Laser-Ranibizumab-Triamcinolone for Proliferative Diabetic Retinopathy

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

Intervention: Ranibizumab (Drug); Triamcinolone Acetonide (Drug); Sham injection (Behavioral)

Phase: Phase 3

Status: Recruiting

Sponsored by: National Eye Institute (NEI)

Official(s) and/or principal investigator(s):
Alexander J. Brucker, M.D., Study Chair, Affiliation: Scheie Eye Institute

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

The purpose of the study is to find out if treatment with an intravitreal injection of triamcinolone or an intravitreal injection of ranibizumab can prevent loss of vision caused by panretinal photocoagulation treatment. At the present time, it is not known whether intravitreal steroid or anti-VEGF injections are beneficial in preventing vision loss after PRP treatment. It is possible that one or both of the types of injections will prevent vision loss after PRP treatment. However, it is not known whether the benefits of the injections will outweigh the risks. It is possible that because of side effects, the injections may not be as good as laser alone in treating the diabetic retinopathy.

Official title: Intravitreal Ranibizumab or Triamcinolone Acetonide as Adjunctive Treatment to Panretinal Photocoagulation for Proliferative Diabetic Retinopathy

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

Primary outcome: Visual Acuity adjusted for the baseline acuity.

Secondary outcome:

Change in retinal thickening from baseline OCT central subfield and retinal volume

Presence and extent of new vessels on fundus photographs

Vitreous hemorrhage

Additional sessions of scatter photocoagulation due to worsening PDR before 14 week visit after completion of initial session

Detailed description: Proliferative diabetic retinopathy (PDR) is manifested in retinal neovascularization at the disc NVD) or elsewhere (NVE). Vitreous hemorrhage or traction detachment from PDR is a leading cause of severe visual loss and new onset blindness. Without intervention, 60 percent of individuals with diabetic retinopathy will eventually develop proliferative retinopathy, resulting in significant visual loss in nearly fifty percent.

Proliferative diabetic retinopathy is currently treated with scatter (panretinal) laser photocoagulation (PRP) which destroys areas of the retina but preserves central vision. PRP is most effectively seen in a regression of new vessels, stabilization of the neovascularization, and reduced risk of visual loss. However, the treatment is associated with unavoidable side effects including macular edema with transient or permanent central vision loss, diminished vision loss, and night vision loss. The treatment applies laser burns to the peripheral retinal tissue, destroying outer photoreceptors and retinal pigment epithelium of the retina, and is thought to exert its effect by increasing oxygen delivery to the inner retina and decreasing viable hypoxic cells which are producing growth factors such as VEGF. Studies have implicated vascular endothelial growth factor (VEGF) as the substance leading to neovascularization and/or increased vascular permeability. Thus, it is reasonable to expect that inhibition of VEGF could reduce both PDR and transient vision loss from macular edema. There are several anti-VEGF drugs. Ranibizumab is the drug to be evaluated in this trial. In one trial of ranibizumab on DME, ten patients with chronic DME received a series of 0. 5mg intraocular injections. The treatments were well tolerated with no ocular or systemic adverse events. Since intraocular injections of ranibizumab significantly reduced foveal thickness and improved visual acuity in all ten patients, there is strong rationale to consider this drug as adjunctive therapy to PRP in a attempt to reduce the acute, transient edema that may occur with PRP.

Similarly, corticosteroids, a class of substances with anti-inflammatory properties, have demonstrated to inhibit the expression of VEGF. Triamcinolone acetonide is often used as a periocular injection for the treatment of cystoid macular edema (CME) secondary to uveitis. Clinically, triamcinolone acetonide is used in the treatment of proliferative vitreoretinopathy and choroidal neovascularization. Studies on patients with proliferative diabetic retinopathy randomly assigned to receive 4mg triamcinolone 10 to 15 days prior to PRP treatment showed a reduction in central macular thickening, and fluorescein leakage was greater in the injection group than in the control group at 9 and 12 months follow up. Mean visual acuity improved by one line in the injection group and worsened by two lines in the control group.

