Official Title: “Intravitreal Ranibizumab or Triamcinolone Acetonide in Combination With Laser Photocoagulation for Diabetic Macular Edema”

The purpose of the study is to find out which is a better treatment for DME: laser alone, laser combined with an intravitreal injection of triamcinolone, laser combined with an intravitreal injection of ranibizumab, or intravitreal injection of ranibizumab alone. At the present time, it is not known whether intravitreal steroid or anti-VEGF injections, with or without laser treatment, are better than just laser by itself. It is possible that one or both of the types of injections, with or without laser treatment, will improve vision more often than will laser without injections. However, even if better vision outcomes are seen with injections, side effects may be more of a problem with the injections than with laser.

Therefore, this study is conducted to find out whether the benefits of the injections will outweigh the risks.

Study Type: Interventional

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

Study Primary Completion Date: March 2011

Thus far the only demonstrated means to reduce the risk of vision loss from diabetic macular edema are laser photocoagulation, intensive glycemic control, and blood pressure control.

Earlier studies have shown that photocoagulation, although effective in reducing the risk of moderate vision loss, can eventually result in retinal and retinal pigment epithelium atrophy resulting in loss of central vision, central scotomata, and decreased color vision.

Consequently, many retinal specialists today tend to treat DME with lighter, less intense laser burns than was originally specified in the Early Treatment Diabetic Retinopathy Study (ETDRS). The additional unsatisfactory outcome from treatments with laser photocoagulation in a significant proportion of eyes with DME has prompted interest in other treatment modalities. One such treatment is pars plana vitrectomy. Studies suggest that vitreomacular traction may play a role in increased retinal vascular permeability, and that removal of the vitreous, or relief of mechanical traction with vitrectomy and membrane stripping may substantially improve macular edema and visual acuity. However, this treatment may be applicable only to a specific subset of eyes with a component of vitreomacular traction secondary to edema. Other treatment modalities such as pharmacologic therapy with oral protein kinase C inhibitors and intravitreal corticosteroids are under investigation.

The use of antibodies targeted at vascular endothelial growth factor (VEGF) is another treatment modality that needs to be further explored for its potential benefits. Increased VEGF levels have been demonstrated in the retina and vitreous of human eyes with diabetic retinopathy. VEGF, also knows as vascular permeability factor, has been shown to increase retinal vascular permeability in in vivo models. Therapy that inhibits VEGF, therefore, may represent a useful therapeutic modality which targets the underlying pathogenesis of diabetic macular edema. Ranibizumab is a promising anti-VEGF drug. Its efficacy and safety have been demonstrated in treatment of AMD. Reports of its use and that of other anti-VEGF drugs in DME have suggested sufficient benefit to warrant evaluation of efficacy and safety in a phase III trial. Corticosteroids, a class of substances with anti-inflammatory properties, have also been demonstrated to inhibit the expression of the VEGF gene. The DRCR Network is currently conducting a phase III randomized clinical trial comparing focal photocoagulation to intravitreal corticosteroids (triamcinolone acetonide) for diabetic macular edema. However, even if triamcinolone or ranibizumab are proven to be efficacious, a major concern, based on clinical observations with intravitreal corticosteroids, is that DME will recur as the effect of the intravitreal drug wears off, necessitating repetitive injections long-term. Combining an intravitreal drug (triamcinolone or ranibizumab) with photocoagulation provides hope that one could get the short-term benefit of the intravitreal drug (decreased retinal thickening and decreased fluid leakage) and the long-term reduction in fluid leakage as a result of photocoagulation. In addition, it is possible that the worsening of macular edema immediately following focal photocoagulation, a known complication of this treatment, could be decreased if an intravitreal drug was present at the time of photocoagulation. This might result in an increased likelihood of vision improvement following photocoagulation and a decreased likelihood of vision loss.

This study is designed to determine if ranibizumab alone or ranibizumab added to laser photocoagulation is more efficacious than photocoagulation alone, and if so, to determine if combining ranibizumab with photocoagulation reduces the total number of injections needed to obtain these benefits. Furthermore, this study is designed to determine if combining photocoagulation with corticosteroids, the only other class of drugs currently being considered for treatment of DME, is efficacious in the population being enrolled.

Subjects will be randomly assigned to one of the following 4 groups:

1. Group A: Sham injection plus focal (macular) photocoagulation

2. Group B: 0.5 mg injection of intravitreal ranibizumab plus focal photocoagulation

3. Group C: 0.5 mg injection of intravitreal ranibizumab plus deferred focal photocoagulation

4. Group D: 4 mg intravitreal triamcinolone plus focal photocoagulation

In groups A, B and D, laser will be given 7-10 days after the initial injection at the time of the injection follow-up safety visit. During the first year, subjects are evaluated for retreatment every 4 weeks. The injection for group A is a sham and for groups B and C ranibizumab. For group D, a triamcinolone injection is given if one has not been given in the prior 15 weeks; otherwise a sham injection is given. For Groups A, B, and D, focal photocoagulation will be given 7 to 10 days later following each injection unless focal photocoagulation has been given in the past 15 weeks or no macular edema is present. In Years 2 and 3, subjects continue to be evaluated for retreatment every 4 weeks unless injections are discontinued due to failure. In that case, follow-up visits occur every 4 months and treatment is at investigator discretion.

Intervention(s) in this Clinical Trial

• Drug: Triamcinolone Acetonide + laser
  • 4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
• Drug: Ranibizumab + laser
  • 0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.
• Drug: Sham injection + laser
  • Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.
• Drug: Ranibizumab + deferred laser
  • 0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
• Experimental: 2
• Experimental: 3
• Experimental: 4

Primary Measures

• Visual Acuity adjusted for the baseline acuity
  • Time Frame: 1 year
    Safety Issue?: No

Secondary Measures

• Change in retinal thickening of central subfield and retinal volume measured on OCT
  • Time Frame: 1 year
    Safety Issue?: No
• Number of injections in first year
  • Time Frame: 1 year
    Safety Issue?: No

• General

Inclusion Criteria

To be eligible, the following inclusion criteria (1-5) must be met:

• Age >= 18 years
• Diagnosis of diabetes mellitus (type 1 or type 2)
• At least one eye meets the study eye criteria
• 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 drug.
• 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 first 12 months of the study.
• Study Eye

Inclusion Criteria

• The subject must have one eye meeting all of the inclusion criteria and none of the exclusion criteria listed below. A subject may have two study eyes only if both are eligible at the time of randomization.
• Best corrected E-ETDRS visual acuity letter score <= 78 (i.e., 20/32 or worse) and >= 24 (i.e., 20/320 or better) within 8 days of randomization.
• On clinical exam, definite retinal thickening due to diabetic macular edema involving the center of the macula.
• OCT central subfield >=250 microns within 8 days of randomization.
• Media clarity, pupillary dilation, and subject cooperation sufficient for adequate fundus photographs.
• If prior macular photocoagulation has been performed, the investigator believes that the study eye may possibly benefit from additional photocoagulation.
• Study Eye

Exclusion Criteria

• The following exclusions apply to the study eye only (i.e., they may be present for the nonstudy eye):
• 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, 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., vein 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 panretinal (scatter) photocoagulation (PRP) within 4 months prior to randomization.
• Anticipated need for PRP in the 6 months following randomization.
• 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: history of 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.

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

Michael J. Elman, M.D. Study Chair Elman Retina Group, PA  

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/NCT00444600

Study ID Number: NEI-133

ClinicalTrials.gov Identifier: NCT00444600

Health Authority: United States: Institutional Review Board

NEI Clinical Studies Database

Diabetic Retinopathy Clinical Research Network