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

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.

Study Type: Interventional

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

Study Primary Completion Date: February 2010

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.

Intervention(s) in this Clinical Trial

• Drug: Ranibizumab
  • Intravitreal injection of 0.5 mg ranibizumab at baseline and 4 weeks
• Drug: 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

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
• Experimental: 2
• Active Comparator: 3

Primary Measures

• Visual Acuity adjusted for the baseline acuity.
  • Time Frame: 14 weeks
    Safety Issue?: No

Secondary Measures

• Change in retinal thickening from baseline OCT central subfield and retinal volume
  • Time Frame: 14 weeks
    Safety Issue?: No
• Presence and extent of new vessels on fundus photographs
  • Time Frame: 14 weeks
    Safety Issue?: No
• Vitreous hemorrhage
  • Time Frame: 14 weeks
    Safety Issue?: Yes
• Additional sessions of scatter photocoagulation due to worsening PDR before 14 week visit after completion of initial session
  • Time Frame: 14 weeks
    Safety Issue?: No

• 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Eye Institute (NEI)

Overall Clinical Trial Officials and Contacts

Alexander J. Brucker, M.D. Study Chair Scheie Eye Institute  

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

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00445003

Study ID Number: NEI-134

ClinicalTrials.gov Identifier: NCT00445003

Health Authority: United States: Institutional Review Board

NEI Clinical Studies Database

Diabetic Retinopathy Clinical Research Network