Dexamethasone Ranibizumab vs Ranibizumab Alone for Persistent CentralInvolved DME Following AntiVEGF Therapy DRCRnet Protocol U Background After at least 6 monthly injections of antiVEGF for DME some eyes still have unresolved DME and reduced VA ID: 663160
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Slide1
Short-Term Evaluation of Combination
Dexamethasone + Ranibizumab vs. Ranibizumab Alone for Persistent Central-Involved DME Following Anti-VEGF Therapy
DRCR.net
Protocol USlide2
Background
After at least 6 monthly injections of anti-VEGF for DME, some eyes still have unresolved DME and reduced VAProtocol IProtocol TSlide3
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 propertiesShown to result in superior visual acuity to sham treatment but worse than laser or anti-VEGF in phakic patientsMay be similar to anti-VEGF in pseudophakic patients, at least for two yearsReduce retinal thickening Slide4
Study Objectives
Eyes with persistent DME and VA impairment despite previous anti-VEGF treatmentShort-term effects on VA and OCT central subfield thickness (CST)Provide information needed
if proceeding to phase III clinical trial
4
Dexamethasone
+ Continued Ranibizumab
“Combination”
Sham
+
Continued
Ranibizumab
“Ranibizumab”
VSSlide5
Study Design
Randomized Multi-center Clinical Trial (N = 116 participants, N = 129 Eyes)
5
≥
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 responseParticipant could have 2 eyes in the study
Outcomes
Primary
Mean Visual Acuity
Change
at 24 Weeks
Secondary
Mean OCT CST Change at 24 WeeksSlide6
Study
Overview
6
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? Slide7
Randomization
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meet the criteria for persistent DME; 9 were either lost to follow-up (2), died (1), requested to withdraw (1), were withdrawn by the site (2), or were believed to no longer need Injections by the investigator (3)†Dropped = 2 eyesSlide8
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
-50Slide9
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 weeksSlide10
Visual Acuity (VA)
10Slide11
VA Mean Change11
+ 3.0Run-In
Randomization
63 (20/63)
Mean Randomization Letter Score (~Snellen Equivalent)Slide12
VA Mean Change12
+ 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
=
0.73Slide13
13
VA Mean ChangePre-Planned SubgroupsSlide14
VA Mean Change: Baseline Lens Status14
PseudophakicPhakic
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 = 0.08Slide15
VA Mean Change: VA Improvement15
VA Improved During Run-InVA Did Not Improve During Run-In
N = 36
N = 33
N = 28
N = 31
N = 28
N = 30
N = 36
N = 34
+3.6
+2.6
+2.8
+2.3
* P
-value for interaction = 0.65Slide16
VA Mean Change: OCT Improvement16
Retinal Thickness on OCT Improved During Run-InRetinal Thickness on OCT Did Not Improve During Run-In
N = 38
N = 37
N = 26
N = 27
N = 26
N = 26
N = 38
N = 38
+4.1
+3.0
+3.0
+0.7
* P
-value for interaction = 0.27Slide17
Change in VA (Letter Score) from Randomization at 24 Weeks17
Change in VA (Letter Score) at 24 WeeksPercentMean SD: 2.7 (9.8)Mean SD: 3.0 (7.1)Slide18
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 Slide19
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
1Slide20
Central Subfield Thickness (CST)
20Slide21
OCT CST Mean Change21
-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
RandomizationSlide22
OCT CST Mean Change22
-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. Slide23
OCT CST Mean Change: AUC23
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. Slide24
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 Slide25
Safety
25Slide26
Ocular Adverse Events26
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%
0Slide27
Conclusion
Mean VA improvement by 6 months was no better in the dexamethasone + ranibizumab group than in the sham + ranibizumab groupOn average, there was a greater reduction in retinal thickness in the dexamethasone + ranibizumab groupStudy was not sufficiently sized to determine whether treatment response might differ by lens status
27