Laser-Ranibizumab-Triamcinolone for Proliferative Diabetic Retinopathy

Diabetic Macular Edema Clinical Trial

— LRTforDME+PRP  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00445003
• Other study ID #: NEI-134
• Secondary ID: U10EY018817-03U1
• Status: Completed
• Phase: Phase 3
• First received: March 6, 2007
• Last updated: August 25, 2016
• Start date: March 2007
• Est. completion date: July 2010

Study information

• Verified date: August 2016
• Source: Jaeb Center for Health Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 333
• Est. completion date: July 2010
• Est. primary completion date: October 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Diabetic Macular Edema
• Diabetic Retinopathy
• Macular Edema
• Proliferative Diabetic Retinopathy
• Retinal Diseases

Intervention

Drug:
• 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

Behavioral:
• Sham injection
Sham injection at baseline and 4 weeks

Procedure:
• Focal/grid laser
Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.

Locations

Country	Name	City	State
United States	West Texas Retina Consultants P.A.	Abilene	Texas
United States	Texas Retina Associates	Arlington	Texas
United States	Sall Research Medical Center	Artesia	California
United States	Southeast Retina Center, P.C.	Augusta	Georgia
United States	Retina Research Center	Austin	Texas
United States	Elman Retina Group, P.A.	Baltimore	Maryland
United States	Wilmer Ophthalmological Institute at Johns Hopkins	Baltimore	Maryland
United States	Maine Vitreoretinal Consultants	Bangor	Maine
United States	Retina-Vitreous Associates Medical Group	Beverly Hills	California
United States	Joslin Diabetes Center	Boston	Massachusetts
United States	Ophthalmic Consultants of Boston	Boston	Massachusetts
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	University of Illinois at Chicago Medical Center	Chicago	Illinois
United States	Case Western Reserve University	Cleveland	Ohio
United States	Carolina Retina Center	Columbia	South Carolina
United States	Palmetto Retina Center	Columbia	South Carolina
United States	Texas Retina Associates	Dallas	Texas
United States	OSU Eye Physicians and Surgeons, LLC.	Dublin	Ohio
United States	Medical Associates Clinic, P.C.	Dubuque	Iowa
United States	Retina Consultants of Southwest Florida	Fort Myers	Florida
United States	Retina Vitreous Consultants	Ft. Lauderdale	Florida
United States	Penn State College of Medicine	Hershey	Pennsylvania
United States	Retina and Vitreous of Texas	Houston	Texas
United States	Vitreoretinal Consultants	Houston	Texas
United States	Raj K. Maturi, M.D., P.C.	Indianapolis	Indiana
United States	University of California, Irvine	Irvine	California
United States	Illinois Retina Associates	Joliet	Illinois
United States	Southeastern Retina Associates, PC	Kingsport	Tennessee
United States	Southeastern Retina Associates, P.C.	Knoxville	Tennessee
United States	Central Florida Retina Institute	Lakeland	Florida
United States	Virginia Retina Center	Leesburg	Virginia
United States	Loma Linda University Health Care, Dept. of Ophthalmology	Loma Linda	California
United States	Eldorado Retina Associates, P.C.	Louisville	Colorado
United States	Texas Retina Associates	Lubbock	Texas
United States	University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service	Madison	Wisconsin
United States	Valley Retina Institute	McAllen	Texas
United States	Retina Center, PA	Minneapolis	Minnesota
United States	University of Minnesota	Minneapolis	Minnesota
United States	John-Kenyon American Eye Institute	New Albany	Indiana
United States	The New York Eye and Ear Infirmary/Faculty Eye Practice	New York	New York
United States	Paducah Retinal Center	Paducah	Kentucky
United States	Southern California Desert Retina Consultants, MC	Palm Springs	California
United States	University of Pennsylvania Scheie Eye Institute	Philadelphia	Pennsylvania
United States	Casey Eye Institute	Portland	Oregon
United States	Retina Northwest, PC	Portland	Oregon
United States	Eyesight Ophthalmic Services, PA	Portsmouth	New Hampshire
United States	Retina Consultants	Providence	Rhode Island
United States	Retina Consultants of Delmarva, P.A.	Salisbury	Maryland
United States	Retinal Consultants of San Antonio	San Antonio	Texas
United States	California Retina Consultants	Santa Barbara	California
United States	University of Washington Medical Center	Seattle	Washington
United States	Retina-Vitreous Surgeons of Central New York, PC	Syracuse	New York
United States	Bay Area Retina Associates	Walnut Creek	California
United States	Wake Forest University Eye Center	Winston-Salem	North Carolina

Sponsors (4)

Lead Sponsor	Collaborator
Jaeb Center for Health Research	Allergan, Genentech, Inc., National Eye Institute (NEI)

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. — View Citation

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. — View Citation

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 Triamci — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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 — View Citation

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 r — View Citation

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. — View Citation

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 tri — View Citation

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 pr — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 14 Weeks	Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.	baseline to 14 weeks
Secondary	Additional Treatments for Diabetic Macular Edema	Each combination of treatment is only counted once per treatment eye. Participants could have 2 study eyes, with random assignments to different treatments.	14 weeks to 56-weeks
Secondary	Change in Optical Coherence Tomography Central Subfield Thickness		Baseline to 14 weeks
Secondary	Total Optical Coherence Tomography Retinal Volume	Missing/ungradable as follows: Sham = 49, Ranibizumab = 37, Triamcinolone = 39. Visits occured between 70 days and 153 days from randomization adjusted for baseline optical coherence tomography (OCT) retinal volume, OCT retinal thickness and visual acuity, number of planned panretinal photocoagulation sittings, and correlation between 2 study eyes. Confidence intervals are adjusted for multiple comparisons.	Baseline to 14-weeks
Secondary	Change in Visual Acuity From Baseline	Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.	baseline to 56-weeks
Secondary	Eyes With Anti-vascular Endothelial Growth Factor Treatment for Diabetic Macular Edema		14 weeks to 56-weeks
Secondary	Number of Eyes With Additional Number of Treatments for Diabetic Macular Edema	Treatments include any type or combination of treatment for diabetic macular edema. Eyes were only counted once, when receiving a combination of treatments.	14 weeks to 56-weeks
Secondary	Change in Optical Coherence Tomography Retinal Volume	Missing or un-gradable data as follows for the sham plus focal/grid/panretinal photocoagulation laser, triamcinolone plus focal/grid panretinal photocoagulation laser, and Ranibizumab groups were 49, 37, and 39, respectively	Baseline to 14 weeks