CompletedNCT01627249Protocol TUpdated Aug 10, 2020Results posted

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

A Phase 3 interventional study of 2.0 mg intravitreal aflibercept and 1.25 mg intravitreal bevacizumab in Diabetic Macular Edema, sponsored by Jaeb Center for Health Research. Completed at 90 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-08-10.

Sponsored by Jaeb Center for Health Research · Phase 3, Interventional, and Treatment

Phase: Phase 3
Study type: Interventional
Enrollment: 660
Allocation: Randomized
Ages: 18 Years and older
Sex: All

Study 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.

Read the detailed description

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

Conditions studied

Diabetic Macular Edema

Browse trials for

Keywords

Diabetic Macular Edema
anti-vascular endothelial growth factor

In context

Macular Edema

841 studies on the registry are indexed under Macular Edema; 56 are open to participants now.

This study's enrollment of 660 is above the median of 50 across 619 interventional studies indexed under Macular Edema.

Browse Macular Edema studies →

Lead sponsor

Jaeb Center for Health Research is the lead sponsor of 126 studies on the registry; 17 are open to participants now.

Of its 16 completed or terminated interventional studies of FDA-regulated products, 14 (88%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: 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

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.

Study design

Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Single (Participant)
Enrollment: 660 participants (actual)

Study arms

Active comparator
Ranibizumab
Drug: 0.3 mg intravitreal ranibizumab
Experimental
Aflibercept
Drug: 2.0 mg intravitreal aflibercept
Experimental
Bevacizumab
Drug: 1.25 mg intravitreal bevacizumab

Interventions

Drug2.0 mg intravitreal aflibercept
Intravitreal injection of 2.0 mg aflibercept at baseline and up to every 4 weeks using defined retreatment criteria.
Drug1.25 mg intravitreal bevacizumab
Intravitreal injection of 1.25 mg bevacizumab at baseline and up to every 4 weeks using defined retreatment criteria.
Drug0.3 mg intravitreal ranibizumab
Intravitreal injection of 0.3 mg ranibizumab (Lucentis™) at baseline and up to every 4 weeks using defined retreatment criteria.

What researchers measure

Primary outcomes

Overall Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year
Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.
Time frame: Baseline to 1-year
Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score <69
Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.
Time frame: Baseline to 1-year
Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score 78-69
Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.
Time frame: Baseline to 1-year

Secondary outcomes

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

Results

Posted Dec 16, 2015

Participant flow

Participant flow — Overall Study
Milestone	Aflibercept	Bevacizumab	Ranibizumab
Started	224	218	218
Completed	208	206	206
Not completed	16	12	12
Withdrew: Death	3	5	3
Withdrew: Withdrawal by subject	12	6	9
Withdrew: Missed visit	1	1	0

Outcome measures

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

Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.

Time frame:: Baseline to 1-year
Reported as:: Mean · units on a scale

Overall Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year
units on a scale	Aflibercept	Bevacizumab	Ranibizumab
Overall Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year	13.3 ± 11.1	9.7 ± 10.1	11.2 ± 9.4

Statistical analysis

Aflibercept vs Bevacizumab · ANCOVA · p = <0.001 · Mean difference (final values): 3.5 · 95% CI 1.4 to 5.7Reported P-values have been adjusted for multiple treatment group comparisons.
Aflibercept vs Ranibizumab · ANCOVA · p = 0.034 · Mean difference (final values): 2.1 · 95% CI 0.1 to 4.2Reported P-values have been adjusted for multiple treatment group comparisons.
Bevacizumab vs Ranibizumab · ANCOVA · p = 0.12 · Mean difference (final values): 1.4 · 95% CI -0.4 to 3.2Reported P-values have been adjusted for multiple treatment group comparisons.

SecondaryOverall Change in Optical Coherence Tomography Central Subfield Thickness

All baseline and 1-year optical coherence tomography (OCT) scans were graded by Duke Reading Center. In addition, a random sample of OCT images from other visits and images for which the investigator believed central grading was needed also were graded by Duke Reading Center. Baseline CSF values were converted from the thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 583 scans. One-year CSF values were converted from a thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 604 scans. When calculating change in CSF thickness, measurements taken on the same machine at both visits were not converted, since the conversion equation slope is nearly 1 and the constant difference does not affect the change calculation. Therefore, change in CSF thickness was calculated after converting either the baseline and/or follow-up thickness value from Spectralis or Cirrus to a Stratus equivalent value in 26 eyes.

