| A. Study Design Randomized, multi-center clinical trial B. Major Eligibility Criteria - Age >=18 years.
- Type 1 or type 2 diabetes
- Diabetic macular edema involving the center of the macula (OCT central subfield thickness >250 microns) responsible for visual acuity of 20/32 or worse
C. Original Treatment Groups Randomization 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 laser photocoagulation 4) Group D: 4 mg intravitreal triamcinolone plus focal photocoagulation In groups A, B and D, laser was to be given 7-10 days after the initial injection at the time of the injection follow-up safety visit. Subjects may have one or two study eyes. Subjects with two study eyes received sham injection/focal photocoagulation in one eye and the other eye was assigned to one of the three other groups. During the first year, subjects were evaluated for retreatment every 4 weeks based on OCT and visual acuity criteria. D. Sample Size - 854 eyes were randomized (691 subjects)
E. Duration of Follow-up - Primary outcome: 1 year
- Secondary outcome: 3 years
- Extension study: 5 years
F. Follow-up Schedule - Follow-up visits occur every 4 weeks during the first 12 months.
- After the first 12 months, visits occur every 4 to 16 weeks depending on treatment group, disease progression, and treatment administered.
- A safety follow-up visit occurs 3-10 days after the first injection for groups A, B, and D when laser is to be given.
- After the first 12 months, a safety visit occurs 4 weeks after each triamcinolone injection for group D.
- Annual visits occur at 2, 3, 4, and 5 years from randomization.
G. Main Efficacy Outcomes Primary: Visual acuity at 12 months adjusted for the baseline acuity Secondary: Change in retinal thickening of central subfield and retinal volume measured on OCT Number of injections in first year H. Main Safety Outcomes Injected-related: endophthalmitis, retinal detachment Ocular drug-related: inflammation, cataract, cataract surgery, increased intraocular pressure, glaucoma medications, glaucoma surgery Systemic drug-related: cardiovascular events I. Extension Study Based on preliminary study results following completion of the primary outcome visits at 1 year, which suggest that intravitreal ranibizumab, either with prompt or deferred (>24 weeks) focal/grid photocoagulation, but not intravitreal triamcinolone, results in superior visual acuity outcomes compared with focal/grid photocoagulation treatment alone, the protocol was revised as follows: · Follow-up extended for each willing study participant to 5 years from randomization. · Eyes originally randomized to Groups A and D will be given the opportunity to receive intravitreal ranibizumab or remain on their current treatment regimen (based on protocol guidelines). J. Schedule of Study Visits and Examination Procedures After the First Year Visits occur every 4 to 16 weeks depending on treatment group, disease progression, and treatment administered. Regardless of the interval, the examination procedures are the same as listed below for Post 52 week visits, with 7-field photographs of the study eye obtained at annual visits only. | | Post 52 week visits | 4w post-injection visits | Annual visits | | | X | X | X | | | X | | X | | | X | X | X | | | | | X | Notes A medical history will be updated at each visit. Concomitant medications will be updated at each visit. Adverse events will be recorded at each visit. a= both eyes at each visit; includes protocol refraction in study eye at each visit except post-injection safety visit when previous refraction is used. Protocol refraction in nonstudy eye is only required at baseline and annual visits. E-ETDRS refers to electronic ETDRS testing using the Electronic Visual Acuity Tester that has been validated against 4-meter chart ETDRS testing. b=study eye only. c=both eyes at each visit. Includes slit lamp exam (including assessment of lens), measurement of intraocular pressure, and dilated ophthalmoscopy. d=7-fields on study eye only; additional photos will also be taken on the study eye at subject’s first Extension study visit. |