1. The Diabetic Retinopathy Clinical Research Network
Randomized Trial Evaluating Short-Term Effects of Intravitreal Ranibizumab or Triamcinolone Acetonide on Diabetic Macular Edema Following Panretinal Photocoagulation
Joseph M. Googe, MD
Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817 

2. Background PRP in Eyes with Central DME
Scatter or panretinal photocoagulation (PRP) is standard treatment for PDR
Reported side effects of PRP include:
Worsening macular edema and loss of visual acuity (prior to OCT)
DRCR.net protocol F reported PRP in 1 or 4 sittings, respectively, results in median +14 or +15 µm increase in OCT CSF (25th, 75th percentile = +5 or +6, +20 or +34 µm) with little decreased acuity 17 weeks after initiating PRP in eyes without central DME

3. Background
Is change in OCT CSF and change in visual acuity similar in eyes receiving PRP with central DME which, around the same time, also receive focal/grid laser for the DME?
3 DRCR.net protocols evaluating focal/grid laser for DME as a monotherapy showed a median decrease in CSF of 30 microns and a median increase in VA of 1 or 2 letters following focal/grid laser of central DME without PRP (at 16 weeks)

4. Background PRP in Eyes with Central DME
Focal/grid laser of central DME in absence of prompt PRP usually associated with short term improvement (at 16 weeks) of macular edema with little change in visual acuity
Protocol N
Median Change in OCT Central Subfield Thickness (25th, 75th quartiles)
Median Change in Visual Acuity (25th, 75th quartiles)
Protocol B
311
-33 (-90, 13)
2 (-4, 7)
Protocol K
119
-27 (-61, 13)
1 (-3, 6)
Protocol I
268
-34 (-101, 10)
2 (-3, 8)

5. Background PRP in Eyes with Central DME
If some eyes with central DME receiving PRP at the time of focal/grid laser have at least short term substantial worsening of macular edema and visual acuity loss, . . .
then reducing the proportion of eyes with worsening of macular edema and visual acuity loss following PRP might improve quality of life for individuals undergoing this therapy in the short term

6. Background Anti-VEGF and Triamcinolone for DME
Inflammation and increased levels of vascular endothelial growth factor (VEGF) contribute to the development or exacerbation of DME
DRCR.net , RESTORE, RIDE and RISE reported benefits for ≥1 year after initiating intravitreal ranibizumab for DME in the absence of DR requiring prompt PRP (Protocol I)
DRCR.net studies and other studies have suggested a benefit of intravitreal corticosteroids for DME (though not superior to ranibizumab or focal/grid laser)
Anti-VEGF drugs or corticosteroids might have a role in reducing PRP-induced exacerbation of macular edema in eyes with DME and severe NPDR or PDR for which PRP is given around the time that focal/grid is given for the DME

7. Laser-Ranibizumab-Triamcinolone+PRP Randomized Clinical Trial for DME
Study Objective
Evaluate short term effects of intravitreal ranibizumab or intravitreal triamcinolone on exacerbation of macular edema and associated visual acuity loss in eyes requiring PRP for severe NPDR or PDR and receiving focal/grid laser for center-involved DME.

8. Randomized, multi-center clinical trial
Study Design
Randomized, multi-center clinical trial
At least 1 eye meeting all of the following criteria:
Severe NPDR or PDR requiring prompt PRP
Presence of central DME on clinical exam and CST on OCT ≥250 microns
Best corrected E-ETDRS visual acuity letter score ≥24 (~20/320 or better)
Sham+
Focal/Grid/PRP Laser
Ranibizumab+
Focal/Grid/PRP Laser
Triamcinolone+
Focal/Grid/PRP Laser
Primary outcome: Change in visual acuity from baseline to 14 weeks (intent to treat analysis)

