Laser-Ranibizumab-Triamcinolone for Diabetic Macular Edema

Condition(s) targeted: Diabetic Retinopathy; Diabetic Macular Edema

Intervention: Triamcinolone Acetonide + laser (Drug); Ranibizumab + laser (Drug); Sham injection + laser (Drug); Ranibizumab + deferred laser (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: National Eye Institute (NEI)

Official(s) and/or principal investigator(s):
Michael J. Elman, M.D., Study Chair, Affiliation: Elman Retina Group, PA

Overall contact:
Roy W. Beck, M.D., Ph.D., Phone: 866-372-7601, Ext: 218, Email: rbeck@jaeb.org

The purpose of the study is to find out which is a better treatment for 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-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.

Official title: Intravitreal Ranibizumab or Triamcinolone Acetonide in Combination With Laser Photocoagulation for Diabetic Macular Edema

Study design: Treatment, Randomized, Double Blind (Subject, Outcomes Assessor), Parallel Assignment, Efficacy Study

Primary outcome: Visual Acuity adjusted for the baseline acuity

Secondary outcome:

Change in retinal thickening of central subfield and retinal volume measured on OCT

Number of injections in first year

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 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 AMD. 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 DRCR Network 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.

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

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-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 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.

- 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 DME 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 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 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.

Roy W. Beck, M.D., Ph.D., Phone: 866-372-7601, Ext: 218, Email: rbeck@jaeb.org

Bay Area Retina Associates, Walnut Creek, California 94598, United States; Recruiting
Stewart A. Daniels, M.D.

California Retina Consultants, Santa Barbara, California 93103, United States; Recruiting
Dante J. Pieramici, M.D.

Loma Linda University Health Care, Dept. of Ophthalmology, Loma Linda, California 92354, United States; Recruiting
Joseph T. Fan, M.D.

Retina-Vitreous Associates Medical Group, Beverly Hills, California 90211, United States; Recruiting
Roger L. Novack, M.D., Ph.D.

Southern California Desert Retina Consultants, MC, Palm Springs, California 92262, United States; Recruiting
Clement K. Chan, M.D., FACS

University of California, Irvine, Irvine, California 92697, United States; Recruiting
Baruch D. Kuppermann, M.D.

Sall Research Medical Center, Artesia, California 90701, United States; Recruiting
Laura A. Teasley, M.D.

Central Florida Retina Institute, Lakeland, Florida 33805, United States; Recruiting
Scott M. Friedman, M.D.

Retina Vitreous Consultants, Ft. Lauderdale, Florida 33334, United States; Recruiting
Ronald J. Glatzer, M.D.

Retina Consultants of Southwest Florida, Fort Myers, Florida 33912, United States; Recruiting
Glenn Wing, M.D.

University of Florida College of Med., Department of Ophthalmology, Jacksonville, Florida 32209, United States; Recruiting
Kakarla V. Chalam, M.D., PhD

Southeast Retina Center, P.C., Augusta, Georgia 30909, United States; Recruiting
Dennis M. Marcus, M.D.

Illinois Retina Associates, Joliet, Illinois 60435, United States; Recruiting
Matthew MacCumber, M.D.

Raj K. Maturi, M.D., P.C., Indianapolis, Indiana 46280, United States; Recruiting
Raj K. Maturi, M.D.

John-Kenyon American Eye Institute, New Albany, Indiana 47150, United States; Recruiting
Howard S. Lazarus, M.D.

Medical Associates Clinic, P.C., Dubuque, Iowa 52002, United States; Recruiting
Michael H. Scott, M.D.

Paducah Retinal Center, Paducah, Kentucky 42001, United States; Recruiting
Carl W. Baker, M.D.

Retina and Vitreous Associates of Kentucky, Lexington, Kentucky 40509-1802, United States; Recruiting
Thomas W. Stone, M.D.

Elman Retina Group, P.A., Baltimore, Maryland 21237, United States; Recruiting
Michael J. Elman, M.D.

Retina Consultants of Delmarva, P.A., Salisbury, Maryland 21801, United States; Recruiting
Jeffrey D. Benner, M.D.

