Clinical trial NCT00367133: Intravitreal Triamcinolone Acetonide Versus Laser for Diabetic Macular Edema
Official title: A Randomized Trial Comparing Intravitreal Triamcinolone Acetonide and Laser Photocoagulation for Diabetic Macular Edema
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetic Macular Edema
Keywords: diabetic
macular
edema
intravitreal
triamcinolone
laser
photocoagulation
DME
Lead sponsor: Jaeb Center for Health Research
Sponsor class: OTHER
Collaborators: name: National Eye Institute (NEI)
name: Allergan
First posted: 2006-08-22
Enrollment: 840
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 study involves the enrollment of patients over 18 years of age with diabetic macular edema(DME). Patients with one study eye will be randomly assigned (stratified by visual acuity and prior laser) with equal probability to one of the three treatment groups:

1. Laser photocoagulation
2. 1mg intravitreal triamcinolone acetonide injection
3. 4mg intravitreal triamcinolone acetonide injection

For patients with two study eyes (both eyes eligible at the time of randomization), the right eye (stratified by visual acuity and prior laser) will be randomly assigned with equal probabilities to one of the three treatment groups listed above. The left eye will be assigned to the alternative treatment (laser or triamcinolone). If the left eye is assigned to triamcinolone, then the dose (1mg or 4 mg) will be randomly assigned to the left eye with equal probability (stratified by visual acuity and prior laser).

The study drug, triamcinolone acetonide, has been manufactured as a sterile intravitreal injectable by Allergan. Study eyes assigned to an intravitreal triamcinolone injection will receive a dose of either 1mg or 4mg. There is no indication of which treatment regimen will be better.

Patients enrolled into the study will be followed for three years and will have study visits every 4 months after receiving their assigned study treatment. In addition, standard of care post-treatment visits will be performed at 4 weeks after each intravitreal injection.

Detailed description: Diabetic retinopathy is a major cause of visual impairment in the United States. Diabetic macular edema (DME) is a manifestation of diabetic retinopathy that produces loss of central vision. Data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) estimate that after 15 years of known diabetes, the prevalence of diabetic macular edema is approximately 20% in patients with type 1 diabetes mellitus (DM), 25% in patients with type 2 DM who are taking insulin, and 14% in patients with type 2 DM who do not take insulin.

In a review of three early studies concerning the natural history of diabetic macular edema, Ferris and Patz found that 53% of 135 eyes with diabetic macular edema, presumably all involving the center of the macula, lost two or more lines of visual acuity over a two year period. In the Early Treatment Diabetic Retinopathy Study (ETDRS), 33% of 221 untreated eyes available for follow-up at the 3-year visit, all with edema involving the center of the macula at baseline, had experienced a 15 or more letter decrease in visual acuity score (equivalent to a doubling of the visual angle, e.g., 20/25 to 20/50, and termed "moderate visual acuity loss").

In the ETDRS, focal/grid photocoagulation of eyes with clinically significant macular edema (CSME) reduced the risk of moderate visual loss by approximately 50% (from 24% to 12%, three years after initiation of treatment). Therefore, 12% of treated eyes developed moderate visual loss in spite of treatment. Furthermore, approximately 40% of treated eyes that had retinal thickening involving the center of the macula at baseline still had thickening involving the center at 12 months, as did 25% of treated eyes at 36 months.

Although several treatment modalities are currently under investigation, the only demonstrated means to reduce the risk of vision loss from diabetic macular edema are laser photocoagulation, as demonstrated by the ETDRS, and intensive glycemic control, as demonstrated by the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS). In the DCCT, intensive glucose control reduced the risk of onset of diabetic macular edema by 23% compared with conventional treatment. Long-term follow-up of patients in the DCCT show a sustained effect of intensive glucose control, with a 58% risk reduction in the development of diabetic macular edema for the DCCT patients followed in the Epidemiology of Diabetes Interventions and Complications Study.