9. Follow-up Schedule 1st injection at baseline Safety visit 3-10 days
Focal/grid laser 3-10 days
Initial PRP (following focal/grid ) 3-14 days
Baseline to
2 Weeks
2nd injection (ranibizumab for ranibizumab group and sham for sham and triamcinolone groups)
Follow-up visit
4 Weeks
Last day to complete PRP was 49 days from baseline
14 Weeks
Primary outcome visit
34 Weeks &
56 Weeks
Safety follow-up visits

10. Study Enrollment Eyes Randomized: N = 364 (333 Study Participants)
Sham+
Focal/Grid Laser & PRP
N = 133
Ranibizumab+
Focal/Grid Laser & PRP
N = 116
Triamcinolone+
Focal/GridLaser & PRP
N = 115
14 Week Visit Completion* (Primary Outcome):
95%
56 Week Visit Completion*:
87%
*Includes deaths

11. Baseline Characteristics (N=345)
Overall
Median age (yrs) 57
Women
39%
Race
White
61%
African-American
13%
Hispanic or Latino
23%
Asian 2%
Other 1%
Unknown/not reported
Median HbA1c (%)
8.1
Diabetes type
Type I
Type II
84%
Uncertain 3%

12. Baseline Characteristics
Sham+
Focal/Grid & PRP
N = 123
Ranibizumab+
N = 113
Triamcinolone+
N = 109
Median E-ETDRS© visual acuity letter score (Snellen equivalent)
67 (20/50)
68 (20/50)
Median OCT CSF thickness (µm)
355
352
359
No prior treatment for DME
65%
66%

13. Panretinal Photocoagulation Treatment
Sham+
Focal/Grid/PRP Laser
Ranibizumab+
Triamcinolone+
Initial PRP on the same day as focal/grid laser planned/performed
Yes/Yes
50%
53%
Yes/No 7% 4% 8%
No/Yes 5% 6%
No/No
37%
33%
34%
PRP and/or focal/laser not done 1% 3%

14. Panretinal Photocoagulation Treatment
Sham+
Focal/Grid/PRP Laser
Ranibizumab+
Triamcinolone+
Number of PRP sittings performed* 1
40%
34%
38% 2
47%
50%
46%
3 or 4†
12%
15%
PRP not done 1% 2%
Number of sittings planned prior to randomization was similar to the number of sittings performed.
† Only 1 study participant had 4 PRP sittings performed

15. Panretinal Photocoagulation Treatment
Sham+
Focal/Grid/PRP Laser
N = 122
Ranibizumab+
N = 111
Triamcinolone+
N = 107
PRP automated pattern used
30%
19%
20%
Median total number of burns
1541
1410
1430
Proportion of eyes with PRP completed in the protocol window
89%
87%
81%

16. Additional Treatment for DME
Sham+
Focal/Grid/PRP Laser
N = 123
Ranibizumab+
N = 113
Triamcinolone+
N = 109
Prior to 14 weeks
Eyes with additional treatments
14 weeks to 56 weeks 71 48 45
Additional treatment*
Bevacizumab (+/- Laser) 22 17 9
Ranibizumab (+/- Laser) 1 3
Triamcinolone (+/- Laser) 10 12 7
Laser 31 21
Vitrectomy 2
Bevacizumab+Triamcinolone (+/- Laser)
Triamcinolone+Vitrectomy
Eyes with non-protocol anti-VEGF trt (# of trts applied)
28 (39)
23 (32)
17 (32)
*Number of eyes, each combination of treatment only counted once

17. Visual Acuity

18. Change in Visual Acuity at 14 Weeks
Primary Outcome
Change in Visual Acuity at 14 Weeks
Change in visual acuity (letters)
Sham+
Focal/Grid/PRP Laser
N = 123
Ranibizumab+
N = 113
Triamcinolone+
N = 109
Mean -4 +1 +2
Difference in mean change from Sham +Focal/Grid/PRP Laser [P Value]*
+5.6
[P < 0.001]
+6.7
*Adjusted for baseline visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