Wilmer Eye Institute at Johns Hopkins, Baltimore, Maryland 21287-9277, United States; Recruiting
Susan Bressler, M.D.

Joslin Diabetes Center, Boston, Massachusetts 02215, United States; Recruiting
George S. Sharuk, M.D.

Ophthalmic Consultants of Boston, Boston, Massachusetts 02114, United States; Recruiting
Trexler Topping, M.D.

Retina Center, PA, Minneapolis, Minnesota 55404, United States; Recruiting
Abdhish Bhavsar, M.D.

Eyesight Ophthalmic Services, PA, Portsmouth, New Hampshire 03801, United States; Recruiting
Richard Chace, M.D.

Retina-Vitreous Surgeons of Central New York, PC, Syracuse, New York 13224, United States; Recruiting
G. R. Hampton, M.D.

The New York Eye and Ear Infirmary/Faculty Eye Practice, New York, New York 10003, United States; Recruiting
Ronald G. Gentile, M.D.

Wake Forest University Eye Center, Winston-Salem, North Carolina 27157, United States; Recruiting
Craig M. Greven, M.D.

Charlotte Eye, Ear, Nose and Throat Assoc., PA, Charlotte, North Carolina 28210, United States; Recruiting
David Browning, M.D.

University of North Carolina, Dept of Ophthalmology, Chapel Hill, North Carolina 27599-7040, United States; Recruiting
Mary Elizabeth R. Hartnett, M.D.

Retina Associates of Cleveland, Inc., Beachwood, Ohio 44122, United States; Recruiting
Lawrence J. Singerman, M.D.

Case Western Reserve University, Cleveland, Ohio 44106, United States; Recruiting
Suber S. Huang, M.D.

Retina Northwest, PC, Portland, Oregon 97210, United States; Recruiting
Mark A. Peters, M.D.

Casey Eye Institute, Portland, Oregon 97239, United States; Recruiting
Andreas K. Lauer, M.D.

Penn State College of Medicine, Hershey, Pennsylvania 17033, United States; Recruiting
Thomas W. Gardner, M.D.

University of Pennsylvania Scheie Eye Institute, Philadelphia, Pennsylvania 19104, United States; Recruiting
Alexander J. Brucker, M.D.

Retina Consultants, Providence, Rhode Island 02903, United States; Recruiting
Caldwell W. Smith, M.D.

Palmetto Retina Center, Columbia, South Carolina 29169, United States; Recruiting
John A. Wells, III, M.D.

Carolina Retina Center, Columbia, South Carolina 29223, United States; Recruiting
Jeffrey G. Gross, M.D.

Southeastern Retina Associates, P.C., Knoxville, Tennessee 37909, United States; Recruiting
Joseph Googe, Jr., M.D.

Southeastern Retina Associates, PC, Kingsport, Tennessee 37660, United States; Recruiting
Howard L. Cummings, M.D., FACS

Retina Research Center, Austin, Texas 78705, United States; Recruiting
Brian B. Berger, M.D.

Texas Retina Associates, Dallas, Texas 75231, United States; Recruiting
Gary E. Fish, M.D.

Texas Retina Associates, Lubbock, Texas 79424, United States; Recruiting
Michel Shami, M.D.

Retina and Vitreous of Texas, Houston, Texas 77025, United States; Recruiting
H. M. Lambert, M.D.

West Texas Retina Consultants P.A., Abilene, Texas 79605, United States; Recruiting
Sunil S. Patel, M.D., Ph.D.

Vitreoretinal Consultants, Houston, Texas 77030, United States; Recruiting
David M. Brown, M.D., FACS

University of Washington Medical Center, Seattle, Washington 98195, United States; Recruiting
James L. Kinyoun, M.D.

Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States; Recruiting
Judy E. Kim, M.D.

University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service, Madison, Wisconsin 53705, United States; Recruiting
Justin Gottlieb, M.D.

NEI Clinical Studies Database

Diabetic Retinopathy Clinical Research Network

Starting date: March 2007
Ending date: March 2011
Last updated: July 1, 2008