The frequency of an unsatisfactory outcome following laser photocoagulation in some eyes with diabetic macular edema has prompted interest in other treatment modalities. One such treatment is pars plana vitrectomy. These studies suggest that vitreomacular traction, or the vitreous itself, may play a role in increased retinal vascular permeability. Removal of the vitreous or relief of mechanical traction with vitrectomy and membrane stripping may be followed by substantial resolution of macular edema and corresponding improvement in visual acuity. However, this treatment may be applicable only to a specific subset of eyes with diabetic macular edema. It also requires a complex surgical intervention with its inherent risks, recovery time, and expense. Other treatment modalities such as pharmacologic therapy with oral protein kinase C inhibitors and antibodies targeted at vascular endothelial growth factor (VEGF) are under investigation. The use of intravitreal corticosteroids is another treatment modality that has generated recent interest.

The optimal dose of corticosteroid to maximize efficacy with minimum side effects is not known. A 4mg dose of Kenalog is principally being used in clinical practice. However, this dose has been used based on feasibility rather than scientific principles.

There is also experience using Kenalog doses of 1mg and 2mg. These doses anecdotally have been reported to reduce the macular edema. There is a rationale for using a dose lower than 4mg. Glucocorticoids bind to glucocorticoid receptors in the cell cytoplasm, and the steroid-receptor complex moves to the nucleus where it regulates gene expression. The steroid-receptor binding occurs with high affinity (low dissociation constant (Kd) which is on the order of 5 to 9 nanomolar). Complete saturation of all the receptors occurs about 20-fold higher levels, i.e., about 100-200 nanomolar. A 4mg dose of triamcinolone yields a final concentration of 7.5 millimolar, or nearly 10,000-fold more than the saturation dose. Thus, the effect of a 1mg dose may be equivalent to that of a 4mg dose, because compared to the 10,000-fold saturation, a 4-fold difference in dose is inconsequential. It is also possible that higher doses of corticosteroid could be less effective than lower doses due to down-regulation of the receptor. The steroid implant studies provide additional justification for evaluating a lower dose, a 0.5mg device which delivers only 0.5 micrograms per day has been observed to have a rapid effect in reducing macular edema.

There has been limited experience using doses greater than 4mg. Jonas' case series reported results using a 25mg dose. However, others have not been able to replicate this dose using the preparation procedure described by Jonas.

In the trial, 4mg and 1mg doses will be evaluated. The former will be used because it is the dose that is currently most commonly used in clinical practice and the latter because there is reasonable evidence for efficacy and the potential for lower risk. Although there is good reason to believe that a 1mg dose will reduce the macular edema, it is possible that the retreatment rate will be higher with this dose compared with 4mg since the latter will remain active in the eye for a longer duration than the former. Insufficient data are available to warrant evaluating a dose higher than 4mg at this time.

Eligibility criteria: To be eligible, the following inclusion criteria must be met:

1. Age ≥18 years
2. Diagnosis of diabetes mellitus (type 1 or type 2)
3. Able and willing to provide informed consent.
4. Patient understands that (1) if both eyes are eligible at the time of randomization, one eye will receive intravitreal triamcinolone acetonide and one eye will receive laser, and (2) if only one eye is eligible at the time of randomization and the fellow eye develops DME later, then the fellow eye will not receive intravitreal triamcinolone acetonide if the study eye received intravitreal triamcinolone acetonide (however, if the study eye was assigned to the laser group, then the fellow eye may be treated with the 4mg dose of the study intravitreal triamcinolone acetonide formulation, provided the eye assigned to laser has not received an intravitreal injection; such an eye will not be a "study eye" but since it is receiving study drug, it will be followed for adverse effects).

Exclusion Criteria

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

7. History of chronic renal failure requiring dialysis or kidney transplant.

8. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure and glycemic control). Note: Patients in poor glycemic control who, within the last 4 months, initiated intensive insulin treatment (a pump or multiple daily injections) or plan to do so in the next 4 months should not be enrolled.

9. Participation in an investigational trial within 30 days of study entry that involved treatment with any drug that has not received regulatory approval at the time of study entry.

10. Known allergy to any corticosteroid or any component of the delivery vehicle.

11. History of systemic (e.g., oral, IV, IM, epidural, bursal) corticosteroids within 4 months prior to randomization or topical, rectal, or inhaled corticosteroids in current use more than 2 times per week.

