Sponsored by the National Eye Institute, An Observational Study of the Development of Diabetic Macular Edema Following Panretinal (Scatter) Photocoagulation (PRP) Given in 1 or 4 Sittings Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services.

Background: Panretinal Photocoagulation (PRP) for PDR PRP is the standard treatment of PDR Usually performed over 1 or more sittings (ETDRS 2 or more sittings) 2004 survey of DRCR.net investigators: one-quarter routinely use one sitting for PRP

PRP and Macular Edema PRP associated complications include macular edema ETDRS - 18% developed macular edema 4 months after full PRP (1200 – 1600 spots) Theories: Oncotic fluid accumulation related to tissue destruction PRP induced inflammation leading to cytokine release and increased permeability of the retinal capillaries

What are Some Pros and Cons of Delivering PRP in 1 Sitting? Convenience Completion before complications occur [e.g., vitreous hemorrhage (VH)] Cons (theoretical): May cause macular edema with VA loss Greater patient discomfort Need for retrobulbar or peribulbar anesthetic Higher risk of acute pressure rise, angle closure, or choroidal effusion

What are Some Pros and Cons of Delivering PRP in More Than One Sitting? Pros (theoretical): Allows edema and associated VA loss to subside before next PRP sitting Cons: Inconvenient Potential for failure to complete intended treatment plan (VH)

Primary Study Objective Determine the incidence of new macular edema on OCT, following PRP in diabetic eyes without center edema at 34 weeks To compare the incidence of macular edema with a 1-sitting versus 4-sitting regimen

Non-Randomized Study: Rational Investigators who complete PRP in one sitting were unwilling to perform PRP in multiple sittings and vice versa Therefore, prospective nonrandomized study conducted

Prospective, Non-Randomized Study Major Eligibility Criteria Assessed: Study Design Prospective, Non-Randomized Study Major Eligibility Criteria Assessed: >18 years old Type 1 or type 2 diabetes Early-PDR or Severe-NPDR (high risk PDR not eligible) Retinal thickness on OCT < 300 microns in the central subfield Visual Acuity letter score > 73 (20/32 or better) No clinical DME requiring treatment Investigator declared, prior to study initiation, if PRP planned for 1 or 4 sittings for all subjects participating in protocol 1 Sitting 4 Sittings

PRP Treatment Regiment 1200-1600 total burns (ETDRS parameters) Retrobulbar/peribulbar anesthesia optional Slit lamp delivery systems 1 Sitting and 4 Sitting Each session 4 weeks apart (+4 days) 300 burns in each of first two sittings Investigator discretion for # of burns in 3rd and 4th sittings Total of 4 sittings between 1200 and 1600 burns 4 Sittings

PRP Burn Characteristics Laser Parameters: Burn Size 200 microns with Rodenstock lens (or equivalent) 500 microns with three mirror contact lens Burn Duration 0.05 – 0.2 seconds (0.1 recommended) Wavelength Green to yellow (red if vitreous hemorrhage present) Intensity Standard mild white burns Distribution Edges at least 1 burn width apart, no closer than one row within the arcades and two disc diameters temporal to the fovea Extent Arcades to at least the equator

Outcome Assessment Visual acuity measured at 3 meters with the Electronic-ETDRS Visual Acuity (EVA) device Central Subfield Thickness Using Zeiss Stratus OCT 3 Day 4 Week 17 Week Central Subfield Thickness Primary Outcome E-ETDRS Visual Acuity 3-Field Fundus Photographs 34 Week

Results

Study Enrollment 155 subjects enrolled at 27 sites 1 sitting 84 subjects 4 sittings 71 subjects 34-week Visit Completion (Primary Outcome) 1 sitting 88% 4 sittings 82% 13

Baseline Characteristics Women: 48% 44% Median Age: 56 yrs 54 yrs Race: White 64% 46% African-American 24% 28% Hispanic or Latino 11% 18% Asian 0 6% More than one race 1% 1% 1 Sitting 4 Sitting

Baseline Characteristics Diabetes Type Type 1 19% 25% Type 2 81% 75% Median Duration of Diab. 18 yrs 20 yrs Median HbA1c (%)* 7.7 8.2 1 Sitting 4 Sitting *HbA1c: Missing 7 in one-sitting group, 13 in 4 sitting group

