Intravitreal Triamcinolone Acetonide Versus Laser for Diabetic Macular Edema

Diabetic Macular Edema Clinical Trial

— IVT  

Official title:

A Randomized Trial Comparing Intravitreal Triamcinolone Acetonide and Laser Photocoagulation for Diabetic Macular Edema

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00367133
• Other study ID #: NEI-105
• Secondary ID: U10EY018817-03U1
• Status: Completed
• Phase: Phase 3
• First received: August 3, 2006
• Last updated: August 25, 2016
• Start date: July 2004
• Est. completion date: October 2008

Study information

• Verified date: August 2016
• Source: Jaeb Center for Health Research
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 840
• Est. completion date: October 2008
• Est. primary completion date: May 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetic Macular Edema
• Edema
• Macular Edema

Intervention

Procedure:
• Standard of Care Group
Standard of care group: conventional treatment consisting of focal/grid photocoagulation.

Drug:
• 1mg triamcinolone acetonide
Intravitreal injection of 1mg of triamcinolone acetonide at baseline. At each 4-month interval visit, the investigator will assess whether persistent or recurrent DME is present that warrants retreatment with the randomization assigned treatment. Retreatment, when indicated, will be performed within four weeks after the follow-up visit. Retreatment should not be performed sooner than 3.5 months from the time of the last treatment.
• 4mg triamcinolone acetonide
4mg intravitreal triamcinolone acetonide injection at baseline. At each 4-month interval visit, the investigator will assess whether persistent or recurrent DME is present that warrants retreatment with the randomization assigned treatment. Retreatment, when indicated, will be performed within four weeks after the follow-up visit. Retreatment should not be performed sooner than 3.5 months from the time of the last treatment.