Time frame:: baseline to 1-year
Reported as:: Mean · microns

Overall Change in Optical Coherence Tomography Central Subfield Thickness
microns	Aflibercept	Bevacizumab	Ranibizumab
Overall Change in Optical Coherence Tomography Central Subfield Thickness	-169 ± 138	-101 ± 121	-147 ± 137

Statistical analysis

Aflibercept vs Bevacizumab · ANCOVA · p = <0.001 · Mean difference (final values): -69.9 · 95% CI -91.1 to -48.6Reported P-values have been adjusted for multiple treatment group comparisons.
Aflibercept vs Ranibizumab · ANCOVA · p = 0.036 · Mean difference (final values): -18.6 · 95% CI -36 to -1.2Reported P-values have been adjusted for multiple treatment group comparisons.
Bevacizumab vs Ranibizumab · ANCOVA · p = <0.001 · Mean difference (final values): -51.2 · 95% CI -71.2 to -31.3Reported P-values have been adjusted for multiple treatment group comparisons.

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

Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.

Time frame:: Baseline to 1-year
Reported as:: Mean · units on a scale

Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score <69
units on a scale	Aflibercept	Bevacizumab	Ranibizumab
Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score <69	18.9 ± 11.5	11.8 ± 12.0	14.2 ± 10.6

Statistical analysis

Aflibercept vs Bevacizumab · ANCOVA · p = 0.001 · Mean difference (final values): 6.5 · 95% CI 2.9 to 10.1Reported P-values have been adjusted for multiple treatment group comparisons.
Aflibercept vs Ranibizumab · ANCOVA · p = 0.0031 · Mean difference (final values): 4.7 · 95% CI 1.4 to 8.0Reported P-values have been adjusted for multiple treatment group comparisons.
Bevacizumab vs Ranibizumab · ANCOVA · p = 0.21 · Mean difference (final values): 1.8 · 95% CI -1.1 to 4.8Reported P-values have been adjusted for multiple treatment group comparisons.

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

Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.

Time frame:: Baseline to 1-year
Reported as:: Mean · units on a scale

Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score 78-69
units on a scale	Aflibercept	Bevacizumab	Ranibizumab
Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score 78-69	8.0 ± 7.6	7.5 ± 7.4	8.3 ± 6.8

Statistical analysis

Aflibercept vs Bevacizumab · ANCOVA · p = 0.69 · Mean difference (final values): 0.7 · 95% CI -1.3 to 2.7Reported P-values have been adjusted for multiple treatment group comparisons.
Aflibercept vs Ranibizumab · ANCOVA · p = 0.69 · Mean difference (final values): -0.4 · 95% CI -2.3 to 1.5Reported P-values have been adjusted for multiple treatment group comparisons.
Bevacizumab vs Ranibizumab · ANCOVA · p = 0.69 · Mean difference (final values): 1.1 · 95% CI -0.9 to 3.1Reported P-values have been adjusted for multiple treatment group comparisons.

SecondaryChange in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score <69

Time frame:: baseline to 1-year
Reported as:: Mean · microns

Change in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score <69
microns	Aflibercept	Bevacizumab	Ranibizumab
Change in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score <69	-210 ± 151	-135 ± 152	-176 ± 151

SecondaryChange in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score 78-69

Time frame:: baseline to 1-year
Reported as:: Mean · microns

Change in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score 78-69
microns	Aflibercept	Bevacizumab	Ranibizumab
Change in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score 78-69	-129 ± 110	-67 ± 65	-119 ± 109

SecondaryOverall Change in Retinal Volume

Baseline volume values were converted from the thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 459 scans. One-year volume values were converted from a thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 472 scans. When calculating change in volume, measurements taken on the same machine at both visits were not converted, because the conversion equation slope is nearly 1 and the constant difference does not affect the change calculation. Therefore, change in volume was calculated after converting either the baseline and/or follow-up value from Spectralis or Cirrus to a Stratus equivalent value in 17 eyes.

Time frame:: Baseline to 1-year
Reported as:: Mean · mm^3

Overall Change in Retinal Volume
mm^3	Aflibercept	Bevacizumab	Ranibizumab
Overall Change in Retinal Volume	-1.7 ± 1.6	-1.0 ± 1.2	-1.7 ± 1.5

SecondaryTotal Number of Injections Prior to 1 Year

Only includes participants that completed the 1 year visit

Time frame:: Baseline to 1-year
Reported as:: Mean · Injections

Total Number of Injections Prior to 1 Year
Injections	Aflibercept	Bevacizumab	Ranibizumab
Total Number of Injections Prior to 1 Year	9.2 ± 2.0	9.7 ± 2.3	9.4 ± 2.1

SecondaryTotal Number of Laser Treatments

Only includes participants that completed the 1 year visit.