Baseline Characteristics 1 Sitting 4 Sitting Prior Focal Macular Laser 14% 11% Median E-ETDRS Letter Score 85 83 (Snellen equivalent) 20/20 20/20 Median OCT CSF Thickness 207µ 198µ CSF 250 – 299 Microns 3 (4%) 1 (1%) Median OCT Retinal Volume 6.9 mm3 7.0 mm3

Baseline Retinopathy Severity 1 Sitting 4 Sitting N 81 66 Mild NPDR 6% 0 Moderate NPDR 9% 3% Moderately Severe NPDR 30% 38% Severe NPDR 6% 8% Mild PDR 23% 15% Moderate PDR 14% 15% High Risk PDR 11% 18% Cannot Grade 1% 3%

Scatter Treatment 1 Sitting 4 Sitting N 84 71 Median # of Burns Median Average Power Retrobulbar Injection Incomplete Treatment Additional PRP 1274 280mW 46% 0% 7% 1 Sitting 1260* 250mW 14%** 15% 0% 4 Sitting * Total over all 4 sittings. **At least once

Central Subfield Thickness 1-sitting 4-sitting P value Baseline 207µ 198µ Change from baseline - median microns 3d +9 +5 0.01 4wks +13 +5 0.003 17wks +14 +15 0.08 34wks +14 +22 0.06

Central Subfield Retinal Thickness: 34 Weeks vs. Baseline Ricks added an 11% line

CSF ≥250 Microns and Change from Baseline ≥ 25 Microns

Macular Edema on Fundus Photos at 34 weeks 8%

Treatment of DME One eye in each group was treated for DME prior to 34 weeks

E-ETDRS Visual Acuity 1 Sitting 4 Sitting P Value Baseline 85 83 Change from baseline 3d −3 −1 0.005 4wks −1 −1 0.37 17wks −1 −1 0.66 34wks 0 −2 0.006 1 Sitting 4 Sitting P Value Mean Letter Score 24 24

E-ETDRS Visual Acuity: 3 Day N=82 N=66 2%

E-ETDRS Visual Acuity: 4 Week N=78 N=67

E-ETDRS Visual Acuity: 17 Week N=77 N=63

E-ETDRS Visual Acuity: 34 Week N=56 N=72 17% 2%

Vitreous Hemorrhage A vitreous hemorrhage reducing visual acuity by 10 or more letters occurred in 2 eyes in each group.

Discussion

Summary Treatment groups balanced on baseline factors Number of total burns similar between treatment groups Retrobulbar anesthesia more commonly used in 1-sitting group

Summary CSF Thickness Remained Normal in Most Eyes 3 Days – CSF Greater in 1 than 4 Sitting Group 34 Weeks – CSF Greater in 4 than 1 Sitting Group Differences Unlikely to be Clinically Relevant VA and OCT Results Consistent

Conclusion Eyes Without Edema Single Sitting PRP – Safe Little Change in VA or Edema 1 Sitting vs. 4 Sitting PRP – Clinically Meaningful Differences Unlikely VA and OCT Changes Similar

Study Limitations 1 Sitting vs. 4 Sitting PRP Small Sample Size Only Large Differences Ruled Out Non – Randomized Study Design Uncontrolled Confounding Possible

Conclusion 1 Sitting vs. 4 Sitting PRP Results Apply Only to Eyes Without Edema Impact if 1 & 4 Sittings Clinically Equivalent One Sitting Benefits and Risks Increased Patient Convenience Decreased Patient Cost – Travel & Productivity Possible Risk of Retrobulbar Anesthesia Unknown if results apply to eyes with DME 35

For further information and all DRCR Network financial disclosures, Thank You Subjects who volunteered to participate in this trial 27 clinical study sites investigators, coordinators, and other staff DRCR Network Data and Safety Monitoring Committee DRCR Network General Steering Committee Other DRCR Network investigators and staff Sponsor: National Eye Institute of the National Institutes of Health (U.S. Department of Health and Human Services For further information and all DRCR Network financial disclosures, go to www.drcr.net 36 36