1. Short-Term Evaluation of Combination
Protocol U
Short-Term Evaluation of Combination
Dexamethasone + Ranibizumab vs. Ranibizumab Alone in Eyes with Persistent DME and VA Impairment Despite Previous Anti-VEGF Treatment
DRCR.net

2. Financial Disclosures
Funding/Support: Cooperative Agreement with NEI and NIDDK of NIH, U.S. Department of Health and Human Services.
Additional Contributions: Genentech provided the Ranibizumab and Allergan, Inc. provided the Dexamethasone for the study. In addition, Allergan provided some funds to the DRCR.net to defray the study’s clinical site costs.
A complete list of all DRCR.net investigator financial disclosures can be found at
Personal Disclosures
Raj K. Maturi, MD receives financial support for clinical trials from Allergan, Genentech-Roche, Allegro Pharmaceuticals, Boehringer-Ingelheim, and Aerpio Therapeutics, LLC.

3. 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

4. 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

5. Run-in Phase: 236 Eyes Enrolled*
Persistent Edema
VA letter score ≤78 and ≥24 (20/32 to 20/320), &
Central-involved DME on clinical exam and OCT
Despite at least 3 anti-VEGF tx prior to enrollment (in 20 wks)
3 injections of study Ranibizumab, given every 4 weeks
78 subjects (33%) did not meet criteria for persistent edema at the end of this 12 week period.
Run-in Phase: 236 Eyes Enrolled*
9 additional subjects were either lost to follow-up (2), died (1), requested to withdraw (1), were withdrawn by the site (2), or were believed to no longer need Injections by the investigator (3)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

6. Eligible for Randomization? Randomization (6 months)
Week 0 4 8 12 16 20 24
65 eyes
Study Overview
DEX
DEX
RAN
RAN
RAN
RAN
RAN
RAN
Week 0 4 8 12
Enrolled (236 eyes)
Week 0 4 8 12 16 20 24
RAN
RAN
RAN
Eligible for Randomization?
RAN
RAN
RAN
RAN
RAN
RAN
SHAM
SHAM
64 eyes
Run-In (3 months)
Randomization (6 months)

7. Excellent Follow-up 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. + Continued Ranibizumab + Continued Ranibizumab
Study Design Randomized Multi-center Clinical Trial (Enrolled = 236 eyes, N = 129 Eyes randomized)
≥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 and OCT
Outcomes
Primary Mean Visual Acuity Change at 24 Weeks
Secondary Mean OCT CST Change at 24 Weeks
Dexamethasone
+ Continued Ranibizumab
“Combination” VS
Sham
+ Continued Ranibizumab
“Ranibizumab”

9. 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
*Stratus equivalent

10. 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

11. Visual Acuity (VA)

12. What Happened in the Run-in Phase?
Randomization
129 eyes remained eligible for randomization
Mean (SD) visual acuity improvement: +3 (7) letters
Mean (SD) CST decrease: 54 (93) microns
80 eyes (34%) no longer had “inadequate response” – i.e., either 20/25 or better, or OCT (central subfield thickness) no longer thickened, or both

13. Enrollment to Run-in Phase
Randomization
Only 17 pseudophakic eyes enrolled between February 2014 and July 2015
Starting July 2015, phakic patients allowed to enroll

14. Change in VA and OCT CST During Run-in Phase
Randomization
Mean (SD) visual acuity improvement: +3 (7) letters

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

16. 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
+ 3.0
+ 2.7
N = 65
N = 63

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

18. VA Mean Change: Baseline Lens Status
Pseudophakic
+5.1
+2.0
N = 32
N = 26
N = 25
N = 32
* P-value for interaction = 0.08

19. 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

20. 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

21. Central Subfield Thickness (CST)

22. 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.

23. OCT CST Mean Change Adjusted Mean Difference: -52 µm
95% Confidence Interval: (-82,-22), P < 0.001
-62
-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.

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 ocular
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

28. Conclusion Lens status
Very few pseudophakic patients likely could be enrolled in a reasonable time to warrant pursuit of a Phase 3 trial in pseudophakic patients
Protocol I and Protocol T data do not suggest that persistent DME following the DRCR Network treatment regimen is a substantial public health issue for visual acuity
30% (aflibercept) to 65% (bevacizumab) of participants in Protocol T had persistent DME at 6 months, and only about half of those are 20/32 or worse
Half of those with persistent DME at 6 months have resolved by 2 years
Most eyes with persistent DME through 2 years are better than 20/32 or gained at least 10 letters from baseline