Time frame:: between 24 weeks and 1 year
Reported as:: Number · participants

Total Number of Laser Treatments
participants	Aflibercept	Bevacizumab	Ranibizumab
0	132	91	111
1	57	85	77
2	19	30	18

SecondaryEyes Receiving 1 or More Alternative Treatments for DME Other Than Laser

Time frame:: Baseline to 1-year
Reported as:: Number · Eyes

Eyes Receiving 1 or More Alternative Treatments for DME Other Than Laser
Eyes	Aflibercept	Bevacizumab	Ranibizumab
Eyes Receiving 1 or More Alternative Treatments for DME Other Than Laser	2	4	1

Adverse events

Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Aflibercept	—	61/224 (27.2%)	152/224 (67.9%)
Bevacizumab	—	46/218 (21.1%)	151/218 (69.3%)
Ranibizumab	—	57/218 (26.1%)	144/218 (66.1%)

Most frequent serious events

Showing 10 of 148

Most frequent serious events
Event	Aflibercept	Bevacizumab	Ranibizumab
Renal failureRenal and urinary disorders	4/224	6/218	9/218
cardiac failure congestiveCardiac disorders	1/224	3/218	6/218
PneumoniaRespiratory, thoracic and mediastinal disorders	3/224	4/218	6/218
CellulitisSkin and subcutaneous tissue disorders	2/224	6/218	2/218
Renal failure chronicRenal and urinary disorders	5/224	0/218	5/218
VomitingGastrointestinal disorders	5/224	4/218	1/218
Chest painGeneral disorders	3/224	4/218	2/218
coronary artery diseaseCardiac disorders	2/224	2/218	3/218
myocardial infarctionCardiac disorders	3/224	1/218	3/218
Abdominal painGastrointestinal disorders	0/224	3/218	1/218

Most frequent other events

Showing 10 of 15

Most frequent other events
Event	Aflibercept	Bevacizumab	Ranibizumab
Vitreous floatersEye disorders	41/224	53/218	37/218
Vision blurredEye disorders	38/224	39/218	45/218
Conjunctival haemorrhageEye disorders	30/224	42/218	25/218
Eye painEye disorders	27/224	37/218	21/218
NasopharyngitisRespiratory, thoracic and mediastinal disorders	27/224	20/218	16/218
HypertensionVascular disorders	24/224	15/218	23/218
Visual acuity reducedEye disorders	18/224	22/218	17/218
Vitreous haemorrhageEye disorders	14/224	18/218	13/218
Eye irritationEye disorders	13/224	16/218	14/218
Lacrimation increasedEye disorders	16/224	7/218	12/218

Baseline characteristics

Age, Customized
Age, Customized(years)	Aflibercept	Bevacizumab	Ranibizumab	Total
Mean	60 ± 10	62 ± 10	60 ± 11	61 ± 10

Sex/Gender, Customized
Sex/Gender, Customized(participants)	Aflibercept	Bevacizumab	Ranibizumab	Total
Women	110	103	94	307
Men	114	115	124	353

Race/Ethnicity, Customized
Race/Ethnicity, Customized(participants)	Aflibercept	Bevacizumab	Ranibizumab	Total
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
Diabetes Type(participants)	Aflibercept	Bevacizumab	Ranibizumab	Total
Type 1	22	12	16	50
Type 2	196	205	196	597
Uncertain	6	1	6	13

Prior Myocardial Infarction
Prior Myocardial Infarction(participants)	Aflibercept	Bevacizumab	Ranibizumab	Total
Number	13	14	16	43

Prior Coronary Artery Disease
Prior Coronary Artery Disease(participants)	Aflibercept	Bevacizumab	Ranibizumab	Total
Number	22	27	34	83

Prior Stroke
Prior Stroke(participants)	Aflibercept	Bevacizumab	Ranibizumab	Total
Number	8	13	10	31

Prior Transient Ischemic attacks
Prior Transient Ischemic attacks(participants)	Aflibercept	Bevacizumab	Ranibizumab	Total
Number	6	8	10	24

9 further baseline measures are reported on the registry.

