https://whatsapp.com/channel/0029Va9r420CBtxIW9j9IE2S

1. Dr.Pushkar Dhir
DHIR EYE HOSPITAL & POST GRADUATE INSTITUTE OF OPHTHALMOLOGY
BHIWANI HARYANA

2. ➢ 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
PDR= IV RANI BETTER AS COMPARED PRP IN PDR PDR= IV RANI + PRP BETTER DME = AFLIBRICEPT BETTER AFTER 6 MONTHS
• Short-Term Evaluation of
Combination Dexamethasone +
Ranibizumab vs. Ranibizumab
Alone for Persistent Central-
Involved DME Following Anti-
VEGF Therapy
DME = DEXA+ RANI BETTER THAN RANI
ALONE
PROTOCOL U

3. PROTOCOL U

4. Protocol U
DME = DEXA + RANI V/S RANI , WHICH IS BETTER.?
DME = AFLIBRICEPT BETTER AFTER 6 MONTHS

5. Short-Term Evaluation of Combination Dexamethasone +
Ranibizumab vs. Ranibizumab Alone for Persistent
Central-Involved DME Following Anti-VEGF Therapy
DRCR.net
Protocol U
PPT/Protocol U/Ophtha/IN180176598/ 15/1/2018
Available at- http://drcrnet.jaeb.org/ViewPage.aspx?PageName=Presentations
accessed on 15.1.2018

6. 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

7. Study Objectives
•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
7
Dexamethasone
+ Continued
Ranibizumab
“Combination”
Sham
+ Continued
Ranibizumab
“Ranibizumab”
VS

8. Study Design
Randomized Multi-center Clinical Trial
(N = 116 participants, N = 129 Eyes)
8
▪ ≥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

9. Week 0 4 8 12
Study
Overview
9
RAN
Enrollment
Run-In (3 months)
RAN
RAN
RAN RAN RAN RAN RAN RAN
RAN RAN RAN RAN RAN RAN
SHAM
SHAM
DEX DEX
Randomization (6 months)
Eligible for
Randomization?
Week 0 4 8 12 16 20 24
Week 0 4 8 12 16 20 24

10. Randomization
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: 236 Eyes Enrolled*
*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

11. Ocular Baseline Characteristics
Combination
Group
(N = 65)
Ranibizumab
Group
(N = 64)
Mean Randomization VA letter score
(Snellen Equivalent)
63
(20/63)
63
(20/63)
Mean VA change during run-in +3 +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

12. DME Treatment
Combination
Group
(N = 65)
Ranibizumab
Group
(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
0 0
* Including participants who completed 24-week visit
† Including participants who completed at least one follow-up visit at 12, 16, or 20 weeks

13. Visual Acuity (VA)
13

14. VA Mean Change
14
-5.
0.
5.
10.
15.
0 4 8 12 16 20 24
VA
Mean
Change
(Letter
Score)
Visit Week
Ranibizumab
N = 64 N = 64
+ 3.0
Run-In Randomization
63 (20/63)
Mean Randomization Letter Score
(~Snellen Equivalent)

15. VA Mean Change
15
-5.
0.
5.
10.
15.
0 4 8 12 16 20 24
VA
Mean
Change
(Letter
Score)
Visit Week
Ranibizumab
Combination
N = 64 N = 64
+ 3.0
N = 65 N = 63
+ 2.7
Run-In Randomization
Adjusted Mean Difference: -0.5 letters
95% Confidence Interval: (-3.6, +2.5), P = 0.73

16. 16
VA Mean Change
Pre-Planned Subgroups

17. VA Mean Change: Baseline Lens Status
17
-5.
0.
5.
10.
15.
0 4 8 12 16 20 24
VA
Mean
Change
(Letter
Score)
Visit Week
Ranibizumab Combination
0 4 8 12 16 20 24
Pseudophakic Phakic
N = 32
N = 25
N = 32
N = 39
N = 32
N = 38
N = 32
N = 26
+5.1
+2.0
+4.1
+1.1
* P-value for interaction = 0.08

18. Binary VA Outcomes*
Combination
Group
(N = 63)
Ranibizumab
Group
(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 6% 5% 0.70
Changes at 24 Weeks
≥15 letters improvement 11% 2% 0.03
≥10 letters improvement 22% 14% 0.34
≥15 letters worsening 6% 5% 0.62
≥10 letters worsening 13% 6% 0.09
* Pre-planned secondary outcomes

19. Outcomes by Lens Status
Combination
Group
(N = 63)
Ranibizumab
Group
(N = 64)
≥15 letters improvement 7 (11%) 1 (2%)
Pseudophakic 3 1
Phakic 4 0
≥15 letters worsening 4 (6%) 3 (5%)
Pseudophakic 1 2
Phakic 3 1

20. Central Subfield Thickness (CST)
20

21. OCT CST Mean Change
21
-150.
-100.
-50.
0.
50.
0 4 8 12 16 20 24
CST
Mean
Change
(µm)
Visit Week
Ranibizumab
-62
N = 64 N = 64
*Outlying values were truncated to 3 SD from the mean. One image was non-gradable due to low resolution.
Run-In Randomization

22. OCT CST Mean Change
22
-150.
-100.
-50.
0.
50.
0 4 8 12 16 20 24
CST
Mean
Change
(µm)
Visit Week
Ranibizumab
Combination
Run-In Randomization
-62
N = 64 N = 64
-110
Adjusted Mean Difference: -52 µm
95% Confidence Interval: (-82,-22), P < 0.001
N = 65 N = 62
*Outlying values were truncated to 3 SD from the mean. One image was nongradable due to low resolution.

23. OCT CST Mean Change: AUC
23
-150.
-100.
-50.
0.
50.
0 4 8 12 16 20 24
CST
Mean
Change
(µm)
Visit Week
Ranibizumab
Combination
Run-In Randomization
N = 64 N = 64
N = 65 N = 62
Adjusted Mean Difference (AUC): -55
95% Confidence Interval: (-78, -31), P < 0.001
-33.5
-86.9
*Outlying values were truncated to 3 SD from the mean. One image was non-gradable due to low resolution.

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

25. Safety
25

26. Ocular Adverse Events
26
Combination
Group
(N = 65)
Ranibizumab
Group
(N = 64)
P-value
Eyes with at least one ocular
adverse event
63% 31% <0.001
Increased IOP at any visit 29% 0 <0.001
Increased ≥10 mmHg
from randomization
23% 0
IOP ≥30 mmHg 15% 0
Received
anti-hypertensives
20% 0

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
27