu D, Jampol LM. Reply. Ophthalmology. 2018 Nov;125(11):e82. doi: 10.1016/j.ophtha.2018.05.004. No abstract available.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Pawloff M, Bogunovic H, Gruber A, Michl M, Riedl S, Schmidt-Erfurth U. SYSTEMATIC CORRELATION OF CENTRAL SUBFIELD THICKNESS WITH RETINAL FLUID VOLUMES QUANTIFIED BY DEEP LEARNING IN THE MAJOR EXUDATIVE MACULAR DISEASES. Retina. 2022 May 1;42(5):831-841. doi: 10.1097/IAE.0000000000003385.

Roberts PK, Vogl WD, Gerendas BS, Glassman AR, Bogunovic H, Jampol LM, Schmidt-Erfurth UM. Quantification of Fluid Resolution and Visual Acuity Gain in Patients With Diabetic Macular Edema Using Deep Learning: A Post Hoc Analysis of a Randomized Clinical Trial. JAMA Ophthalmol. 2020 Sep 1;138(9):945-953. doi: 10.1001/jamaophthalmol.2020.2457.

Layout table for additonal information

Responsible Party:	Jaeb Center for Health Research
ClinicalTrials.gov Identifier:	NCT01627249
Other Study ID Numbers:	DRCR.net Protocol T EY14231 ( Other Grant/Funding Number: National Eye Institute ) EY23207 ( Other Grant/Funding Number: National Eye Institute ) EY18817 ( Other Grant/Funding Number: National Eye Institute )
First Submitted:	June 21, 2012
First Posted:	June 25, 2012
Results First Submitted:	September 29, 2015
Results First Posted:	December 16, 2015
Last Update Posted:	August 10, 2020

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