19. Mean Change in Visual Acuity* from Baseline
On the graph of Ranibizumab the mean change in VA was 1 letter at 14 weeks but graph shows it closer to 2. This needs to be fixed please.
Randomized Phase
(DME treatment according to protocol)
Safety Phase
(DME treatment at investigator discretion)
Safety Phase
(DME treatment at investigator discretion)
* Values that were ±30 letters were assigned a value of 30

20. Change in Visual Acuity at 56 Weeks
Change in visual acuity (letters)
Sham+
Focal/Grid/PRP Laser
N = 111
Ranibizumab+
N = 95
Triamcinolone+
N = 93
Mean -6 -4 -5
Difference in mean change from Sham +Focal/Grid/PRP Laser [P Value]*
+1.9
[P = 0.44]
+1.2
[P = 0.63]
*Adjusted for baseline visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

21. Visual Acuity Subgroup Analysis

22. Subgroup Analyses
No obvious clinically important difference in results at 14-week primary outcome visit for any of the following subgroups:
Prior treatment for DME
Baseline visual acuity
Baseline OCT-measured central subfield thickening
Baseline level of diabetic retinopathy on photos
Baseline HbA1c level
Description of edema by ophthalmologist as predominantly focal or predominantly diffuse
PRP in a single sitting vs. multiple sittings
What about duration of DME as defined by clinician? Did that effect VA outcomes? 22 22

23. Retinal Thickening

24. Change in Retinal Thickening at 14 Weeks*
Change in OCT Central Subfield Thickening*
Sham+
Focal/Grid/PRP Laser
N = 115
Ranibizumab+
N = 100
Triamcinolone+
N = 103
Mean change from baseline (µm) -5
-39
-92
Difference in mean change from Sham+ Focal/Grid/PRP Laser
[P Value] †
-35
[P = 0.007]
-100
[P < 0.001]
Thickness ≥10% increase with at least a 25 µm increase from baseline
38%
17%
10%
Thickness <250 µm with at least a 25 µm decrease from baseline
27%
* Missing (or ungradeable) data as follows for the sham+focal/grid/PRP laser group, ranibizumab+focal/grid/PRP laser group, and triamcinolone+focal/grid/PRP laser groups, respectively: 3, 3, 2
† Adjusted for baseline OCT retinal thickness and visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

25. Correlation between Visual Acuity and Central Subfield Thickness at 14 Weeks
Sham+
Focal/Grid/PRP Laser
Ranibizumab+
Triamcinolone+
Central subfield thickness ≥10% increase with at least a 25 µm increase from baseline
N=44
N=17
N=10
Above OCT CST change AND concordant decrease in visual acuity of ≥10 letters at 14 weeks
15 (34%)
2 (12%)
1 (10%)
Of the 44 eyes in the sham group exhibiting central subfield thickness increase ≥ 10% with a least a 25 micron increase, 15 (34%) had concordant decrease in visual acuity of ≥ 10 letters at 14 weeks, and represented approximately half of the eyes in this group with this amount of visual acuity loss. Similarly, of the 17 and 10 eyes, respectively, in the ranibizumab and triamcinolone groups with central subfield thickness increase ≥10% with at least a 25 micron increase at 14 weeks, 2 (12%) and 1 (10%) had concordant decreases in visual acuity of ≥10 letters at 14 weeks.

