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Intravitreal Triamcinolone Acetonide Versus Laser for Diabetic Macular Edema

Information source: Diabetic Retinopathy Clinical Research Network
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Diabetic Macular Edema

Intervention: Standard of Care Group (Procedure); 1mg triamcinolone acetonide (Drug); 4mg triamcinolone acetonide (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Diabetic Retinopathy Clinical Research Network

Official(s) and/or principal investigator(s):
Michael Ip, M.D., Study Chair, Affiliation: University of Wisconsin Medical School

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.

Clinical Details

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

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

Primary outcome:

Change In Visual Acuity [Measured With Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS)]Baseline to 2 Years.

Median Change in Visual Acuity Baseline to 2 Years

Distribution of Change in Visual Acuity Baseline to 2 Years

Secondary outcome:

Central Subfield Thickness at 2 Years

Mean Change in Central Subfield Thickness Baseline to 2 Years

Median Change in Central Subfield Thickness Baseline to 2 Years

Overall Central Subfield Thickening Decreased by >=50% Baseline to 2 Years

Central Subfield Thickness < 250 Microns at 2 Years

Change in Visual Acuity From Baseline to 3 Years

Change in Visual Acuity From Baseline to 3 Years

Distribution of Visual Acuity Change Baseline to 3 Years

Central Subfield Thickness on Optical Coherence Tomography (OCT) at Three Years

Change in Central Subfield Thickness on OCT Baseline to 3 Years

Change in Central Subfield Thickness on OCT Baseline to 3 Years

Percentage of Eyes With a Change in Central Subfield Thickness on OCT <250 Microns From Baseline to 3 Years

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

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Locations and Contacts

Jones Eye Institute/University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199, United States

SCPMG Regional Offices - Kaiser Permanente, Baldwin Park, California 91706, United States

Retina-Vitreous Associates Medical Group, Beverly Hills, California 90211, United States

University of California, Irvine, Irvine, California 92697, United States

Loma Linda University Health Care, Dept. of Ophthalmology, Loma Linda, California 92354, United States

Doheny Eye Institute, Los Angeles, California 90033, United States

Jules Stein Eye Institute, Los Angeles, California 90095, United States

Southern California Desert Retina Consultants, MC, Palm Springs, California 92262, United States

West Coast Retina Medical Group, Inc., San Francisco, California 94107, United States

Orange County Retina Medical Group, Santa Ana, California 92705, United States

California Retina Consultants, Santa Barbara, California 93103, United States

Bay Area Retina Associates, Walnut Creek, California 94598, United States

Denver Health Medical Center, Denver, Colorado 80204, United States

Eldorado Retina Associates, P.C., Louisville, Colorado 80027, United States

Connecticut Retina Consultants, New Haven, Connecticut 06519-1600, United States

Connecticut Retina Consultants, New Haven, Connecticut 06519, United States

National Ophthalmic Research Institute, Fort Myers, Florida 33912, United States

Retina Group of Florida, Ft. Lauderdale, Florida 33334, United States

Central Florida Retina Institute, Lakeland, Florida 33805, United States

Florida Retina Consultants, Lakeland, Florida 33805, United States

Sarasota Retina Institute, Sarasota, Florida 34239, United States

International Eye Center, Tampa, Florida 33603, United States

Southeast Retina Center, P.C., Augusta, Georgia 30909, United States

Retina Consultants of Hawaii, Inc., Aiea, Hawaii 96701, United States

Retina Associates of Hawaii, Inc., Honolulu, Hawaii 96813, United States

Northwestern Medical Faculty Foundation, Chicago, Illinois 60611, United States

Rush University Medical Center, Chicago, Illinois 60612, United States

Illinois Retina Associates, Joliet, Illinois 60435, United States

Raj K. Maturi, M.D., P.C., Indianapolis, Indiana 46290, United States

John-Kenyon American Eye Institute, New Albany, Indiana 47150, United States

Retina and Vitreous Associates of Kentucky, Lexington, Kentucky 40509-1802, United States

