Clinical trial NCT00444600: Laser-Ranibizumab-Triamcinolone for Diabetic Macular Edema
Official title: Intravitreal Ranibizumab or Triamcinolone Acetonide in Combination With Laser Photocoagulation for Diabetic Macular Edema
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetic Retinopathy
Diabetic Macular Edema
Keywords: Diabetic Retinopathy
Diabetic Macular Edema
Lucentis
Ranibizumab
Triamcinolone
Laser photocoagulation
Combination Therapy
Lead sponsor: Jaeb Center for Health Research
Sponsor class: OTHER
Collaborators: name: National Eye Institute (NEI)
name: Allergan
name: Genentech, Inc.
First posted: 2007-03-08
Enrollment: 691
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to find out which is a better treatment for diabetic macular edema (DME): laser alone, laser combined with an intravitreal injection of triamcinolone, laser combined with an intravitreal injection of ranibizumab, or intravitreal injection of ranibizumab alone. At the present time, it is not known whether intravitreal steroid or anti-vascular endothelial growth factor (anti-VEGF) injections, with or without laser treatment, are better than just laser by itself. It is possible that one or both of the types of injections, with or without laser treatment, will improve vision more often than will laser without injections. However, even if better vision outcomes are seen with injections, side effects may be more of a problem with the injections than with laser. Therefore, this study is conducted to find out whether the benefits of the injections will outweigh the risks.

Detailed description: Thus far the only demonstrated means to reduce the risk of vision loss from diabetic macular edema are laser photocoagulation, intensive glycemic control, and blood pressure control. Earlier studies have shown that photocoagulation, although effective in reducing the risk of moderate vision loss, can eventually result in retinal and retinal pigment epithelium atrophy resulting in loss of central vision, central scotomata, and decreased color vision. Consequently, many retinal specialists today tend to treat diabetic macular edema (DME) with lighter, less intense laser burns than was originally specified in the Early Treatment Diabetic Retinopathy Study (ETDRS). The additional unsatisfactory outcome from treatments with laser photocoagulation in a significant proportion of eyes with DME has prompted interest in other treatment modalities. One such treatment is pars plana vitrectomy. Studies suggest that vitreomacular traction may play a role in increased retinal vascular permeability, and that removal of the vitreous, or relief of mechanical traction with vitrectomy and membrane stripping may substantially improve macular edema and visual acuity. However, this treatment may be applicable only to a specific subset of eyes with a component of vitreomacular traction secondary to edema. Other treatment modalities such as pharmacologic therapy with oral protein kinase C inhibitors and intravitreal corticosteroids are under investigation.

The use of antibodies targeted at vascular endothelial growth factor (VEGF) is another treatment modality that needs to be further explored for its potential benefits. Increased VEGF levels have been demonstrated in the retina and vitreous of human eyes with diabetic retinopathy. VEGF, also knows as vascular permeability factor, has been shown to increase retinal vascular permeability in in vivo models. Therapy that inhibits VEGF, therefore, may represent a useful therapeutic modality which targets the underlying pathogenesis of diabetic macular edema. Ranibizumab is a promising anti-VEGF drug. Its efficacy and safety have been demonstrated in treatment of age-related macular degeneration. Reports of its use and that of other anti-VEGF drugs in DME have suggested sufficient benefit to warrant evaluation of efficacy and safety in a phase III trial. Corticosteroids, a class of substances with anti-inflammatory properties, have also been demonstrated to inhibit the expression of the VEGF gene. The Diabetic Retinopathy Clinical Research Network (DRCR.net) is currently conducting a phase III randomized clinical trial comparing focal photocoagulation to intravitreal corticosteroids (triamcinolone acetonide) for diabetic macular edema. However, even if triamcinolone or ranibizumab are proven to be efficacious, a major concern, based on clinical observations with intravitreal corticosteroids, is that DME will recur as the effect of the intravitreal drug wears off, necessitating repetitive injections long-term. Combining an intravitreal drug (triamcinolone or ranibizumab) with photocoagulation provides hope that one could get the short-term benefit of the intravitreal drug (decreased retinal thickening and decreased fluid leakage) and the long-term reduction in fluid leakage as a result of photocoagulation. In addition, it is possible that the worsening of macular edema immediately following focal photocoagulation, a known complication of this treatment, could be decreased if an intravitreal drug was present at the time of photocoagulation. This might result in an increased likelihood of vision improvement following photocoagulation and a decreased likelihood of vision loss.