26. Change in Retinal Thickening at 56 Weeks*
Change in OCT Central Subfield Thickening*
Sham+
Focal/Grid/PRP Laser
N = 101
Ranibizumab+
N = 92
Triamcinolone+
N = 89
Mean change from baseline (µm)
-71
-52
-40
Difference in mean change from Sham+ Focal/Grid/PRP Laser
[P Value] †
+22
[P = 0.25]
+15
[P = 0.45]
Thickness ≥10% increase with at least a 25 µm increase from baseline
28%
20%
Thickness <250 µm with at least a 25 µm decrease from baseline
27%
29%
*Missing (or ungradeable) data as follows for the sham+focal/grid/PRP laser group, ranibizumab+focal/grid/PRP laser group, and triamcinolone+focal/grid/PRP laser group, and respectively: 10, 3, 4
† Adjusted for baseline OCT retinal thickness and visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

27. Mean Change in Retinal Thickness from Baseline
Randomized Phase
(DME treatment according to protocol)
Safety Phase
(DME treatment at investigator discretion)
Safety Phase
(DME discretion)

28. ≥ 2 Step Improvement in LogOCT Central Subfield Thickness from Baseline
Randomized Phase
(DME treatment according to protocol)
Safety Phase
(DME treatment at investigator discretion)
Safety Phase
(DME discretion)

29. Safety

30. Major Ocular Adverse Events Prior to the 14-Week Visit
Sham+
Focal/Grid/PRP Laser
N = 133
Ranibizumab+
N = 116
Triamcinolone+
N = 115
Number of injections
227
115
Endophthalmitis*
1 (0.9%)
Ocular vascular event
Traction retinal detachment
3 (2%)
1 (1%)
Vitrectomy
Vitreous Hemorrhage
16 (12%)
6 (5%)
7 (6%)
Endophthalmitis occurred 2 days after the second injection
* One case related to study drug injection in the ranibizumab+focal/grid/PRP laser group. 30 30

31. Major Ocular Adverse Events from 14 Weeks to 56 Weeks
Adverse events from 14 to 56 weeks
Sham+
Focal/Grid/PRP Laser
N = 131
Ranibizumab+
N = 111
Triamcinolone+
N = 112
Endophthalmitis
Ocular vascular event
Traction retinal detachment
4 (3%)
5 (5%)
1 (1%)
Vitrectomy
17 (13%)
8 (7%)
7 (6%)
Vitreous Hemorrhage
28 (21%)
25 (23%)
20 (18%) 31 31

32. Elevated Intraocular Pressure/Glaucoma Prior to the 14-Week Visit
Sham+
Focal/Grid/PRP Laser
N = 133
Ranibizumab+
N = 116
Triamcinolone+
N = 115
Number of injections
227
115
Elevated Intraocular Pressure/Glaucoma
Increase ≥10 mmHg from baseline
3 (2%)
20 (17%)
IOP ≥30 mmHg
2 (2%)
5 (4%)
Initiation of IOP-lowering meds at any visit*
Number of eyes meeting ≥1 of the above
Glaucoma surgery 32
*Excludes eyes with IOP lowering medications at baseline 32

33. Elevated Intraocular Pressure/Glaucoma from 14 Weeks to 56 Weeks
Sham+
Focal/Grid/PRP Laser
N = 131
Ranibizumab+
N = 111
Triamcinolone+
N = 112
Increase ≥10 mmHg from baseline
6 (5%)
10 (9%)
IOP ≥30 mmHg
4 (3%)
4 (4%)
Initiation of IOP-lowering meds at any visit*
7 (5%)
5 (5%)
17 (15%)
Number of eyes meeting ≥1 of the above
11 (8%)
7 (6%)
20 (18%)
Glaucoma surgery†
1 (1%)
*Excludes eyes with IOP lowering medications at baseline
† Includes 2 Ahmed valve (neovascular glaucoma) 33 33

34. Cataract Surgery During Follow-up
Up to 14 weeks none of the phakic eyes in all groups required CE
14 to 56 weeks CE was performed in a small percentage of patients (2 to 3 % in sham and ranibizumab groups and 6% in the TA group).

