1. New Concepts on Panretinal Photocoagulation for Proliferative Diabetic Retinopathy with highlights from the DRCR Network
Neil M. Bressler, MD
The James P. Gills Professor of Ophthalmology; Chief, Retina Division – Wilmer Eye Institute, Johns Hopkins University School of Medicine
Baltimore, USA

2. Disclosures
Off-label use of drugs or devices: ranibizumab, bevacizumab, intravitreal triamcinolone
Data from human research is presented
Genentech (provided the ranibizumab) and Allergan, Inc. (provided the triamcinolone) for the study and collaborated in a manner consistent with the 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.

3. Financial Disclosures
Grants to investigators at The Johns Hopkins University are negotiated and administered by the School of Medicine) which receives the grants, through the Office of Research Administration. Individual investigators who participate in sponsored projects are not directly compensated by the sponsor, but may receive salary or other support from the institution to support their effort on the projects.
Dr. Neil Bressler is Principal Investigator of grants at The Johns Hopkins University sponsored by the following entities (not including the National Institutes of Health): Abbott Medical Optics Inc.; Allergan; Bausch & Lomb; Carl Zeiss Meditec; EMMES Corporation; ForSight Labs, LLC; Genentech; Genzyme Corporation; Lumenis; Notal Vision; Novartis; Ora, Inc.; QLT Inc.; Regeneron; and Steba Biotech.
Dr. Susan Bressler (spouse) is co-investigator of grants at The Johns Hopkins University sponsored by the following entities (not including the National Institutes of Health): Genentech; Notal Vision; Novartis.
Dr. Susan Bressler is presently a consultant for the following entities: GlaxoSmithKline.

4. Thank you to the Diabetic Retinopathy Clinical Research Network (DRCR
Thank you to the Diabetic Retinopathy Clinical Research Network (DRCR.net) for much of the content included in this presentation.
Many of the DRCR.net slides and publications and data are available at no charge at the DRCR.net public web site at

5. Topics
Panretinal photocoagulation in the absence of diabetic macular edema
Panretinal photocoagulation in the presence of diabetic macular edema (and therefore, typically also treated with focal/grid laser until recently)
Panretinal photocoagulation in an era of anti-VEGF drugs for proliferative diabetic retinopathy

6. Protocol Update: Demonstrating Life Cycle of Protocols in a Network
Recruitment Follow-Up

7. Diabetic Retinopathy Clinical Research Network.
Development of DME Following Panretinal Scatter Photocoagulation Given in 1 or 4 Sittings in Eyes Without DME at Initiation of PRP
Diabetic Retinopathy Clinical Research Network.
Arch Ophthalmol. 2009;127:
Writing Committee:
Lead Authors: Alexander J. Brucker, Haijing Qin. Additional Members (Alphabetical): Andrew N. Antoszyk, Roy W. Beck, Neil M. Bressler, David J. Browning, Michael J. Elman, Adam R. Glassman, Jeffrey G. Gross, Craig Kollman, John A. Wells III. 7

8. Development of DME Following Panretinal Scatter Photocoagulation Given in 1 or 4 Sittings (Protocol F)
>300 spots q 4 wks
Over 12 wks
NOT
randomized
1 Sitting
N=84
4 Sittings
N=71
P Value*
Median baseline CSF thickness
207
198
Median change from baseline (microns) at follow-up
3 days
4 weeks
17 weeks
34 weeks
*P values are based on van der Waerden scores

9. Development of DME Following Panretinal Scatter Photocoagulation Given in 1 or 4 Sittings (Protocol F)
1 Sitting
N=84
4 Sittings
N=71
P Value*
Median baseline CSF thickness
207
198
Median change from baseline (microns) at follow-up
3 days +9 +5
0.01
4 weeks
+13
0.003
17 weeks
+14
+15
0.08
34 weeks
+22
0.06
*P values are based on van der Waerden scores

10. Development of DME Following Panretinal Scatter Photocoagulation Given in 1 or 4 Sittings (Protocol F)
Visual Acuity
1 Sitting
N=84
4 Sittings
N=71
P Value*
Median baseline (letter score)
85 (~20/20)
83 (~20/20)
Median change from baseline (letters)
3 days -3 -1
0.005
4 weeks
0.37
17 weeks
0.66
34 weeks -2
0.006
*P values are based on van der Waerden scores