12. Patient is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the 3 years of the study.

13. Blood pressure \> 180/110 (systolic above 180 OR diastolic above 110). Note: If blood pressure is brought below 180/110 by anti-hypertensive treatment, patient can become eligible.

Study Eye Eligibility

Inclusion

1. Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (e-ETDRS) visual acuity score of ≥ 24 letters (i.e., 20/320 or better) and ≤73 letters (i.e., 20/40 or worse).
2. Definite retinal thickening due to diabetic macular edema based on clinical exam involving the center of the macula.
3. Mean retinal thickness on two Optical Coherence Tomography (OCT) measurements ≥250 microns in the central subfield.
4. Media clarity, pupillary dilation, and patient cooperation sufficient for adequate fundus photographs.

   Exclusion
5. Macular edema is considered to be due to a cause other than diabetic macular edema.
6. An ocular condition is present such that, in the opinion of the investigator, visual acuity would not improve from resolution of macular edema (e.g., foveal atrophy, pigmentary changes, dense subfoveal hard exudates, nonretinal condition).
7. 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, Irvine-Gass Syndrome, etc.)
8. 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).
9. History of prior treatment with intravitreal corticosteroids.
10. History of peribulbar steroid injection within 6 months prior to randomization.
11. History of focal/grid macular photocoagulation within 15 weeks (3.5 months) prior to randomization.Note: Patients are not required to have had prior macular photocoagulation to be enrolled. If prior macular photocoagulation has been performed, the investigator should believe that the patient may possibly benefit from additional photocoagulation.
12. History of panretinal scatter photocoagulation (PRP) within 4 months prior to randomization.
13. Anticipated need for PRP in the 4 months following randomization.
14. History of prior pars plana vitrectomy.
15. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 6 months or anticipated within the next 6 months following randomization.
16. History of YAG capsulotomy performed within 2 months prior to randomization.
17. Intraocular pressure ≥25 mmHg.
18. History of open-angle glaucoma (either primary open-angle glaucoma or other cause of open-angle glaucoma.) Note: Angle-closure glaucoma is not an exclusion. A history of ocular hypertension is not an exclusion as long as (1) intraocular pressure (IOP) is \<25 mm Hg, (2) the patient is using no more than one topical glaucoma medication, (3) the most recent visual field, performed within the last 12 months, is normal (if abnormalities are present on the visual field they must be attributable to the patient's diabetic retinopathy), and (4) the optic disc does not appear glaucomatous. If the intraocular pressure is 22 to \<25 mm Hg, then the above criteria for ocular hypertension eligibility must be met.
19. History of steroid-induced intraocular pressure elevation that required IOP-lowering treatment.
20. History of prior herpetic ocular infection.
21. Exam evidence of ocular toxoplasmosis.
22. Aphakia.
23. Exam evidence of pseudoexfoliation.
24. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

In patients with only one eye meeting criteria to be a study eye at the time of randomization, the fellow eye must meet the following criteria:

1. Best corrected e-ETDRS visual acuity score ≥19 letters (i.e., 20/400 or better).
2. No prior treatment with intravitreal corticosteroids.
3. Intraocular pressure \< 25 mmHg.
4. No history of open-angle glaucoma (either primary open-angle glaucoma or other cause of open-angle glaucoma.)Note: Angle-closure glaucoma is not an exclusion. A history of ocular hypertension is not an exclusion as long as (1) intraocular pressure is \<25 mmHg, (2) the patient is using no more than one topical glaucoma medication, (3) the most recent visual field, performed within the last 12 months, is normal (if abnormalities are present on the visual field they must be attributable to the patient's diabetic retinopathy), and (4) the optic disc does not appear glaucomatous. If the intraocular pressure is 22 to \<25 mmHg, then the above criteria for ocular hypertension eligibility must be met.
5. No history of steroid-induced intraocular pressure elevation that required IOP-lowering treatment.
6. No exam evidence of pseudoexfoliation.