35. Cataract Surgery During Follow-up
Sham+
Focal/Grid/PRP Laser
Ranibizumab+
Triamcinolone+
Prior to 14 week visit
Phakic at baseline
N = 120
N = 93
N = 105
Eyes that had cataract surgery
14 to 56 week visit
Phakic at 14 weeks
N = 119
N = 91
N = 102
2 (2%)
3 (3%)
6 (6%) 35

36. Number of Deaths Sham N = 133 Ranibizumab N = 116 Triamcinolone2

37. Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’ Collaboration through 56 Weeks
ATC Event
Sham
N* = 102
Ranibizumab
N* = 116
Triamcinolone
N* = 115
Non-fatal myocardial infarction
1 (1%)
3 (3%)
Non-fatal cerebrovascular accident-ischemic or hemorrhagic (or unknown)
4 (3%)
Vascular death (from any potential vascular or unknown cause)
2 (2%)
Any APTC event
4 (4%)
8† (7%)
Antiplatelet Trialists’ Collaboration. BMJ Jan 8;308(6921):
*N=Number of Study Participants. Study participants with 2 study eyes are assigned to the non-sham group. Multiple events within a study participant are only counted once per event.
† 1event occurred between baseline and 4 week injections, 1 event occurred about 3 weeks after the 4 week injection, and the other events from the remaining 6 study participants occurred over 4 weeks after the 4 week injection 37

38. Cardiovascular Events According to Antiplatelet Trialists’ Collaboration* through 56 Weeks
Vascular or unknown death
Sham
Ranibizumab
Missing deaths in TA group and 1 in sham group. Would add into this slide and we can delete slide 36 and 37
Triamcinolone 4 14 34 56
Randomized Phase
(DME treatment according to protocol)
Safety Phase
(DME treatment at investigator discretion)
*Antiplatelet Trialists’ Collaboration. BMJ Jan 8;308(6921):
Non-fatal cerebrovascular accidents include ischemic, hemorrhagic or unknown. Vascular death includes any potential vascular or unknown cause.

39. Discussion

40. Summary Randomized Phase 14 week primary outcome visit: Safety Phase
Both ranibizumab and triamcinolone significantly improved visual acuity (+5.6 and +6.7 letters) and retinal thickness (-35 and -100 microns) compared to sham injection in eyes with central DME receiving focal/grid laser and requiring prompt PRP
Safety Phase
14 week to 56 week visits:
Differences in visual acuity and retinal thickness outcomes seen at 14 weeks not sustained

41. Median Change in Visual Acuity from Baseline to 16 Weeks
Summary Macular Edema after Prompt PRP in Eyes with Central DME Also Receiving Focal/Grid Laser – Sham Injection Group
Focal/grid laser of central DME in absence of prompt PRP usually associated decreased macular edema by 16 weeks
Protocols by DRCR.net Involving Focal/Grid Laser as Monotherapy for DME without PRP given for Severe NPDR or PDR
Median Change in OCT Central Subfield Thickness from Baseline to 16 Weeks (25th, 75th quartiles)
Median Change in Visual Acuity from Baseline to 16 Weeks
(25th, 75th quartiles)
Protocol B (“Laser vs. Steroids for DME”)
-33 (-90, 13)
2 (-4, 7)
Protocol K (“Response to Laser for DME”)
-27 (-61, 13)
1 (-3, 6)
Protocol I (“LRT for DME”)
-34 (-101, 10)
2 (-3, 8)
Protocol J (Sham group only at 14 weeks) – Laser-Ranibizumab-Triamcinolone for DME Plus PRP for Diabetic Retinopathy”)
0 (-80, +70)
-2 (-8, +3)

42. Macular Edema after Prompt PRP in Eyes with Central DME Receiving Focal/ Grid Laser – Sham Injection Group Compared to Eyes without Central DME and No Focal/Grid Laser
14 week primary outcome visit:
The magnitude and frequency of short term OCT central subfield thickening and visual acuity loss following prompt PRP appears similar in eyes with central DME receiving focal/grid laser than eyes without central DME
Thickness ≥10% increase with at least a 25 µm increase from baseline
Median Change in Visual Acuity
(25th, 75th quartiles)
Protocol F - eyes w/ PRP but w/o central DME: 17 week follow-up
28%
-1 (-4, +2)
Protocol J - eyes w/ sham injection plus focal/grid plus PRP: 14 week follow-up
38%
-2 (-8, +3)

