Laser-Ranibizumab-Triamcinolone for Proliferative Diabetic Retinopathy
NCT ID: NCT00445003
Last Updated: 2016-08-26
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
333 participants
INTERVENTIONAL
2007-03-31
2010-07-31
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
Study Groups
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Sham injection plus laser
Sham injection at baseline and 4 weeks. Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.
Sham injection
Sham injection at baseline and 4 weeks
Focal/grid laser
Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.
0.5mg Ranibizumab plus laser
Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks. Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.
Ranibizumab
Intravitreal injection of 0.5 mg ranibizumab at baseline and 4 weeks
Focal/grid laser
Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.
4-mg Triamcinolone Acetonide plus Laser
4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks. Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.
Triamcinolone Acetonide
Intravitreal injection of 4 mg triamcinolone acetonide at baseline and sham injection at 4 weeks
Focal/grid laser
Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.
Interventions
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Ranibizumab
Intravitreal injection of 0.5 mg ranibizumab at baseline and 4 weeks
Triamcinolone Acetonide
Intravitreal injection of 4 mg triamcinolone acetonide at baseline and sham injection at 4 weeks
Sham injection
Sham injection at baseline and 4 weeks
Focal/grid laser
Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Diagnosis of diabetes mellitus (type 1 or type 2)
* Fellow eye (if not a study eye) meets criteria.
* 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.
Exclusion Criteria
* 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.
* 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.
18 Years
ALL
No
Sponsors
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National Eye Institute (NEI)
NIH
Genentech, Inc.
INDUSTRY
Allergan
INDUSTRY
Jaeb Center for Health Research
OTHER
Responsible Party
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Principal Investigators
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Alexander J. Brucker, M.D.
Role: STUDY_CHAIR
Scheie Eye Institute
Joseph Googe, Jr., M.D.
Role: STUDY_CHAIR
Southeastern Retina Associates, P.C.
Locations
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Sall Research Medical Center
Artesia, California, United States
Retina-Vitreous Associates Medical Group
Beverly Hills, California, United States
University of California, Irvine
Irvine, California, United States
Loma Linda University Health Care, Dept. of Ophthalmology
Loma Linda, California, United States
Southern California Desert Retina Consultants, MC
Palm Springs, California, United States
California Retina Consultants
Santa Barbara, California, United States
Bay Area Retina Associates
Walnut Creek, California, United States
Eldorado Retina Associates, P.C.
Louisville, Colorado, United States
Retina Vitreous Consultants
Fort Lauderdale, Florida, United States
Retina Consultants of Southwest Florida
Fort Myers, Florida, United States
Central Florida Retina Institute
Lakeland, Florida, United States
Southeast Retina Center, P.C.
Augusta, Georgia, United States
University of Illinois at Chicago Medical Center
Chicago, Illinois, United States
Illinois Retina Associates
Joliet, Illinois, United States
Raj K. Maturi, M.D., P.C.
Indianapolis, Indiana, United States
John-Kenyon American Eye Institute
New Albany, Indiana, United States
Medical Associates Clinic, P.C.
Dubuque, Iowa, United States
Paducah Retinal Center
Paducah, Kentucky, United States
Maine Vitreoretinal Consultants
Bangor, Maine, United States
Elman Retina Group, P.A.
Baltimore, Maryland, United States
Wilmer Ophthalmological Institute at Johns Hopkins
Baltimore, Maryland, United States
Retina Consultants of Delmarva, P.A.
Salisbury, Maryland, United States
Ophthalmic Consultants of Boston
Boston, Massachusetts, United States
Joslin Diabetes Center
Boston, Massachusetts, United States
Retina Center, PA
Minneapolis, Minnesota, United States
University of Minnesota
Minneapolis, Minnesota, United States
Eyesight Ophthalmic Services, PA
Portsmouth, New Hampshire, United States
The New York Eye and Ear Infirmary/Faculty Eye Practice
New York, New York, United States
Retina-Vitreous Surgeons of Central New York, PC
Syracuse, New York, 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
Wake Forest University Eye Center
Winston-Salem, North Carolina, United States
Case Western Reserve University
Cleveland, Ohio, United States
OSU Eye Physicians and Surgeons, LLC.
Dublin, Ohio, United States
Retina Northwest, PC
Portland, Oregon, United States
Casey Eye Institute
Portland, Oregon, United States
Penn State College of Medicine
Hershey, Pennsylvania, United States
University of Pennsylvania Scheie Eye Institute
Philadelphia, Pennsylvania, United States
Retina Consultants
Providence, Rhode Island, United States
Palmetto Retina Center
Columbia, South Carolina, United States
Carolina Retina Center
Columbia, South Carolina, United States
Southeastern Retina Associates, PC
Kingsport, Tennessee, United States
Southeastern Retina Associates, P.C.
Knoxville, Tennessee, United States
West Texas Retina Consultants P.A.
Abilene, Texas, United States
Texas Retina Associates
Arlington, Texas, United States
Retina Research Center
Austin, Texas, United States
Texas Retina Associates
Dallas, Texas, United States
Retina and Vitreous of Texas
Houston, Texas, United States
Vitreoretinal Consultants
Houston, Texas, United States
Texas Retina Associates
Lubbock, Texas, United States
Valley Retina Institute
McAllen, Texas, United States
Retinal Consultants of San Antonio
San Antonio, Texas, United States
Virginia Retina Center
Leesburg, Virginia, United States
University of Washington Medical Center
Seattle, Washington, United States
University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service
Madison, Wisconsin, United States
Countries
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References
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Diabetic Retinopathy Clinical Research Network; Writing Committee; Aiello LP, Beck RW, Bressler NM, Browning DJ, Chalam KV, Davis M, Ferris FL 3rd, Glassman AR, Maturi RK, Stockdale CR, Topping TM. Rationale for the diabetic retinopathy clinical research network treatment protocol for center-involved diabetic macular edema. Ophthalmology. 2011 Dec;118(12):e5-14. doi: 10.1016/j.ophtha.2011.09.058.
