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Laser-Ranibizumab-Triamcinolone for Proliferative Diabetic Retinopathy

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: Proliferative Diabetic Retinopathy; Diabetic Macular Edema

Intervention: Ranibizumab (Drug); Triamcinolone Acetonide (Drug); Sham injection (Behavioral); Focal/grid laser (Procedure)

Phase: Phase 3

Status: Completed

Sponsored by: Diabetic Retinopathy Clinical Research Network

Official(s) and/or principal investigator(s):
Alexander J. Brucker, M.D., Study Chair, Affiliation: Scheie Eye Institute
Joseph Googe, Jr., M.D., Study Chair, Affiliation: Southeastern Retina Associates, P.C.

Summary

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-vascular endothelial growth factor (anti-VEGF) injections are beneficial in preventing vision loss after panretinal photocoagulation (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.

Clinical Details

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

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

Primary outcome: Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 14 Weeks

Secondary outcome:

Additional Treatments for Diabetic Macular Edema

Change in Optical Coherence Tomography Central Subfield Thickness

Total Optical Coherence Tomography Retinal Volume

Change in Visual Acuity From Baseline

Eyes With Anti-vascular Endothelial Growth Factor Treatment for Diabetic Macular Edema

Number of Eyes With Additional Number of Treatments for Diabetic Macular Edema

Change in Optical Coherence Tomography Retinal Volume

Detailed description: Proliferative diabetic retinopathy (PDR) is manifested in retinal neovascularization at the disc (NVD) or elsewhere (NVE). Vitreous hemorrhage or tractional 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 PDR, resulting in significant visual loss in nearly fifty percent. Proliferative diabetic retinopathy is currently treated with panretinal 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. 5 mg 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 4 mg 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.

Eligibility

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

Criteria:

General Inclusion Criteria

- 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. Study Eye Inclusion Criteria Subjects

may have one or two study eyes. Subjects with two study eyes will be randomly assigned to receive sham injection at baseline and 4 weeks in one eye and either ranibizumab or triamcinolone in the other eye.

- Presence of severe nonproliferative or proliferative diabetic retinopathy for which

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

- Diabetic macular edema(DME) present on clinical exam and central subfield thickness

on Optical Coherence Tomography (OCT) >250 microns, within 8 days of randomization.

- Best corrected Electronic-Early Treatment Diabetic Retinopathy Study 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. General Exclusion Criteria

- 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-vascular endothelial growth factor(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 Exclusion Criteria, Study eye only:

- 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, non-retinal 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 Yttrium Aluminum Garnet 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 intraocular

pressure-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

- 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

intraocular pressure-lowering treatment.

- No exam evidence of pseudoexfoliation.

Locations and Contacts

Sall Research Medical Center, Artesia, California 90701, 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

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

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

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

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

Retina Consultants of Southwest Florida, Fort Myers, Florida 33912, United States

Retina Vitreous Consultants, Ft. Lauderdale, Florida 33334, United States

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

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

University of Illinois at Chicago Medical Center, Chicago, Illinois 60612, United States

Illinois Retina Associates, Joliet, Illinois 60435, United States

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

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

Medical Associates Clinic, P.C., Dubuque, Iowa 52002, 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

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

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

University of Minnesota, Minneapolis, Minnesota 55455, United States

Eyesight Ophthalmic Services, PA, Portsmouth, New Hampshire 03801, United States

The New York Eye and Ear Infirmary/Faculty Eye Practice, New York, New York 10003, 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 27599-7040, 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

Case Western Reserve University, Cleveland, Ohio 44106, United States

OSU Eye Physicians and Surgeons, LLC., Dublin, Ohio 43017, 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

Southeastern Retina Associates, PC, Kingsport, Tennessee 37660, United States

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

Retina and Vitreous of Texas, Houston, Texas 77025, United States

Vitreoretinal Consultants, Houston, Texas 77030, United States

Texas Retina Associates, Lubbock, Texas 79424, United States

Valley Retina Institute, McAllen, Texas 78503, United States

Retinal Consultants of San Antonio, San Antonio, Texas 78240, United States

Virginia Retina Center, Leesburg, Virginia 20176, United States

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

University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service, Madison, Wisconsin 53705, United States

Additional Information

Starting date: March 2007
Last updated: January 30, 2013

Page last updated: August 23, 2015

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