Primary outcomes:
measure: Change In Visual Acuity [Measured With Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS)]Baseline to 2 Years.
timeFrame: Baseline to 2 Years
measure: Median Change in Visual Acuity Baseline to 2 Years
timeFrame: Baseline to 2 Years
measure: Distribution of Change in Visual Acuity Baseline to 2 Years
timeFrame: baseline to 2 years
Secondary outcomes:
measure: Central Subfield Thickness at 2 Years
timeFrame: 2 Years
measure: Mean Change in Central Subfield Thickness Baseline to 2 Years
timeFrame: Baseline to 2 years
measure: Median Change in Central Subfield Thickness Baseline to 2 Years
timeFrame: Baseline to 2 Years
measure: Overall Central Subfield Thickening Decreased by >=50% Baseline to 2 Years
timeFrame: Baseline to 2 Years
measure: Central Subfield Thickness < 250 Microns at 2 Years
timeFrame: 2 Years
measure: Change in Visual Acuity From Baseline to 3 Years
timeFrame: Baseline to 3 year
measure: Change in Visual Acuity From Baseline to 3 Years
timeFrame: Baseline to 3 year
measure: Distribution of Visual Acuity Change Baseline to 3 Years
timeFrame: Baseline to 3 years
measure: Central Subfield Thickness on Optical Coherence Tomography (OCT) at Three Years
timeFrame: 3 years
measure: Change in Central Subfield Thickness on OCT Baseline to 3 Years
timeFrame: Baseline to 3 years
measure: Percentage of Eyes With a Change in Central Subfield Thickness on OCT <250 Microns From Baseline to 3 Years
timeFrame: Baseline to 3 years
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Jones Eye Institute/University of Arkansas for Medical Sciences
state: Arkansas
city: Baldwin Park
country: United States
facility: SCPMG Regional Offices - Kaiser Permanente
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: Los Angeles
country: United States
facility: Doheny Eye Institute
state: California
city: Los Angeles
country: United States
facility: Jules Stein Eye Institute
state: California
city: Palm Springs
country: United States
facility: Southern California Desert Retina Consultants, MC
state: California
city: San Francisco
country: United States
facility: West Coast Retina Medical Group, Inc.
state: California
city: Santa Ana
country: United States
facility: Orange County Retina Medical Group
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: Denver
country: United States
facility: Denver Health Medical Center
state: Colorado
city: Louisville
country: United States
facility: Eldorado Retina Associates, P.C.
state: Colorado
city: New Haven
country: United States
facility: Connecticut Retina Consultants
state: Connecticut
city: New Haven
country: United States
facility: Connecticut Retina Consultants
state: Connecticut
city: Fort Myers
country: United States
facility: National Ophthalmic Research Institute
state: Florida
city: Ft. Lauderdale
country: United States
facility: Retina Group of Florida
state: Florida
city: Lakeland
country: United States
facility: Central Florida Retina Institute
state: Florida
city: Lakeland
country: United States
facility: Florida Retina Consultants
state: Florida
city: Sarasota
country: United States
facility: Sarasota Retina Institute
state: Florida
city: Tampa
country: United States
facility: International Eye Center
state: Florida
city: Augusta
country: United States
facility: Southeast Retina Center, P.C.
state: Georgia
city: Aiea
country: United States
facility: Retina Consultants of Hawaii, Inc.
state: Hawaii
city: Honolulu
country: United States
facility: Retina Associates of Hawaii, Inc.
state: Hawaii
city: Chicago
country: United States
facility: Northwestern Medical Faculty Foundation
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
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: 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: Bangor
country: United States
facility: Maine Vitreoretinal Consultants
state: Maine
city: Baltimore
country: United States
facility: Elman Retina Group, P.A.
state: Maryland
city: Baltimore
country: United States
facility: Wilmer Ophthalmological Institute at Johns Hopkins
state: Maryland
city: Greenbelt
country: United States
facility: The Retina Group of Washington
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: Detroit
country: United States
facility: Kresge Eye Institute
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System, Dept of Ophthalmology and Eye Care Services
state: Michigan
city: Grand Rapids
country: United States
facility: Associated Retinal Consultants
state: Michigan
city: Royal Oak
country: United States