Glassman AR, Stockdale CR, Beck RW, Baker C, Bressler NM; Diabetic Retinopathy Clinical Research Network. Evaluation of masking study participants to intravitreal injections in a randomized clinical trial. Arch Ophthalmol. 2012 Feb;130(2):190-4. doi: 10.1001/archophthalmol.2011.387.
Bressler SB, Qin H, Beck RW, Chalam KV, Kim JE, Melia M, Wells JA 3rd; Diabetic Retinopathy Clinical Research Network. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol. 2012 Sep;130(9):1153-61. doi: 10.1001/archophthalmol.2012.1107.
Bressler SB, Qin H, Melia M, Bressler NM, Beck RW, Chan CK, Grover S, Miller DG; Diabetic Retinopathy Clinical Research Network. Exploratory analysis of the effect of intravitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial. JAMA Ophthalmol. 2013 Aug;131(8):1033-40. doi: 10.1001/jamaophthalmol.2013.4154.
Bressler SB, Almukhtar T, Aiello LP, Bressler NM, Ferris FL 3rd, Glassman AR, Greven CM; Diabetic Retinopathy Clinical Research Network. Green or yellow laser treatment for diabetic macular edema: exploratory assessment within the Diabetic Retinopathy Clinical Research Network. Retina. 2013 Nov-Dec;33(10):2080-8. doi: 10.1097/IAE.0b013e318295f744.
Bressler SB, Almukhtar T, Bhorade A, Bressler NM, Glassman AR, Huang SS, Jampol LM, Kim JE, Melia M; Diabetic Retinopathy Clinical Research Network Investigators. Repeated intravitreous ranibizumab injections for diabetic macular edema and the risk of sustained elevation of intraocular pressure or the need for ocular hypotensive treatment. JAMA Ophthalmol. 2015 May;133(5):589-97. doi: 10.1001/jamaophthalmol.2015.186.
Bressler SB, Melia M, Glassman AR, Almukhtar T, Jampol LM, Shami M, Berger BB, Bressler NM; Diabetic Retinopathy Clinical Research Network. RANIBIZUMAB PLUS PROMPT OR DEFERRED LASER FOR DIABETIC MACULAR EDEMA IN EYES WITH VITRECTOMY BEFORE ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY. Retina. 2015 Dec;35(12):2516-28. doi: 10.1097/IAE.0000000000000617.
Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3rd, Friedman SM, Glassman AR, Scott IU, Stockdale CR, Sun JK; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011 Apr;118(4):609-14. doi: 10.1016/j.ophtha.2010.12.033.
Diabetic Retinopathy Clinical Research Network; Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, Ferris FL 3rd, Friedman SM, Glassman AR, Miller KM, Scott IU, Stockdale CR, Sun JK. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010 Jun;117(6):1064-1077.e35. doi: 10.1016/j.ophtha.2010.02.031. Epub 2010 Apr 28.
Diabetic Retinopathy Clinical Research Network; Elman MJ, Qin H, Aiello LP, Beck RW, Bressler NM, Ferris FL 3rd, Glassman AR, Maturi RK, Melia M. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology. 2012 Nov;119(11):2312-8. doi: 10.1016/j.ophtha.2012.08.022. Epub 2012 Sep 19.
Bressler SB, Glassman AR, Almukhtar T, Bressler NM, Ferris FL, Googe JM Jr, Gupta SK, Jampol LM, Melia M, Wells JA 3rd; Diabetic Retinopathy Clinical Research Network. Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema. Am J Ophthalmol. 2016 Apr;164:57-68. doi: 10.1016/j.ajo.2015.12.025. Epub 2016 Jan 21.
Elman MJ, Ayala A, Bressler NM, Browning D, Flaxel CJ, Glassman AR, Jampol LM, Stone TW; Diabetic Retinopathy Clinical Research Network. Intravitreal Ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015 Feb;122(2):375-81. doi: 10.1016/j.ophtha.2014.08.047. Epub 2014 Oct 28.
Gangaputra S, Almukhtar T, Glassman AR, Aiello LP, Bressler N, Bressler SB, Danis RP, Davis MD; Diabetic Retinopathy Clinical Research Network. Comparison of film and digital fundus photographs in eyes of individuals with diabetes mellitus. Invest Ophthalmol Vis Sci. 2011 Aug 3;52(9):6168-73. doi: 10.1167/iovs.11-7321.
Bhavsar AR, Googe JM Jr, Stockdale CR, Bressler NM, Brucker AJ, Elman MJ, Glassman AR; Diabetic Retinopathy Clinical Research Network. Risk of endophthalmitis after intravitreal drug injection when topical antibiotics are not required: the diabetic retinopathy clinical research network laser-ranibizumab-triamcinolone clinical trials. Arch Ophthalmol. 2009 Dec;127(12):1581-3. doi: 10.1001/archophthalmol.2009.304.
Other Identifiers
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