This study is designed to determine if ranibizumab alone or ranibizumab added to laser photocoagulation is more efficacious than photocoagulation alone, and if so, to determine if combining ranibizumab with photocoagulation reduces the total number of injections needed to obtain these benefits. Furthermore, this study is designed to determine if combining photocoagulation with corticosteroids, the only other class of drugs currently being considered for treatment of DME, is efficacious in the population being enrolled.

Subjects will be randomly assigned to one of the following 4 groups:

1. Group A: Sham injection plus focal (macular) photocoagulation
2. Group B: 0.5 mg injection of intravitreal ranibizumab plus focal photocoagulation
3. Group C: 0.5 mg injection of intravitreal ranibizumab plus deferred focal photocoagulation
4. Group D: 4 mg intravitreal triamcinolone plus focal photocoagulation

In groups A, B and D, laser will be given 7-10 days after the initial injection at the time of the injection follow-up safety visit. During the first year, subjects are evaluated for retreatment every 4 weeks. The injection for group A is a sham and for groups B and C ranibizumab. For group D, a triamcinolone injection is given if one has not been given in the prior 15 weeks; otherwise a sham injection is given. For Groups A, B, and D, focal photocoagulation will be given 7 to 10 days later following each injection unless focal photocoagulation has been given in the past 15 weeks or no macular edema is present. In Years 2 and 3, subjects continue to be evaluated for retreatment every 4 weeks unless injections are discontinued due to failure. In that case, follow-up visits occur every 4 months and treatment is at investigator discretion.

Eligibility criteria: General Inclusion Criteria

To be eligible, the following inclusion criteria (1-5) must be met:

* Age \>= 18 years
* Diagnosis of diabetes mellitus (type 1 or type 2)
* At least one eye meets the study eye criteria
* Fellow eye (if not a study eye) meets criteria
* Able and willing to provide informed consent

General Exclusion Criteria

A subject is not eligible if any of the following exclusion criteria are present:

* 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).
* Participation in an investigational trial within 30 days of randomization that involved treatment with any drug that has not received regulatory approval at the time of study entry.
* Known allergy to any component of the study drug.
* Blood pressure \> 180/110 (systolic above 180 OR diastolic above 110).
* Major surgery within 28 days prior to randomization or major surgery planned during the next 6 months.
* Myocardial infarction, other cardiac event requiring hospitalization, stroke, transient ischemic attack, or treatment for acute congestive heart failure within 4 months prior to randomization.
* Systemic anti-vascular growth factor (anti-VEGF) or pro-VEGF treatment within 4 months prior to randomization.
* For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 12 months.
* Subject is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the first 12 months of the study.

Study Eye Inclusion Criteria

The subject must have one eye meeting all of the inclusion criteria and none of the exclusion criteria listed below. A subject may have two study eyes only if both are eligible at the time of randomization.

* Best corrected electronic Early Treatment Diabetic Retinopathy (E-ETDRS) visual acuity letter score \<= 78 (i.e., 20/32 or worse) and \>= 24 (i.e., 20/320 or better) within 8 days of randomization.
* On clinical exam, definite retinal thickening due to diabetic macular edema involving the center of the macula.
* Ocular coherence tomography (OCT) central subfield \>=250 microns within 8 days of randomization.
* Media clarity, pupillary dilation, and subject cooperation sufficient for adequate fundus photographs.
* If prior macular photocoagulation has been performed, the investigator believes that the study eye may possibly benefit from additional photocoagulation.

Study Eye Exclusion Criteria

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 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 3 lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye was otherwise normal).
* History of treatment for diabetic macular edema at any time in the past 4 months (such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids, anti-VEGF drugs, or any other treatment).
* History of panretinal (scatter) photocoagulation (PRP) within 4 months prior to randomization.
* Anticipated need for PRP in the 6 months following randomization.
* History of major ocular surgery (including vitrectomy, cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization.
* History of yttrium aluminum garnet (YAG) capsulotomy performed within 2 months prior to randomization.
* Aphakia.
* Intraocular pressure \>= 25 mmHg.
* History of open-angle glaucoma (either primary open-angle glaucoma or other cause of open-angle glaucoma; note: history of angle-closure glaucoma is not an exclusion criterion).
* History of steroid-induced intraocular pressure (IOP) elevation that required IOP-lowering treatment.
* History of prior herpetic ocular infection.
* Exam evidence of ocular toxoplasmosis.
* Exam evidence of pseudoexfoliation.
* Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