Paducah Retinal Center, Paducah, Kentucky 42001, United States

Maine Vitreoretinal Consultants, Bangor, Maine 04401, United States

Elman Retina Group, P.A., Baltimore, Maryland 21237, United States

Wilmer Ophthalmological Institute at Johns Hopkins, Baltimore, Maryland 21287-9277, United States

The Retina Group of Washington, Greenbelt, Maryland 20770-3502, United States

Retina Consultants of Delmarva, P.A., Salisbury, Maryland 21801, United States

Joslin Diabetes Center, Boston, Massachusetts 02215, United States

Ophthalmic Consultants of Boston, Boston, Massachusetts 02114, United States

Henry Ford Health System, Dept of Ophthalmology and Eye Care Services, Detroit, Michigan 48202, United States

Kresge Eye Institute, Detroit, Michigan 48201-1423, United States

Associated Retinal Consultants, Grand Rapids, Michigan 49546, United States

Vision Research Foundation, Royal Oak, Michigan 48073, United States

Retina Center, PA, Minneapolis, Minnesota 55404, United States

University of Minnesota, Minneapolis, Minnesota 55455, United States

Barnes Retina Institute, St. Louis, Missouri 63110, United States

St. Louis University Eye Institute, St. Louis, Missouri 63104, United States

Delaware Valley Retina Associates, Lawrenceville, New Jersey 08648, United States

The New York Eye and Ear Infirmary/Faculty Eye Practice, New York, New York 10003, United States

University of Rochester, Rochester, New York 14642, United States

Retina Consultants, PLLC, Slingerlands, New York 12159, United States

Retina-Vitreous Surgeons of Central New York, PC, Syracuse, New York 13224, United States

University of North Carolina, Dept. of Ophthalmology, Chapel Hill, North Carolina 27599, United States

Charlotte Eye Ear Nose and Throat Assoc, PA, Charlotte, North Carolina 28210, United States

Horizon Eye Care, PA, Charlotte, North Carolina 28211, 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., Dublin, Ohio 43017, United States

Dean A. McGee Eye Institute, Oklahoma City, Oklahoma 73104, United States

Casey Eye Institute, Portland, Oregon 97239, United States

Retina Northwest, PC, Portland, Oregon 97210, United States

Penn State College of Medicine, Hershey, Pennsylvania 17033, United States

University of Pennsylvania Scheie Eye Institute, Philadelphia, Pennsylvania 19104, United States

Retina Consultants, Providence, Rhode Island 02903, United States

Carolina Retina Center, Columbia, South Carolina 29223, United States

Palmetto Retina Center, Columbia, South Carolina 29169, United States

Black Hills Regional Eye Institute, Rapid City, South Dakota 57701, United States

Southeastern Retina Associates, P.C., Knoxville, Tennessee 37909, United States

Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States

West Texas Retina Consultants P.A., Abilene, Texas 79605, United States

Texas Retina Associates, Arlington, Texas 76012, United States

Retina Research Center, Austin, Texas 78705, United States

Texas Retina Associates, Dallas, Texas 75231, United States

University of Texas Medical Branch, Dept of Ophthalmology and Visual Sciences, Galveston, Texas 77555-1106, United States

Charles A. Garcia, PA & Associates, Houston, Texas 77002, United States

Retina and Vitreous of Texas, Houston, Texas 77025, 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

Rocky Mountain Retina Consultants, Salt Lake City, Utah 84107, United States

University of Washington Medical Center, Seattle, Washington 98195, United States

University of Wisconsin-Madison, Dept. of Ophthalmology, Madison, Wisconsin 53705, United States

Medical College of Wiconsin, Milwaukee, Wisconsin 53226, United States

Additional Information

Starting date: July 2004
Last updated: March 18, 2011

Page last updated: August 23, 2015

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