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

2. 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

3. 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

4. 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

5. 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

6. 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)

7. 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meet the criteria for persistent DME; 9 were either lost to follow-up (2), died (1), requested to withdraw (1), were withdrawn by the site (2), or were believed to no longer need Injections by the investigator (3)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

8. 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

9. 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

10. Visual Acuity (VA)

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

12. 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

13. Pre-Planned Subgroups
VA Mean Change
Pre-Planned Subgroups

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. Central Subfield Thickness (CST)

21. 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.

22. 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.

23. 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.

24. 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

25. Safety

26. 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%

27. 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