Primary outcomes:
measure: Mean Change in Visual Acuity (Letters) From Baseline to 1 Year Adjusted for Baseline Visual Acuity
timeFrame: from baseline to 1 Year
measure: Distribution of Change in Visual Acuity (Letters) From Baseline to 1 Year
timeFrame: from baseline to 1 Year
measure: Change in Visual Acuity From Baseline to 1 Year Among Eyes That Were Pseudophakic at Baseline
timeFrame: from baseline to 1 Year
measure: Change in Visual Acuity From Baseline to 1 Year Among Eyes That Had Prior Treatment for Diabetic Macular Edema
timeFrame: from baseline to 1 Year
measure: Change in Visual Acuity From Baseline to 1 Year Grouped by Baseline Visual Acuity Letter Score
timeFrame: from baseline to 1 Year
measure: Change in Visual Acuity From Baseline to 1 Year Grouped by Optical Coherence Tomography Central Subfield Thickness
timeFrame: from baseline to 1 Year
measure: Change in Visual Acuity From Baseline to 1 Year Grouped by Diabetic Retinopathy Severity
timeFrame: from baseline to 1 Year
measure: Change in Visual Acuity From Baseline to 1 Year Grouped by Diffuse vs. Focal Edema as Characterized by the Investigator
timeFrame: from baseline to 1 Year
Secondary outcomes:
measure: Change in Retinal Thickening of Central Subfield on Optical Coherence Tomography From Baseline to 1 Year
timeFrame: from baseline to 1 year
measure: Number of Injections in First Year
timeFrame: from baseline to 1 year
measure: Number of Laser Treatments Received Prior to the 1 Year Visit
timeFrame: 1 Year
measure: Percentage of Eyes Receiving Laser at the 48 Week Visit (%)
timeFrame: 1 Year
measure: Mean Optical Coherence Tomography Retinal Volume at 1 Year
timeFrame: 1 Year
measure: Mean Change in Optical Coherence Tomography Retinal Volume From Baseline to 1 Year
timeFrame: from baseline to 1 Year
Other outcomes:
measure: Central Subfield Thickness < 250 With at Least a 25 Micron Decrease From Baseline to 1 Year
timeFrame: 1 Year
measure: Distribution of Logarithmic Transformation of Optical Coherence Tomography (LogOCT) Improvement and Worsening
timeFrame: 1 Year
measure: Eyes With Alternative Treatments Prior to the 1-year Visit
timeFrame: 1 Year
measure: Change From Moderately Severe Non-proliferative Diabetic Retinopathy or Better From Baseline to 1-year
timeFrame: from baseline to 1 Year
measure: Change From Severe Non-proliferative Diabetic Retinopathy or Worse From Baseline to 1-year
timeFrame: from baseline to 1 Year
measure: Cardiovascular Events According to Antiplatelet Trialists' Collaboration Through 1 Year
timeFrame: 1 Year
measure: Major Ocular Adverse Events During First Year of Follow-Up
timeFrame: 1 Year
Locations:
city: Artesia
country: United States
facility: Sall Research Medical Center
state: California
city: Beverly Hills
country: United States
facility: Retina-Vitreous Associates Medical Group
state: California
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Health Care, Dept. of Ophthalmology
state: California
city: Palm Springs
country: United States
facility: Southern California Desert Retina Consultants, MC
state: California
city: Santa Barbara
country: United States
facility: California Retina Consultants
state: California
city: Walnut Creek
country: United States
facility: Bay Area Retina Associates
state: California
city: Fort Lauderdale
country: United States
facility: Retina Vitreous Consultants
state: Florida
city: Fort Myers
country: United States
facility: Retina Consultants of Southwest Florida
state: Florida
city: Jacksonville
country: United States
facility: University of Florida College of Med., Department of Ophthalmology
state: Florida
city: Lakeland
country: United States
facility: Central Florida Retina Institute
state: Florida
city: Augusta
country: United States
facility: Southeast Retina Center, P.C.
state: Georgia
city: Joliet
country: United States
facility: Illinois Retina Associates
state: Illinois
city: Indianapolis
country: United States
facility: Raj K. Maturi, M.D., P.C.
state: Indiana
city: New Albany
country: United States
facility: John-Kenyon American Eye Institute
state: Indiana
city: Dubuque
country: United States
facility: Medical Associates Clinic, P.C.
