A Pilot Study of Laser Photocoagulation for Diabetic Macular Edema

Diabetic retinopathy is a disorder of major public health importance, accounting for the majority of visual loss among working age Americans. Diabetic macular edema (DME) is a manifestation of diabetic retinopathy that produces loss of central vision. Data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) estimate that after 15 years of known diabetes, the prevalence of diabetic macular edema is approximately 20 percent in patients with type 1 diabetes mellitus (DM), 25 in patients with type 2 DM who are taking insulin, and 14 percent in patients with type 2 DM who do not take insulin. The Early Treatment Diabetic Retinopathy Study (ETDRS) showed that moderate vision loss, defined as a doubling of the visual angle (e.g., 20/20 reduced to 20/40), can be reduced by 50 percent or more by focal/grid laser photocoagulation according to ETDRS protocol. Although several treatment modalities are currently under investigation, the only demonstrated means to reduce the risk of vision loss from diabetic macular edema are ETDRS laser photocoagulation, as demonstrated by the ETDRS, and intensive glycemic control, as demonstrated by the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS). In the DCCT, intensive glucose control reduced the risk of onset of diabetic macular edema by 23 percent compared with conventional treatment. Long-term follow-up of patients in the DCCT show a sustained effect of intensive glucose control, with a 58 percent risk reduction in the development of diabetic macular edema for the DCCT patients followed in the Epidemiology of Diabetes Interventions and Complications Study.

In brief, the study protocol involves the enrollment of patients >18 years of age who have DME involving or threatening the center of the macula and who have not had prior focal/grid laser photocoagulation for DME. These are patients for whom the standard of care would be to treat with laser photocoagulation. Eligible eyes will be randomly assigned to receive either the modified-ETDRS technique or the mild macular grid (MMG) technique. Outcome assessments will include Optical Coherence Tomography (OCT), fundus photography, fluorescein angiography and standardized best-corrected visual acuity.

The study consists of two phases: Phase 1 (the primary study), which consists of the first 12 months of follow up, during which a structured protocol is followed; and Phase 2, which consists of the second and third years of follow up, during which the management of DME can include techniques other than laser photocoagulation, at discretion of the investigator.

During Phase 1, follow-up visits will occur at 15 weeks (3.5 months) +14 days, 34 weeks (8 months) + 28 days, and 52 weeks (12 months) + 28 days. The primary outcome for phase 1 is at 12 months.

The primary study objectives of Phase 1 include:

• Develop standardized study procedures for future DME studies
• Obtain outcome data (e.g. changes in retinal thickness, area of retinal thickening, area of hard exudate, need for retreatment, onset of new areas of DME and changes in visual acuity) following use of the modified-ETDRS photocoagulation technique for patients with DME and various levels of retinopathy severity.
• Collect pilot data using the MMG technique to determine whether a subsequent large scale definitive trial should be conducted

Phase 2 (2nd and 3rd years of follow up) is being conducted to collect data on, and generate hypotheses from, the long-term outcome of DME, irrespective of treatment received. Protocol visits will occur at 2 years + 8 weeks and 3 years + 8 weeks. During this phase of the study, therapies other than laser photocoagulation may be used to treat DME at the investigator's discretion. Because treatment other than photocoagulation will be allowed after one year, 'pure' results regarding outcomes with each laser technique cannot be obtained in all groups, but will be available in a subset of patients. The data are being collected at relatively low cost and no risk over and above usual care. Therefore, the collection of potentially hypothesis-generating data from exploratory analysis is justified and could be important in designing future studies. Interpretation of the results of the above analyses will be complicated by the lack of a standardized protocol with regard to which patients receive treatment and what treatment is provided. Therefore, the results will be interpreted with caution.

The phase 2 data collection may be useful for the following:

• Evaluation of retreatment rates in patients who responded to laser such that no additional treatment was required at 12 months. This is a long term analysis on a "pure" group of patients and will provide important information on the DME recurrence rate and need for retreatment in study eyes of those patients whose DME improved with either of the two protocol-specified treatments received in Phase 1 such that further treatment was not necessary at the 12-month visit.
• Provide long-term safety data for MMG. This is important due to the less well studied nature of MMG, especially over the long term.
• Provide long-term outcome data on current standard treatment (modified ETDRS laser) in today's patient populations to assist in powering future studies that will require at least 3 years of follow up.
• Provide data on outcome of intravitreal steroids in patients in whom laser treatment is not successful. For many patients who still have DME at 12 months, it is anticipated that intravitreal steroids will be administered. The continued follow up of these patients will provide an opportunity to explore the effect of the steroids on retinal thickness and visual acuity.