Diabetic Retinopathy Clinical Research Network PRP vs intravitreous ranibizumab for PDR: Comparison of the peripapillary RNFL in a Randomized Clinical Trial Glenn J. Jaffe, M.D. Supported through a cooperative agreement from the National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817   1

Protocol S primary results Eyes treated with intravitreous ranibizumab for PDR had a mean visual acuity that was not worse than eyes treated with PRP at 2 years Eyes randomly assigned to 0.5 mg intravitreous ranibizumab had less visual field loss and less frequent DME development JAMA. 2015;314(20)2137-2146

Literature RNFL thinning associated with VF loss Thinning of RNFL with PRP and anti-VEGF DME: thicker RNFL, inner retinal edema

Literature cont’d Diabetic RNFL +/- DR thinner than normal Normal RNFL thickness could be edematous ME resolution: thinner than normal RNFL

Objectives Pre-planned To compare changes in the peripapillary RNFL at 2 years between the ranibizumab and PRP groups

Objectives Pre-planned To compare changes in the peripapillary RNFL at 2 years between the ranibizumab and PRP groups Post-Hoc To correlate changes in RNFL with changes in VF sensitivities at 2 yrs 60-4 HFV Mean deviation 30-2 HVF Mean deviation To correlate changes in RNFL with changes in CST at 2 yrs

Imaging of the RNFL Spectralis or Zeiss Cirrus OCT RNFL Images readjusted by DRC if automated measurement inaccurate b/c: Decentration Artifacts Segmentation algorithm failure

Baseline characteristics Participants Included Ranibizumab Group (N = 77) PRP (N = 69) Age (yrs) – Median 52 50 Women 43% Race White 64% 58% Visual Acuity (letter score) Median 80 (20/25) 81 (20/25) Central Subfield Thickness (µm)- Median 219 227

Pre-Planned Objective TREATMENT GROUP COMPARISON OF CHANGES IN THE RNFL at 2 yrs

Average RNFL Measurements of the 2-Year Cohort Ranibizumab Group (N = 68) PRP (N = 57) Heidelberg Spectralis N=35 N=32 Baseline 96 ± 19 97 ± 20 At 2 years 85 ± 15 95 ± 19 Zeiss Cirrus N=33 N=25 94 ± 21 97 ± 23 83 ± 16 89 ± 12

Average RNFL: At Baseline Lower than normal Cirrus: < 76.9 µm Heidelberg OCT: < 80.4 µm Normal Cirrus: 76.9-120.5 µm Heidelberg OCT: 80.4-131.6 µm Above normal Cirrus: > 120.5 µm Heidelberg OCT: >131.6 µm Percentage of Eyes

Average RNFL: At 2 Years Lower than normal Cirrus: < 76.9 µm Heidelberg OCT: < 80.4 µm Normal Cirrus: 76.9-120.5 µm Heidelberg OCT: 80.4-131.6 µm Above normal Cirrus: > 120.5 µm Heidelberg OCT: >131.6 µm Percentage of Eyes

Eyes with Normal Average RNFL at Baseline Percentage of Eyes

Mean change in Average RNFL Missing 2-Year Outcome was imputed using last observation carried forward Adjusted Mean Difference at 2 years : -4.9 µm (P-value<0.001) 95% CI: (-7.2 µm, -2.6 µm) At 2 years N = 74 N = 66

Mean change in Average RNFL: No Baseline DME Adjusted Mean Difference at 2 years : -5.0 µm (P-value<0.001) 95% CI: (-7.8 µm, -2.3 µm) At 2 years N=56 N=48

Mean change in Average RNFL: With Baseline DME Adjusted Mean Difference at 2 years : -2.3 µm (P-value=0.32) 95% CI: (-6.7 µm, +2.2 µm) At 2 years N=18 N=18

Post-Hoc Objectives Correlate changes in the RNFL with changes in visual field sensitivities at 2 years Correlate changes in the RNFL with changes in the central subfield thickness (CST) at 2 years

2-Year correlation of RNFL changes with Change in Mean Deviation (60-4 Test) Ranibizumab Group N = 45 PRP Group N = 40 r= +0.33 P-value=0.035 r=-0.27 P-value=0.07

2-Year correlation of RNFL changes with CSF changes Ranibizumab Group N = 74 PRP Group N = 66 r= +0.63 Pvalue <0.001 r= +0.34 Pvalue=0.005

2-Year correlation of RNFL changes with CSF changes: No Baseline DME Ranibizumab Group N = 56 PRP Group N = 48 r= +0.59 P-value <0.001 r= +0.05 P-value=0.75

Example Eye has no DME at baseline Weighted mean deviation of the 60-4 test for this eye was -4.27 at baseline and -5.83 at 2 years No history of glaucoma Baseline 2 Years

Conclusions RNFL thinning with RBZ and PRP at 2 years Significantly greater RNFL reduction with RBZ Most RNFL differences in yr. 1 RNFL thinning in yr. 2 similar RNFL thinning mechanism in 2 groups may differ

Discussion VF sensitivity and RNFL changes: minimal in both groups; however sample size was relatively small In RBZ group RNFL thinning may be from decreased retinal edema

Clinical Implication OCT-derived RNFL thickness measurements are used to provide objective means to assess glaucoma progression in non-PDR eyes Due to fluid changes in the inner retina during ranibizumab therapy, RNFL measurements would be a poor means to diagnose and monitor the progression of glaucoma in these eyes.

Thank You on Behalf of the Diabetic Retinopathy Clinical Research Network (DRCR.net) 25