Study locations

90 sites

Retina Associates
Tucson, Arizona 85710, United States
Retina-Vitreous Associates Medical Group
Beverly Hills, California 90211, United States
Loma Linda University Health Care, Dept. of Ophthalmology
Loma Linda, California 92354, United States
Southern California Desert Retina Consultants, MC
Palm Desert, California 92211, United States
California Retina Consultants
Santa Barbara, California 93103, United States
Bay Area Retina Associates
Walnut Creek, California 94598, United States
Retinal Consultants of Southern California Medical Group, Inc.
Westlake Village, California 91361, United States
New England Retina Associates
Norwich, Connecticut 06360, United States
Gulf Coast Retina Center
Clearwater, Florida 33761, United States
Retina Group of Florida
Fort Lauderdale, Florida 33334, United States
National Ophthalmic Research Institute
Fort Myers, Florida 33912, United States
Central Florida Retina Institute
Lakeland, Florida 33805, United States
Ocala Eye Retina Consultants
Ocala, Florida 34474, United States
Magruder Eye Institute
Orlando, Florida 32803, United States
Fort Lauderdale Eye Institute
Plantation, Florida 33324, United States
Sarasota Retina Institute
Sarasota, Florida 34239, United States
Retina Associates of Florida, P.A.
Tampa, Florida 33609, United States
Emory Eye Center
Atlanta, Georgia 30322, United States
Georgia Retina, P.C.
Atlanta, Georgia 30342, United States
Thomas Eye Group
Atlanta, Georgia 30342, United States
Southeast Retina Center, P.C.
Augusta, Georgia 30909, United States
Retina Consultants of Hawaii, Inc.
Honolulu, Hawaii 96701, United States
Northwestern Medical Faculty Foundation
Chicago, Illinois 60611, United States
University of Illinois at Chicago Medical Center
Chicago, Illinois 60612, United States
NorthShore University HealthSystem
Glenview, Illinois 60026, United States
Raj K. Maturi, M.D., P.C.
Indianapolis, Indiana 46280, United States
John-Kenyon American Eye Institute
New Albany, Indiana 47150, United States
Medical Associates Clinic, P.C.
Dubuque, Iowa 52002, United States
Wolfe Eye Clinic
West Des Moines, Iowa 50266, United States
Retina Associates, P.A.
Shawnee Mission, Kansas 66204, United States
Retina and Vitreous Associates of Kentucky
Lexington, Kentucky 40509-1802, United States
Paducah Retinal Center
Paducah, Kentucky 42001, United States
Elman Retina Group, P.A.
Baltimore, Maryland 21237, United States
Wilmer Eye Institute at Johns Hopkins
Baltimore, Maryland 21287-9277, United States
Ophthalmic Consultants of Boston
Boston, Massachusetts 02114, United States
Joslin Diabetes Center
Boston, Massachusetts 02215, United States
Vitreo-Retinal Associates, PC
Worcester, Massachusetts 01605, United States
Henry Ford Health System, Dept of Ophthalmology and Eye Care Services
Detroit, Michigan 48202, United States
Retina Vitrous Center
Grand Blanc, Michigan 48439, United States
Retina Specialists of Michigan
Grand Rapids, Michigan 49525, United States
Vitreo-Retinal Associates
Grand Rapids, Michigan 49525, United States
Retina Center, PA
Minneapolis, Minnesota 55404, United States
Mayo Clinic Department of Ophthalmology
Rochester, Minnesota 55905, United States
Barnes Retina Institute
Saint Louis, Missouri 63110, United States
Eyesight Ophthalmic Services, PA
Portsmouth, New Hampshire 03801, United States
The Institute of Ophthalmology and Visual Science (IOVS)
Newark, New Jersey 07103, United States
Eye Associates of New Mexico
Albuquerque, New Mexico 87102, United States
University of New Mexico Health Sciences Center
Albuquerque, New Mexico 871310001, United States
Montefiore Medical Center
Bronx, New York 10467-2401, United States
The New York Eye and Ear Infirmary/Faculty Eye Practice
New York, New York 10003, United States
MaculaCare
New York, New York 10021, United States
Mount Sinai School of Medicine, Dept. of Ophthalmology
New York, New York 10029, United States
Retina Associates of Western New York
Rochester, New York 14618, United States
University of Rochester
Rochester, New York 14642, United States
Retina-Vitreous Surgeons of Central New York, PC
Syracuse, New York 13224, United States
Western Carolina Retinal Associates, PA
Asheville, North Carolina 28803, United States
University of North Carolina
Chapel Hill, North Carolina 27599-7040, United States
Charlotte Eye, Ear, Nose and Throat Assoc., PA
Charlotte, North Carolina 28210, United States
Wake Forest University Eye Center
Winston-Salem, North Carolina 27157, United States
Retina Associates of Cleveland, Inc.
Beachwood, Ohio 44122, United States
Case Western Reserve University
Cleveland, Ohio 44106, United States
OSU Eye Physicians and Surgeons, LLC.
Columbus, Ohio 43212, United States
Retina Vitreous Center
Edmond, Oklahoma 73013, United States
Dean A. McGee Eye Institute
Oklahoma City, Oklahoma 73104, United States
Retina Northwest, PC
Portland, Oregon 97210, United States
Casey Eye Institute
Portland, Oregon 97239, United States
Family Eye Group
Lancaster, Pennsylvania 17601-2644, United States
University of Pennsylvania Scheie Eye Institute
Philadelphia, Pennsylvania 19104, United States
Retina Vitrous Consultants
Pittsburgh, Pennsylvania 15213, United States
Storm Eye Institute, Medical University of South Carolina
Charleston, South Carolina 29425, United States
Palmetto Retina Center
Columbia, South Carolina 29169, United States
Carolina Retina Center
Columbia, South Carolina 29223, United States
Southeastern Retina Associates, PC
Kingsport, Tennessee 37660, United States
Southeastern Retina Associates, P.C.
Knoxville, Tennessee 37909, United States
Southwest Retina Specialists
Amarillo, Texas 79106, United States
Austin Retina Associates
Austin, Texas 78705, United States
Retina Research Center
Austin, Texas 78705, United States
Retina and Vitreous of Texas
Houston, Texas 77025, United States
Baylor Eye Physicians and Surgeons
Houston, Texas 77030, United States
Retina Consultants of Houston, PA
Houston, Texas 77030, United States
Texas Retina Associates
Lubbock, Texas 79424, United States
Valley Retina Institute
McAllen, Texas 78503, United States
Retinal Consultants of San Antonio
San Antonio, Texas 78240, United States
Retina Associates of Utah, P.C.
Salt Lake City, Utah 84107, United States
Virginia Retina Center
Leesburg, Virginia 20176, United States
Retina Institute of Virginia
Richmond, Virginia 23235, United States
University of Washington Medical Center
Seattle, Washington 98195, United States
Spokane Eye Clinic
Spokane, Washington 99204, United States
University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service
Madison, Wisconsin 53705, United States
Medical College of Wiconsin
Milwaukee, Wisconsin 53226, United States