Locations

Country	Name	City	State
United States	West Texas Retina Consultants P.A.	Abilene	Texas
United States	Retina Consultants of Hawaii, Inc.	Aiea	Hawaii
United States	Texas Retina Associates	Arlington	Texas
United States	Southeast Retina Center, P.C.	Augusta	Georgia
United States	Retina Research Center	Austin	Texas
United States	SCPMG Regional Offices - Kaiser Permanente	Baldwin Park	California
United States	Elman Retina Group, P.A.	Baltimore	Maryland
United States	Wilmer Ophthalmological Institute at Johns Hopkins	Baltimore	Maryland
United States	Maine Vitreoretinal Consultants	Bangor	Maine
United States	Retina Associates of Cleveland, Inc.	Beachwood	Ohio
United States	Retina-Vitreous Associates Medical Group	Beverly Hills	California
United States	Joslin Diabetes Center	Boston	Massachusetts
United States	Ophthalmic Consultants of Boston	Boston	Massachusetts
United States	University of North Carolina, Dept. of Ophthalmology	Chapel Hill	North Carolina
United States	Charlotte Eye Ear Nose and Throat Assoc, PA	Charlotte	North Carolina
United States	Horizon Eye Care, PA	Charlotte	North Carolina
United States	Northwestern Medical Faculty Foundation	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Case Western Reserve University	Cleveland	Ohio
United States	Carolina Retina Center	Columbia	South Carolina
United States	Palmetto Retina Center	Columbia	South Carolina
United States	Texas Retina Associates	Dallas	Texas
United States	Denver Health Medical Center	Denver	Colorado
United States	Henry Ford Health System, Dept of Ophthalmology and Eye Care Services	Detroit	Michigan
United States	Kresge Eye Institute	Detroit	Michigan
United States	OSU Eye Physicians and Surgeons, LLC.	Dublin	Ohio
United States	National Ophthalmic Research Institute	Fort Myers	Florida
United States	Retina Group of Florida	Ft. Lauderdale	Florida
United States	University of Texas Medical Branch, Dept of Ophthalmology and Visual Sciences	Galveston	Texas
United States	Associated Retinal Consultants	Grand Rapids	Michigan
United States	The Retina Group of Washington	Greenbelt	Maryland
United States	Penn State College of Medicine	Hershey	Pennsylvania
United States	Retina Associates of Hawaii, Inc.	Honolulu	Hawaii
United States	Charles A. Garcia, PA & Associates	Houston	Texas
United States	Retina and Vitreous of Texas	Houston	Texas
United States	Retina Consultants of Houston, PA	Houston	Texas
United States	Raj K. Maturi, M.D., P.C.	Indianapolis	Indiana
United States	University of California, Irvine	Irvine	California
United States	Illinois Retina Associates	Joliet	Illinois
United States	Southeastern Retina Associates, P.C.	Knoxville	Tennessee
United States	Central Florida Retina Institute	Lakeland	Florida
United States	Florida Retina Consultants	Lakeland	Florida
United States	Delaware Valley Retina Associates	Lawrenceville	New Jersey
United States	Retina and Vitreous Associates of Kentucky	Lexington	Kentucky
United States	Jones Eye Institute/University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Loma Linda University Health Care, Dept. of Ophthalmology	Loma Linda	California
United States	Doheny Eye Institute	Los Angeles	California
United States	Jules Stein Eye Institute	Los Angeles	California
United States	Eldorado Retina Associates, P.C.	Louisville	Colorado
United States	Texas Retina Associates	Lubbock	Texas
United States	University of Wisconsin-Madison, Dept. of Ophthalmology	Madison	Wisconsin
United States	Valley Retina Institute	McAllen	Texas
United States	Medical College of Wiconsin	Milwaukee	Wisconsin
United States	Retina Center, PA	Minneapolis	Minnesota
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	John-Kenyon American Eye Institute	New Albany	Indiana
United States	Connecticut Retina Consultants	New Haven	Connecticut
United States	Connecticut Retina Consultants	New Haven	Connecticut
United States	The New York Eye and Ear Infirmary/Faculty Eye Practice	New York	New York
United States	Dean A. McGee Eye Institute	Oklahoma City	Oklahoma
United States	Paducah Retinal Center	Paducah	Kentucky
United States	Southern California Desert Retina Consultants, MC	Palm Springs	California
United States	University of Pennsylvania Scheie Eye Institute	Philadelphia	Pennsylvania
United States	Casey Eye Institute	Portland	Oregon
United States	Retina Northwest, PC	Portland	Oregon
United States	Retina Consultants	Providence	Rhode Island
United States	Black Hills Regional Eye Institute	Rapid City	South Dakota
United States	University of Rochester	Rochester	New York
United States	Vision Research Foundation	Royal Oak	Michigan
United States	Retina Consultants of Delmarva, P.A.	Salisbury	Maryland
United States	Rocky Mountain Retina Consultants	Salt Lake City	Utah
United States	West Coast Retina Medical Group, Inc.	San Francisco	California
United States	Orange County Retina Medical Group	Santa Ana	California
United States	California Retina Consultants	Santa Barbara	California
United States	Sarasota Retina Institute	Sarasota	Florida
United States	University of Washington Medical Center	Seattle	Washington
United States	Retina Consultants, PLLC	Slingerlands	New York
United States	Barnes Retina Institute	St. Louis	Missouri
United States	St. Louis University Eye Institute	St. Louis	Missouri
United States	Retina-Vitreous Surgeons of Central New York, PC	Syracuse	New York
United States	International Eye Center	Tampa	Florida
United States	Bay Area Retina Associates	Walnut Creek	California
United States	Wake Forest University Eye Center	Winston-Salem	North Carolina

Sponsors (3)

Lead Sponsor	Collaborator
Jaeb Center for Health Research	Allergan, National Eye Institute (NEI)

Country where clinical trial is conducted

United States, 

References & Publications (6)