state: Iowa
city: Lexington
country: United States
facility: Retina and Vitreous Associates of Kentucky
state: Kentucky
city: Paducah
country: United States
facility: Paducah Retinal Center
state: Kentucky
city: Baltimore
country: United States
facility: Elman Retina Group, P.A.
state: Maryland
city: Baltimore
country: United States
facility: Wilmer Eye Institute at Johns Hopkins
state: Maryland
city: Salisbury
country: United States
facility: Retina Consultants of Delmarva, P.A.
state: Maryland
city: Boston
country: United States
facility: Ophthalmic Consultants of Boston
state: Massachusetts
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
city: Minneapolis
country: United States
facility: Retina Center, PA
state: Minnesota
city: Portsmouth
country: United States
facility: Eyesight Ophthalmic Services, PA
state: New Hampshire
city: New York
country: United States
facility: The New York Eye and Ear Infirmary/Faculty Eye Practice
state: New York
city: Syracuse
country: United States
facility: Retina-Vitreous Surgeons of Central New York, PC
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina, Dept of Ophthalmology
state: North Carolina
city: Charlotte
country: United States
facility: Charlotte Eye, Ear, Nose and Throat Assoc., PA
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Eye Center
state: North Carolina
city: Beachwood
country: United States
facility: Retina Associates of Cleveland, Inc.
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Portland
country: United States
facility: Retina Northwest, PC
state: Oregon
city: Portland
country: United States
facility: Casey Eye Institute
state: Oregon
city: Hershey
country: United States
facility: Penn State College of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania Scheie Eye Institute
state: Pennsylvania
city: Providence
country: United States
facility: Retina Consultants
state: Rhode Island
city: Columbia
country: United States
facility: Palmetto Retina Center
state: South Carolina
city: Columbia
country: United States
facility: Carolina Retina Center
state: South Carolina
city: Kingsport
country: United States
facility: Southeastern Retina Associates, PC
state: Tennessee
city: Knoxville
country: United States
facility: Southeastern Retina Associates, P.C.
state: Tennessee
city: Abilene
country: United States
facility: West Texas Retina Consultants P.A.
state: Texas
city: Austin
country: United States
facility: Retina Research Center
state: Texas
city: Dallas
country: United States
facility: Texas Retina Associates
state: Texas
city: Houston
country: United States
facility: Retina and Vitreous of Texas
state: Texas
city: Houston
country: United States
facility: Vitreoretinal Consultants
state: Texas
city: Lubbock
country: United States
facility: Texas Retina Associates
state: Texas
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Elman Retina Group, PA
name: Michael J. Elman, M.D.
role: STUDY_CHAIR
References:
citation: Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3rd, Friedman SM, Glassman AR, Scott IU, Stockdale CR, Sun JK; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011 Apr;118(4):609-14. doi: 10.1016/j.ophtha.2010.12.033.
citation: Diabetic Retinopathy Clinical Research Network; Writing Committee; Aiello LP, Beck RW, Bressler NM, Browning DJ, Chalam KV, Davis M, Ferris FL 3rd, Glassman AR, Maturi RK, Stockdale CR, Topping TM. Rationale for the diabetic retinopathy clinical research network treatment protocol for center-involved diabetic macular edema. Ophthalmology. 2011 Dec;118(12):e5-14. doi: 10.1016/j.ophtha.2011.09.058.
citation: Glassman AR, Stockdale CR, Beck RW, Baker C, Bressler NM; Diabetic Retinopathy Clinical Research Network. Evaluation of masking study participants to intravitreal injections in a randomized clinical trial. Arch Ophthalmol. 2012 Feb;130(2):190-4. doi: 10.1001/archophthalmol.2011.387.
citation: Bressler SB, Qin H, Beck RW, Chalam KV, Kim JE, Melia M, Wells JA 3rd; Diabetic Retinopathy Clinical Research Network. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol. 2012 Sep;130(9):1153-61. doi: 10.1001/archophthalmol.2012.1107.