43. Macular Edema after Prompt PRP in Eyes with Central DME Receiving Focal/ Grid Laser – Sham Injection Group Compared to Eyes without Central DME and No Focal/Grid Laser
34 week visit:
The magnitude and frequency of OCT central subfield thickening and visual acuity loss following prompt PRP appears similar in eyes with central DME receiving focal/grid laser than eyes without central DME
34 Week Visit
Thickness ≥10% increase with at least a 25 µm increase from baseline
Median Change in Visual Acuity
(25th, 75th quartiles)
Protocol F - eyes w/ PRP but w/o central DME: 34 week follow-up
34%
-1 (-5, +2)
Protocol J - eyes w/ sham injection plus focal/grid plus PRP: 34 week follow-up
30%
0 (-7, +6)

44. Summary Safety Ranibizumab: Triamcinolone:
Endophthalmitis: one eye receiving ranibizumab
Long term safety of ranibizumab injections remains largely unknown
Triamcinolone:
Increased risk of elevated IOP between 14 and 56 weeks; even with only one treatment at baseline
Not associated with higher incidence of cataract surgery (unlike prior studies)
Why? Only 1 injection? Younger cohort? Lower enthusiasm to operate on cataracts in this advance DR cohort? Other factors?

45. Summary Safety
This study did not identify an increased risk of traction retinal detachments beyond that which could be attributed to chance alone in these eyes which were receiving PRP for PDR or severe NPDR.
Cerebrovascular or cardiovascular events did not occur with a difference in frequency among the 3 groups that could not be attributed to chance alone.

46. Conclusions
Eyes with central DME receiving prompt PRP at time of focal/grid laser for DME appear more likely to have increased macular edema and visual acuity loss in short term than:
Eyes without central DME receiving prompt PRP but no focal/grid laser
Eyes with central DME receiving foca/grid laser but no prompt PRP

47. Conclusions
The risk of short-term exacerbation of macular edema and associated visual acuity loss following prompt PRP in eyes also receiving focal/grid laser for DME can be reduced by intravitreal triamcinolone or ranibizumab.
Benefits were not maintained at 1 year, but study injections were discontinued after 1 (triamcinolone) or 2 (ranibizumab) injections

48. Conclusions – Other Considerations
Eyes with central DME requiring prompt PRP which receive ranibizumab or triamcinolone at the time of PRP and focal/grid laser may be less likely to need additional PRP, develop vitreous hemorrhage, develop traction retinal detachment, or undergo vitrectomy

49. Conclusions – Other Considerations
Effects of ranibizumab or triamcinolone on diabetic retinopathy appear consistent with similar findings in eyes with the following:
Central DME not requiring prompt PRP treated with triamcinolone alone (Protocol B) or triamcinolone + prompt focal/grid laser (Protocol I)
Central DME not requiring prompt PRP treated with intravitreal ranibizumab with deferred (>24 weeks) or prompt focal/grid laser (Protocol I)

50. Conclusions – Other Considerations
Single study injection of intravitreal triamcinolone appears associated with increased risk of elevated IOP, even between 14 and 56 weeks
Further study seems necessary to assess long-term risks and benefits of intravitreal injections of ranibizumab or corticosteroids in persons with central DME also receiving prompt PRP

51. Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)
48 clinical study sites
Study participants who volunteered to participate in this trial
DRCR.net Data and Safety Monitoring Committee
Genentech (provided the ranibizumab) and Allergan, Inc. (provided the triamcinolone) for the study and collaborated in a manner consistent with the Network’s DRCR.net Industry Collaboration Guidelines, the DRCR.net had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol.
DRCR.net investigators and staff 51