11. Summary PRP in 1 sitting vs. 4 sittings spread over 12 weeks:
Clinically meaningful differences are unlikely in OCT thickness or visual acuity
PRP for diabetic retinopathy can be safely administered in 1 sitting in patients with good VA and no pre- existing center-involved ME
Although nearly half of 1-sitting PRP used retrobulbar anesthetic

12. Topics
Panretinal photocoagulation in the absence of diabetic macular edema
Panretinal photocoagulation in the presence of diabetic macular edema (and therefore, typically also treated with focal/grid laser until recently)
Panretinal photocoagulation in an era of anti-VEGF drugs for proliferative diabetic retinopathy

13. Protocol Update: Demonstrating Life Cycle of Protocols in a Network
Recruitment Follow-Up

14. 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
Retina 2011
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 

15. Background PRP in Eyes with Central DME
Reported side effects of PRP include:
Worsening macular edema and loss of visual acuity (prior to OCT)
DRCR.net 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
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?

16. 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)

17. Background PRP in Eyes with Central DME
What 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 could improve quality of life for individuals undergoing this therapy, in the short term

18. 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.

19. 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)

20. Follow-up Schedule 1st injection at baseline Safety visit 3-10 days
Sham, Ranibizumab
Or Triamcinolone
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

21. 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%

22. 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

23. 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.

24. Mean Change in Visual Acuity* from Baseline
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

25. 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%
~ -30um in
absence of PRP
* 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.

26. 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 44 17 10
Central subfield thickness ≥10% increase with at least a 25 µm increase from baseline AND with concordant decreases 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.

27. 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. 27 27

28. 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 28
*Excludes eyes with IOP lowering medications at baseline 28

29. 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%) 29

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

31. 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 31

32. Cardiovascular Events According to Antiplatelet Trialists’ Collaboration* through 56 Weeks
Vascular or unknown death
Sham
Ranibizumab
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.

33. Summary Randomized Phase of Trial 14 week primary outcome visit:
On average, both ranibizumab and triamcinolone statistically significantly improve visual acuity and retinal thickness compared to sham injection in eyes with central DME receiving focal/grid laser and requiring prompt PRP
Safety Phase of Trial
14 week to 56 week visits:
Differences in visual acuity and retinal thickness outcomes above no longer significant, BUT no long-term harm from these “acute” management strategies were found

34. 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
Protocol
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
-33 (-90, 13)
2 (-4, 7)
Protocol K
-27 (-61, 13)
1 (-3, 6)
Protocol I
-34 (-101, 10)
2 (-3, 8)

35. 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
Protocol
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
-33 (-90, 13)
2 (-4, 7)
Protocol K
-27 (-61, 13)
1 (-3, 6)
Protocol I
-34 (-101, 10)
2 (-3, 8)
Protocol J (Sham group only at 14 weeks)
0 (-80, +70)
-2 (-8, +3)

36. Summary Safety Ranibizumab: Triamcinolone:
Endophthalmitis: one eye receiving ranibizumab
Long term (>1 yr) safety of ranibizumab injections in persons with characteristics similar to those enrolled in this protocol remains largely unknown
Triamcinolone:
Associated with increased risk of elevated IOP between 14 and 56 weeks; even with only one treatment at baseline
Unlike prior studies, not associated with higher incidence of cataract surgery
Why? Only 1 injection? Younger cohort? Lower enthusiasm to operate on cataracts in this advance DR cohort? Other factors?

37. Summary Safety
This study did not identify an increased risk of traction retinal detachments beyond that which could be attributed to chance alone.
Cerebrovascular or cardiovascular events did not occur with a difference in frequency among the 3 groups that could not be attributed to chance alone – further study indicated.