citation: Bressler SB, Qin H, Melia M, Bressler NM, Beck RW, Chan CK, Grover S, Miller DG; Diabetic Retinopathy Clinical Research Network. Exploratory analysis of the effect of intravitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial. JAMA Ophthalmol. 2013 Aug;131(8):1033-40. doi: 10.1001/jamaophthalmol.2013.4154.
citation: Bressler SB, Almukhtar T, Aiello LP, Bressler NM, Ferris FL 3rd, Glassman AR, Greven CM; Diabetic Retinopathy Clinical Research Network. Green or yellow laser treatment for diabetic macular edema: exploratory assessment within the Diabetic Retinopathy Clinical Research Network. Retina. 2013 Nov-Dec;33(10):2080-8. doi: 10.1097/IAE.0b013e318295f744.
citation: Bressler SB, Almukhtar T, Bhorade A, Bressler NM, Glassman AR, Huang SS, Jampol LM, Kim JE, Melia M; Diabetic Retinopathy Clinical Research Network Investigators. Repeated intravitreous ranibizumab injections for diabetic macular edema and the risk of sustained elevation of intraocular pressure or the need for ocular hypotensive treatment. JAMA Ophthalmol. 2015 May;133(5):589-97. doi: 10.1001/jamaophthalmol.2015.186.
citation: Bressler SB, Odia I, Glassman AR, Danis RP, Grover S, Hampton GR, Jampol LM, Maguire MG, Melia M. CHANGES IN DIABETIC RETINOPATHY SEVERITY WHEN TREATING DIABETIC MACULAR EDEMA WITH RANIBIZUMAB: DRCR.net Protocol I 5-Year Report. Retina. 2018 Oct;38(10):1896-1904. doi: 10.1097/IAE.0000000000002302.
citation: Bressler SB, Melia M, Glassman AR, Almukhtar T, Jampol LM, Shami M, Berger BB, Bressler NM; Diabetic Retinopathy Clinical Research Network. RANIBIZUMAB PLUS PROMPT OR DEFERRED LASER FOR DIABETIC MACULAR EDEMA IN EYES WITH VITRECTOMY BEFORE ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY. Retina. 2015 Dec;35(12):2516-28. doi: 10.1097/IAE.0000000000000617.
citation: Bressler SB, Ayala AR, Bressler NM, Melia M, Qin H, Ferris FL 3rd, Flaxel CJ, Friedman SM, Glassman AR, Jampol LM, Rauser ME; Diabetic Retinopathy Clinical Research Network. Persistent Macular Thickening After Ranibizumab Treatment for Diabetic Macular Edema With Vision Impairment. JAMA Ophthalmol. 2016 Mar;134(3):278-85. doi: 10.1001/jamaophthalmol.2015.5346.
citation: Diabetic Retinopathy Clinical Research Network; Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, Ferris FL 3rd, Friedman SM, Glassman AR, Miller KM, Scott IU, Stockdale CR, Sun JK. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010 Jun;117(6):1064-1077.e35. doi: 10.1016/j.ophtha.2010.02.031. Epub 2010 Apr 28.
citation: Diabetic Retinopathy Clinical Research Network; Elman MJ, Qin H, Aiello LP, Beck RW, Bressler NM, Ferris FL 3rd, Glassman AR, Maturi RK, Melia M. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology. 2012 Nov;119(11):2312-8. doi: 10.1016/j.ophtha.2012.08.022. Epub 2012 Sep 19.
citation: Bressler SB, Glassman AR, Almukhtar T, Bressler NM, Ferris FL, Googe JM Jr, Gupta SK, Jampol LM, Melia M, Wells JA 3rd; Diabetic Retinopathy Clinical Research Network. Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema. Am J Ophthalmol. 2016 Apr;164:57-68. doi: 10.1016/j.ajo.2015.12.025. Epub 2016 Jan 21.
citation: Elman MJ, Ayala A, Bressler NM, Browning D, Flaxel CJ, Glassman AR, Jampol LM, Stone TW; Diabetic Retinopathy Clinical Research Network. Intravitreal Ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015 Feb;122(2):375-81. doi: 10.1016/j.ophtha.2014.08.047. Epub 2014 Oct 28.
citation: Gangaputra S, Almukhtar T, Glassman AR, Aiello LP, Bressler N, Bressler SB, Danis RP, Davis MD; Diabetic Retinopathy Clinical Research Network. Comparison of film and digital fundus photographs in eyes of individuals with diabetes mellitus. Invest Ophthalmol Vis Sci. 2011 Aug 3;52(9):6168-73. doi: 10.1167/iovs.11-7321.
citation: Bhavsar AR, Googe JM Jr, Stockdale CR, Bressler NM, Brucker AJ, Elman MJ, Glassman AR; Diabetic Retinopathy Clinical Research Network. Risk of endophthalmitis after intravitreal drug injection when topical antibiotics are not required: the diabetic retinopathy clinical research network laser-ranibizumab-triamcinolone clinical trials. Arch Ophthalmol. 2009 Dec;127(12):1581-3. doi: 10.1001/archophthalmol.2009.304.