facility: Vision Research Foundation
state: Michigan
city: Minneapolis
country: United States
facility: Retina Center, PA
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: St. Louis
country: United States
facility: St. Louis University Eye Institute
state: Missouri
city: St. Louis
country: United States
facility: Barnes Retina Institute
state: Missouri
city: Lawrenceville
country: United States
facility: Delaware Valley Retina Associates
state: New Jersey
city: New York
country: United States
facility: The New York Eye and Ear Infirmary/Faculty Eye Practice
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Slingerlands
country: United States
facility: Retina Consultants, PLLC
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: Charlotte
country: United States
facility: Horizon Eye Care, 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: Dublin
country: United States
facility: OSU Eye Physicians and Surgeons, LLC.
state: Ohio
city: Oklahoma City
country: United States
facility: Dean A. McGee Eye Institute
state: Oklahoma
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: Rapid City
country: United States
facility: Black Hills Regional Eye Institute
state: South Dakota
city: Knoxville
country: United States
facility: Southeastern Retina Associates, P.C.
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Abilene
country: United States
facility: West Texas Retina Consultants P.A.
state: Texas
city: Arlington
country: United States
facility: Texas Retina Associates
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: Galveston
country: United States
facility: University of Texas Medical Branch, Dept of Ophthalmology and Visual Sciences
state: Texas
city: Houston
country: United States
facility: Charles A. Garcia, PA & Associates
state: Texas
city: Houston
country: United States
facility: Retina and Vitreous of Texas
state: Texas
city: Houston
country: United States
facility: Retina Consultants of Houston, PA
state: Texas
city: Lubbock
country: United States
facility: Texas Retina Associates
state: Texas
city: McAllen
country: United States
facility: Valley Retina Institute
state: Texas
city: Salt Lake City
country: United States
facility: Rocky Mountain Retina Consultants
state: Utah
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
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wiconsin
state: Wisconsin
Study officials:
affiliation: University of Wisconsin Medical School
name: Michael Ip, M.D.
role: STUDY_CHAIR
References:
citation: Bhavsar AR, Ip MS, Glassman AR; DRCRnet and the SCORE Study Groups. The risk of endophthalmitis following intravitreal triamcinolone injection in the DRCRnet and SCORE clinical trials. Am J Ophthalmol. 2007 Sep;144(3):454-6. doi: 10.1016/j.ajo.2007.04.011.
citation: Ip MS, Bressler SB, Antoszyk AN, Flaxel CJ, Kim JE, Friedman SM, Qin H; Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone and focal/grid photocoagulation for diabetic macular edema: baseline features. Retina. 2008 Jul-Aug;28(7):919-30. doi: 10.1097/IAE.0b013e31818144a7.
citation: Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008 Sep;115(9):1447-9, 1449.e1-10. doi: 10.1016/j.ophtha.2008.06.015. Epub 2008 Jul 26.
citation: Diabetic Retinopathy Clinical Research Network (DRCR.net); Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, Glassman AR, Hartnett E, Ip MS, Kim JE, Kollman C. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009 Mar;127(3):245-51. doi: 10.1001/archophthalmol.2008.610.
citation: Aiello LP, Edwards AR, Beck RW, Bressler NM, Davis MD, Ferris F, Glassman AR, Ip MS, Miller KM; Diabetic Retinopathy Clinical Research Network. Factors associated with improvement and worsening of visual acuity 2 years after focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2010 May;117(5):946-53. doi: 10.1016/j.ophtha.2009.10.002. Epub 2010 Feb 1.
citation: Bressler NM, Edwards AR, Beck RW, Flaxel CJ, Glassman AR, Ip MS, Kollman C, Kuppermann BD, Stone TW; Diabetic Retinopathy Clinical Research Network. Exploratory analysis of diabetic retinopathy progression through 3 years in a randomized clinical trial that compares intravitreal triamcinolone acetonide with focal/grid photocoagulation. Arch Ophthalmol. 2009 Dec;127(12):1566-71. doi: 10.1001/archophthalmol.2009.308.
citation: Rittiphairoj T, Mir TA, Li T, Virgili G. Intravitreal steroids for macular edema in diabetes. Cochrane Database Syst Rev. 2020 Nov 17;11(11):CD005656. doi: 10.1002/14651858.CD005656.pub3.
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.