Protocol U Short-Term Evaluation of Combination Dexamethasone + Ranibizumab vs. Ranibizumab Alone for Persistent Central-Involved DME Following Anti-VEGF Therapy DRCR.net

Background After at least 6 monthly injections of anti-VEGF for DME, some eyes still have unresolved DME and reduced VA Protocol I Protocol T

Background Corticosteroids have been considered as an alternative treatment for DME Known to decrease inflammation, reduce breakdown of the blood-retinal barrier, and have anti-angiogenic properties Shown to result in superior visual acuity to sham treatment but worse than laser or anti-VEGF in phakic patients May be similar to anti-VEGF in pseudophakic patients, at least for two years Reduce retinal thickening

Study Objectives Dexamethasone + Continued Ranibizumab “Combination” Eyes with persistent DME and VA impairment despite previous anti-VEGF treatment Short-term effects on VA and OCT central subfield thickness (CST) Provide information needed if proceeding to phase III clinical trial Dexamethasone + Continued Ranibizumab “Combination” Sham + Continued Ranibizumab “Ranibizumab” VS

Study Design Randomized Multi-center Clinical Trial (N = 116 participants, N = 129 Eyes) ≥18 years old with Type 1 or Type 2 diabetes ≥3 injections of any anti-VEGF within the prior 20 weeks VA letter score ≤78 and ≥24 (20/32 to 20/320) Central-involved DME on clinical exam OCT Central Subfield Thickness (CST): Zeiss Cirrus: ≥290 women; ≥305 men Heidelberg Spectralis: ≥305 women; ≥320 men No history of glaucoma or steroid IOP response Participant could have 2 eyes in the study Outcomes Primary Mean Visual Acuity Change at 24 Weeks Secondary Mean OCT CST Change at 24 Weeks

Eligible for Randomization? Randomization (6 months) Week 0 4 8 12 16 20 24 Study Overview DEX DEX RAN RAN RAN RAN RAN RAN Week 0 4 8 12 Week 0 4 8 12 16 20 24 RAN RAN RAN Eligible for Randomization? Enrollment RAN RAN RAN RAN RAN RAN SHAM SHAM Run-In (3 months) Randomization (6 months)

Run-in Phase: 236 Eyes Enrolled* Randomization Run-in Phase: 236 Eyes Enrolled* Combination Group Eyes Randomized N = 65 24-Week Completers† N = 63 (97%) Ranibizumab Group Eyes Randomized N = 64 24-Week Completers N = 64 (100%) *Run-in Phase: 78 participants were not eligible for randomization because they did not meet the criteria for persistent DME; 9 were either lost to follow-up (2), died (1), requested to withdraw (1), were withdrawn by the site (2), or were believed to no longer need Injections by the investigator (3) †Dropped = 2 eyes

Ocular Baseline Characteristics Combination Group (N = 65) Ranibizumab (N = 64) Mean Randomization VA letter score (Snellen Equivalent) 63 (20/63) Mean VA change during run-in +3 Mean OCT Randomization CST* 375 396 < 350 µm 52% 50% 350 to 449 µm 26% 23% ≥ 450 µm 22% 27% Mean OCT Change during run-in (µm) -58 -50

DME Treatment Combination Group (N = 65) Ranibizumab (N = 64) No. of ranibizumab injections through 24 weeks (max possible = 6)* 5.6 5.7 No. of eyes received second combination injection (sham or dexamethasone) through 20 weeks† 97% 98% No. of eyes received non-protocol treatment for DME * Including participants who completed 24-week visit † Including participants who completed at least one follow-up visit at 12, 16, or 20 weeks

Visual Acuity (VA)

Mean Randomization Letter Score (~Snellen Equivalent) VA Mean Change Run-In Randomization 63 (20/63) Mean Randomization Letter Score (~Snellen Equivalent) + 3.0