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 fo — View 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. — View 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 th — View 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 intra — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change In Visual Acuity [Measured With Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS)]Baseline to 2 Years.	Change in best correct visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement. Best value on the scale 97, worst 0.	Baseline to 2 Years	No
Primary	Median Change in Visual Acuity Baseline to 2 Years	Change in best correct visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement.	Baseline to 2 Years	No
Primary	Distribution of Change in Visual Acuity Baseline to 2 Years	Change in best correct visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method.	baseline to 2 years	No
Secondary	Central Subfield Thickness at 2 Years	Median central subfield thickness at two-years. Optical coherence Tomography (OCT) images were obtained by a certified operator using the Zeiss Stratus OCT machine. If the automated thickness measurements were judged by the reading center to be inaccurate, center point thickness was measured manually, and this value was used to impute a value for the central subfield.	2 Years	No
Secondary	Mean Change in Central Subfield Thickness Baseline to 2 Years	Overall central subfield change from baseline. Optical coherence Tomography (OCT) images were obtained by a certified operator using the Zeiss Stratus OCT machine. The average of 2 baseline central subfield thickness measurements was used for analysis.If the automated thickness measurements were judged by the reading center to be inaccurate, center point thickness was measured manually, and this value was used to impute a value for the central subfield. Negative change denotes and improvement.	Baseline to 2 years	No
Secondary	Median Change in Central Subfield Thickness Baseline to 2 Years	Overall central subfield change from baseline. Optical coherence Tomography (OCT) images were obtained by a certified operator using the Zeiss Stratus OCT machine. The average of 2 baseline central subfield thickness measurements was used for analysis.If the automated thickness measurements were judged by the reading center to be inaccurate, center point thickness was measured manually, and this value was used to impute a value for the central subfield. Negative change denotes an improvement.	Baseline to 2 Years	No
Secondary	Overall Central Subfield Thickening Decreased by >=50% Baseline to 2 Years	Overall central subfield change from baseline. Optical coherence Tomography (OCT) images were obtained by a certified operator using the Zeiss Stratus OCT machine. If the automated thickness measurements were judged by the reading center to be inaccurate, center point thickness was measured manually, and this value was used to impute a value for the central subfield.	Baseline to 2 Years	No
Secondary	Central Subfield Thickness < 250 Microns at 2 Years	Overall central subfield change from baseline. Optical coherence Tomography (OCT) images were obtained by a certified operator using the Zeiss Stratus OCT machine. If the automated thickness measurements were judged by the reading center to be inaccurate, center point thickness was measured manually, and this value was used to impute a value for the central subfield.	2 Years	No
Secondary	Change in Visual Acuity From Baseline to 3 Years	Change in best correct visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement.	Baseline to 3 year	No
Secondary	Change in Visual Acuity From Baseline to 3 Years	Change in best correct visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement. Best Value on the scale=97, Worst Value=0	Baseline to 3 year	No
Secondary	Distribution of Visual Acuity Change Baseline to 3 Years	Change in best correct visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement. Best value on the scale=97, worst=0	Baseline to 3 years	No
Secondary	Central Subfield Thickness on Optical Coherence Tomography (OCT) at Three Years	Overall central subfield change from baseline. Optical coherence Tomography (OCT) images were obtained by a certified operator using the Zeiss Stratus OCT machine. If the automated thickness measurements were judged by the reading center to be inaccurate, center point thickness was measured manually, and this value was used to impute a value for the central subfield.	3 years	No
Secondary	Change in Central Subfield Thickness on OCT Baseline to 3 Years	Overall central subfield change from baseline. Optical coherence Tomography (OCT) images were obtained by a certified operator using the Zeiss Stratus OCT machine. The average of 2 baseline central subfield thickness measurements was used for analysis.If the automated thickness measurements were judged by the reading center to be inaccurate, center point thickness was measured manually, and this value was used to impute a value for the central subfield. Negative change denotes an improvement.	Baseline to 3 years	No
Secondary	Percentage of Eyes With a Change in Central Subfield Thickness on OCT <250 Microns From Baseline to 3 Years	Overall central subfield change from baseline. Optical coherence Tomography (OCT) images were obtained by a certified operator using the Zeiss Stratus OCT machine. The average of 2 baseline central subfield thickness measurements was used for analysis.If the automated thickness measurements were judged by the reading center to be inaccurate, center point thickness was measured manually, and this value was used to impute a value for the central subfield. Negative change denotes an improvement.	Baseline to 3 years	No