38. 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

39. 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

40. Topics
Panretinal photocoagulation in the absence of diabetic macular edema
Panretinal photocoagulation in the presence of diabetic macular edema (and therefore, typically also treated with focal/grid laser until recently)
Panretinal photocoagulation in an era of anti-VEGF drugs for proliferative diabetic retinopathy

41. Protocol Update: Demonstrating Life Cycle of Protocols in a Network
Recruitment Follow-Up

42. Laser or Deferred Laser
Step Changes of Improvement/Worsening in Diabetic Retinopathy by Baseline Severity
Change from Baseline to 1-Year Visit*
Sham
+ Prompt
Laser
Ranibizumab
Laser or Deferred Laser
Triamcinolone
Baseline Severity:
Moderately Severe NPDR or Better
N = 150
N = 182
N = 80
Improved by ≥2 levels 4%
25%
Worsened by ≥2 levels 7% 3%
P value for comparison with Sham
P = .08
P = .17
*Photos were missing or ungradeable for 61 eyes in the sham + prompt laser group, 72 eyes in the ranibizumab groups, and 33 eyes in the triamcinolone + prompt laser group.
NPDR = nonproliferative diabetic retinopathy. 42

43. Laser or Deferred Laser
Step Changes of Improvement/Worsening in Diabetic Retinopathy by Baseline Severity
Change from Baseline to 1-Year Visit*
Sham
+ Prompt
Laser
Ranibizumab
Laser or Deferred Laser
Triamcinolone
Baseline Severity:
Moderately Severe NPDR or Better
N = 150
N = 182
N = 80
Improved by ≥2 levels 4%
25%
Worsened by ≥2 levels 7% 3%
P value for comparison with Sham
P = .08
P = .17
Severe NPDR or Worse
N = 83
N = 121
N = 70
19%
28%
13% 8% 1%
P = .03
*Photos were missing or ungradeable for 61 eyes in the sham + prompt laser group, 72 eyes in the ranibizumab groups, and 33 eyes in the triamcinolone + prompt laser group.
NPDR = nonproliferative diabetic retinopathy. 43

44. Background
Current treatment for PDR is panretinal photocoagulation (PRP)
Inherently destructive
Adverse effects on visual function
Some eyes with PDR+DME now receive anti-VEGF as standard care for DME
Would initial treatment of PDR with intravitreal anti-VEGF delay or prevent need for PRP? 44

45. Study Objective and Treatment Groups
To determine if visual acuity outcomes at 2 years in eyes with PDR (with or without concurrent DME) that receive anti-VEGF therapy with deferred PRP are non-inferior to those in eyes that receive prompt PRP therapy.
(Note: Study ranibizumab may be given as needed for DME using Protocol I retreatment as guidelines.)
Prompt PRP
0.5mg ranibizumab with deferred PRP
4545

46. Important Secondary Objectives (assuming visual acuity outcomes are non-inferior)
Compare visual function outcomes (including Humphrey visual field testing and study participant self-reports of visual function)
Determine percent of eyes not requiring PRP when intravitreal anti-VEGF is given in the absence of prompt PRP
Compare safety outcomes
Perform cost effectiveness analysis 46

47. Topics
Panretinal photocoagulation in the absence of diabetic macular edema
Panretinal photocoagulation in the presence of diabetic macular edema (and therefore, typically also treated with focal/grid laser until recently)
Panretinal photocoagulation in an era of anti-VEGF drugs for proliferative diabetic retinopathy

49. Risk of Severe Visual Loss or Vitrectomy Eyes with SNPDR or Early PDR
Event
Rate
Deferred Scatter
Type 1 Diabetes
Early Scatter
10% 5%
P=0.43 0% 1 2 3 4 5
Years

50. Risk of Severe Visual Loss or Vitrectomy Eyes with SNPDR or Early PDR
Event
Rate
Deferred Scatter
Type 2 Diabetes
Early Scatter
10% 5%
P=0.0001 0% 1 2 3 4 5
Years

51. Eyes With Proliferative Retinopathy
Risk of Visual Acuity 20/200 or Worse
Eyes With Proliferative Retinopathy
Event
Rate
DRS
Untreated Eye
40%
30%
20%
ETDRS
10%
Eyes
Patients 0% 1 2 3 4 5
Years

52. Eyes With Proliferative Retinopathy
Risk of Visual Acuity 5/200 or Worse
Eyes With Proliferative Retinopathy
Event
Rate
40%
DRS
Untreated Eye
30%
20%
10%
ETDRS
Eyes 0%
Patients 1 2 3 4 5
Years