VA Mean Change Adjusted Mean Difference: -0.5 letters Run-In Randomization Adjusted Mean Difference: -0.5 letters 95% Confidence Interval: (-3.6, +2.5), P = 0.73 Adjusted mean difference from randomization to 24 weeks. + 3.0 + 2.7 N = 65 N = 63

Pre-Planned Subgroups VA Mean Change Pre-Planned Subgroups

VA Mean Change: Baseline Lens Status Pseudophakic Phakic +5.1 +4.1 +1.1 +2.0 N = 32 N = 26 N = 25 N = 39 N = 38 N = 32 N = 32 N = 32 * P-value for interaction = 0.08

VA Mean Change: VA Improvement VA Did Not Improve During Run-In VA Improved During Run-In +3.6 +2.8 +2.6 +2.3 N = 36 N = 34 N = 33 N = 31 N = 30 N = 36 N = 28 N = 28 * P-value for interaction = 0.65

VA Mean Change: OCT Improvement Retinal Thickness on OCT Did Not Improve During Run-In Retinal Thickness on OCT Improved During Run-In +4.1 +3.0 +3.0 +0.7 N = 38 N = 37 N = 27 N = 26 N = 38 N = 26 N = 26 * P-value for interaction = 0.27

Change in VA (Letter Score) from Randomization at 24 Weeks Mean SD: 2.7 (9.8) Mean SD: 3.0 (7.1) Percent Change in VA (Letter Score) at 24 Weeks

Binary VA Outcomes* Combination Group (N = 63) Ranibizumab (N = 64) P-value VA at 24 Weeks 20/20 or better 6% 5% 0.70 20/40 or better 51% 52% 0.80 20/200 or worse Changes at 24 Weeks ≥15 letters improvement 11% 2% 0.03 ≥10 letters improvement 22% 14% 0.34 ≥15 letters worsening 0.62 ≥10 letters worsening 13% 0.09 * Pre-planned secondary outcomes

Outcomes by Lens Status Combination Group (N = 63) Ranibizumab (N = 64) ≥15 letters improvement 7 (11%) 1 (2%)          Pseudophakic 3 1          Phakic 4 ≥15 letters worsening 4 (6%) 3 (5%) 2

Central Subfield Thickness (CST)

OCT CST Mean Change -62 N = 64 N = 64 Randomization Run-In *Outlying values were truncated to 3 SD from the mean. One image was non-gradable due to low resolution.

OCT CST Mean Change Adjusted Mean Difference: -52 µm 95% Confidence Interval: (-82,-22), P < 0.001 -62 Adjusted mean difference from randomization to 24 weeks. -110 N = 65 N = 62 N = 64 N = 64 *Outlying values were truncated to 3 SD from the mean. One image was nongradable due to low resolution.

OCT CST Mean Change: AUC Adjusted Mean Difference (AUC): -55 95% Confidence Interval: (-78, -31), P < 0.001 -33.5 Adjusted mean difference from randomization to 24 weeks. -86.9 N = 65 N = 62 N = 64 N = 64 *Outlying values were truncated to 3 SD from the mean. One image was non-gradable due to low resolution.

Binary OCT Outcome* CST at 24 Weeks Below gender-machine Combination Group (N = 62) Ranibizumab (N = 64) P-value CST at 24 Weeks Below gender-machine specific values 52% 31% 0.02 * Pre-planned secondary outcome

Safety

Ocular Adverse Events Combination Group (N = 65) Ranibizumab (N = 64) P-value Eyes with at least one ocular adverse event 63% 31% <0.001 Increased IOP at any visit 29% Increased ≥10 mmHg from randomization 23% IOP ≥30 mmHg 15% Received anti-hypertensives 20%

Conclusion Mean VA improvement by 6 months was no better in the dexamethasone + ranibizumab group than in the sham + ranibizumab group On average, there was a greater reduction in retinal thickness in the dexamethasone + ranibizumab group Study was not sufficiently sized to determine whether treatment response might differ by lens status