References and documents

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. doi: 10.1001/jamaophthalmol.2016.0428. PubMed 26605836 ↗
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. PubMed 26935357 ↗
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. PubMed 26087135 ↗
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. PubMed 27711918 ↗
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. PubMed 27280850 ↗
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. PubMed 26222565 ↗
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. PubMed 28152135 ↗
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. PubMed 28448655 ↗
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. doi: 10.1001/jamaophthalmol.2018.0795. PubMed 29392288 ↗
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. PubMed 29625440 ↗
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. PubMed 29525602 ↗
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. PubMed 30077569 ↗
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. doi: 10.1001/jamaophthalmol.2022.3558. PubMed 30676635 ↗
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. PubMed 31246237 ↗
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. PubMed 27993277 ↗
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. PubMed 28219510 ↗
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. PubMed 28335949 ↗
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. PubMed 30318048 ↗
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. PubMed 25692915 ↗
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. PubMed 34934034 ↗
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. PubMed 32722799 ↗

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Aug 10, 2020, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT01627249
Lead sponsor: Jaeb Center for Health Research
Collaborators: National Eye Institute (NEI), Genentech, Inc., Regeneron Pharmaceuticals
Responsible party: Sponsor
First posted: Jun 25, 2012
Start date: Aug 2012
Primary completion: Oct 2014
Completion: Apr 18, 2019
Results posted: Dec 16, 2015
Last update: Aug 10, 2020

Study contacts

John A Wells, MD

study chair · Palmetto Retina Center

Oversight

Data monitoring committee: Yes

View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Jul 2020. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Macular Edema→

Other studies from this sponsor

Jaeb Center for Health Research

Start the discussion

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

Study summary

Conditions studied

Browse trials for

Keywords

In context

Macular Edema

Lead sponsor

Who can participate

✓Inclusion criteria

✕Exclusion criteria

Study design

Study arms

Interventions

What researchers measure

Primary outcomes

Secondary outcomes

Results

Participant flow

Outcome measures

Adverse events

Baseline characteristics

Study locations

References and documents

Publications

Updates

Registry details

Key details

Study contacts

Oversight

Not currently enrolling

Follow this study

Discussion

Other studies in this condition

Other studies from this sponsor

Inclusion criteria

Exclusion criteria