Factors Associated with Changes in Visual Acuity and OCT Thickness at 1 Year after Treatment for Diabetic Macular Edema Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services 1

Laser-Ranibizumab-Triamcinolone Randomized Clinical Trial for DME: Mean Change in Visual Acuity * 2 * Values that were ±30 letters were assigned a value of 30 P-values for difference in mean change in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; and triamcinolone+prompt laser=0.31. weeks Letters Improved

 To identify factors associated with improvement of visual acuity, and those associated with improvement in OCT CSF at 1 year in the ranibizumab treated eyes  Because 1-year outcomes were similar, data from the two ranibizumab arms in the trial (361 eyes) were pooled for this analysis Purpose 3

 Poisson regression models adjusted for baseline* were used to evaluate the association of 37 assorted baseline factors:  Demographic  Clinical  OCT  Fundus photographic variables with visual acuity/OCT CSF improvement from baseline to 1 year Statistical Methods: Model 1 *Vision analyses adjusted for baseline VA; OCT analyses adjusted for baseline CSF 4

 OCT improvement at various time points and VA at 1 year was evaluated to explore the impact of anatomic changes during ranibizumab treatment on the visual outcome at 1 year. Statistical Methods: Model 2 5

 OCT CSF improvement* Improved at all times (4, 8, and 12 months) : “early and consistent” Improved at 4 month but not sustained at both 8 and 12 month: “early but inconsistent” Not improved at 4 month but improved at 8 and/or 12 month: “late bloomers” Not improved at any time (4, 8, and 12 months): “never/evers” Methods: Factors Evaluated in Model 2 Included Select Follow-up Variables *improvement of ≥20% reduction in CSF vs. baseline 6

Methods: Factors Evaluated Model 1 and Model 2  Participant Characteristics at Baseline  Race/Ethnicity  Gender  Diabetes type  Diabetes duration  Age  Insulin use  Mean arterial blood pressure*  HbA1c* 7 * obtained on exam

 Participant Characteristics obtained by History at Baseline (continued)  Hypertension  Elevated cholesterol  Cardiovascular disease  Renal disease  Neurologic disease  Prescribed glitazones  Prescribed statins Methods: Factors Evaluated Model 1 and Model 2 Methods: Factors Evaluated Model 1 and Model 2 8

 Historical Ocular Characteristics present at Baseline  Prior DME treatment  Timing of most recent prior DME treatment  Prior laser for DME  Timing of prior laser for DME  Prior PRP  Timing of prior PRP  Timing of prior cataract extraction  History of YAG capsulotomy Methods: Factors Evaluated Model 1 and Model 2 Methods: Factors Evaluated Model 1 and Model 2 9

 Baseline Ocular Characteristics on exam:  Visual acuity  Visual acuity in non-study eye  Lens status  Diabetic Retinopathy Severity on clinical exam (investigator assessment)  Type of DME on clinical exam (investigator assessment ) Methods: Factors Evaluated Model 1 and Model 2 Methods: Factors Evaluated Model 1 and Model 2 10

 Baseline OCT Characteristics per Reading Center  Central subfield thickness  Retinal volume  Cystoid abnormalities  Subretinal fluid  Vitreoretinal abnormalities Methods: Factors Evaluated Model 1 and Model 2 Methods: Factors Evaluated Model 1 and Model 2 11

 Baseline Ocular Characteristics provided by Photograph Reading Center  Diabetic Retinopathy Severity Level  Hemorrhages/Microaneurysms severity in macular grid  Hard exudates  Surface wrinkling retinopathy Methods: Factors Evaluated Model 1 and Model 2 Methods: Factors Evaluated Model 1 and Model 2 12

 Visual Acuity:  Continuous outcome: VA change from baseline  Binary outcomes ≥10 letter improvement ≥15 letter improvement ≥ 20/32 (restricted to eyes < 20/32 at baseline)  OCT:  Continuous outcome: CSF change from baseline  Binary outcomes 20% or more reduction in CSF 50% or more reduction in CSF CSF < 250 and decrease of ≥ 25 µm from baseline Outcome Measures at 1 Year Model 1 and Model 2 Outcome Measures at 1 Year Model 1 and Model 2 13

Results of Multivariate Model 1 for Vision or CSF Change Results of Multivariate Model 1 for Vision or CSF Change 14

Baseline Characteristics Associated with 1 Year Visual Acuity Change 15

Association between Baseline CSF and 1 Yr Change in CSF 16

 Baseline OCT CSF (P < 0.001) For every 100 µm thicker baseline OCT CSF, 1 year CSF decreased an additional 70 µm on average Baseline Factors Associated with CSF Change (continuous variable) Baseline Factors Associated with CSF Change (continuous variable) 17

 Thicker baseline OCT CSF was associated with 20% or 50% reduction in thickness (P < 0.001)  No baseline factors were associated with CSF < 250 and decrease of ≥ 25 µm from baseline Baseline Factors Associated with Binary CSF Outcomes Baseline Factors Associated with Binary CSF Outcomes 18

Results of Multivariate Model 2 for Vision or CSF Change (Includes Select Ocular Factors During Follow -Up) Results of Multivariate Model 2 for Vision or CSF Change (Includes Select Ocular Factors During Follow -Up) 19

Relationship between CSF Improvement During Follow-up and Vision Outcome 20 (p<0.001)

 Baseline Visual Acuity (P < 0.001) Similar magnitude to model 1  CSF improvement during follow-up (P < 0.001) Baseline or Select Follow-up Factors Associated with Visual Acuity Change (continuous variable) Baseline or Select Follow-up Factors Associated with Visual Acuity Change (continuous variable) 21

 Baseline visual acuity (P < 0.001) Lower (worse) levels of initial VA more likely to improve at least 10 or 15 letters Higher (better) levels of initial VA more likely to achieve 20/32 or better VA of >20/32 at 1-year was achieved by 76% of eyes with ≥ 66 letters at baseline compared to 38% of eyes with < 66 letters Factors Associated with VA Binary Outcomes Model 1 and Model 2 Factors Associated with VA Binary Outcomes Model 1 and Model 2 22

Summary 23  Baseline visual acuity was the only consistent baseline predictor of 1 year vision outcomes  Baseline CSF was the only consistent baseline predictor of 1 year CSF outcomes  Results may be due to ceiling and floor effects of these variables  Highlights importance of noting baseline values of cohort to understand magnitude of vision and OCT outcomes

Summary 24  CSF improvement prior to 1 year was also associated with 1 year vision outcomes

Thank you!  Susan B. Bressler  Haijing Qin  The Diabetic Retinopathy Clinical Research Network Subjects Investigators Staff 25