In summary, there is strong rationale that using either intravitreal ranibizumab or intravitreal triamcinolone acetonide as an adjunct to PRP could reduce the magnitude of vision loss.

This study is being conducted to determine whether intravitreal injection of an anti-VEGF drug or an intravitreal injection of a corticosteroid can reduce the occurrence of macular edema and visual acuity impairment following PRP. Subjects will be randomly assigned with equal probability to one of the following three injection groups:

- Intravitreal injection of 0. 5 mg ranibizumab (Lucentis™) at baseline and 4 weeks

- Intravitreal injection of 4 mg triamcinolone acetonide at baseline and sham injection at

4 weeks

- Sham injection at baseline and 4 weeks

The initial injection (or sham) is given on the day of randomization. Focal (macular) photocoagulation is given 7 to 10 days following the injection. Panretinal (scatter) photocoagulation can be initiated either on the same day as the focal photocoagulation (immediately following the focal photocoagulation) or on a subsequent day but must be initiated within 14 days of the baseline injection. Required follow-up visits occur at 4, 14, 34 and 56 weeks.

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

Criteria:

General Inclusion Criteria

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

- Age >= 18 years

- Diagnosis of diabetes mellitus (type 1 or type 2)

- 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 drugs.

- 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 12 months of the study.

Study Eye Inclusion Criteria The subject must have at least one eye meeting all of the inclusion criteria and none of the exclusion criteria listed below. A subject can have only one study eye. If both eyes are eligible at the time of randomization, the study eye will be selected by the investigator and subject before randomization.

- Presence of severe nonproliferative or proliferative diabetic retinopathy for which

investigator intends to complete panretinal photocoagulation within 49 days after randomization.

- Diabetic macular edema present on clinical exam and central subfield thickness on OCT

>250 microns, within 8 days of randomization.

- Best corrected E-ETDRS visual acuity letter score >=24 (i. e., 20/320 or better),

within 8 days of randomization.

- Media clarity, pupillary dilation, and subject cooperation sufficient to administer

panretinal photocoagulation and obtain adequate fundus photographs and OCT.

- If prior macular photocoagulation has been performed, the investigator believes that

the study eye may possibly benefit from additional focal photocoagulation.

Study Eye Exclusion Criteria

The following exclusions apply to the study eye only (i. e., they may be present for the nonstudy eye unless otherwise specified):

- Prior panretinal photocoagulation that was sufficiently extensive that the

investigator does not believe that at least 1200 additional burns are needed or possible within 49 days after randomization.

- 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,

preventing 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., retinal vein or artery 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 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: 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.

Fellow Eye Criteria

The fellow eye must meet the following criteria:

- Intraocular pressure < 25 mmHg.

- 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 criterion).

- No history of steroid-induced intraocular pressure elevation that required

IOP-lowering treatment.

- No exam evidence of pseudoexfoliation.

Roy W. Beck, M.D., Ph.D., Phone: (866) 372-7601, 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.

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

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

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

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

The George Washington University, Department of Ophthalmology, Washington, District of Columbia 20037, United States; Recruiting
Jeevan R. Mathura, Jr., 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.

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.

University of Illinois at Chicago Medical Center, Chicago, Illinois 60612, United States; Recruiting
Jennifer I. Lim, M.D.

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

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

Maine Vitreoretinal Consultants, Bangor, Maine 04401, United States; Recruiting
Deborah Hoffert, M.D., FACS

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

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

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

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

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

University of North Carolina, Dept of Ophthalmology, Chapel Hill, North Carolina 27599-7040, United States; Active, not recruiting

Horizon Eye Care, PA, Charlotte, North Carolina 28211, United States; Recruiting
Miriam E. Ridley, M.D.

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

OSU Eye Physicians and Surgeons, LLC., Dublin, Ohio 43017, United States; Recruiting
Frederick H. Davidorf, 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.

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

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

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

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

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

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

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

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

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.

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

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

Texas Retina Associates, Arlington, Texas 76012, United States; Recruiting
David G. Callanan, M.D.

University of Washington Medical Center, Seattle, Washington 98195, United States; Recruiting
James L. Kinyoun, 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: December 2010
Last updated: July 1, 2008