1. The Diabetic Retinopathy Clinical Research Network
Prompt PRP
vs.
Ranibizumab + Deferred PRP
for PDR Study
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  1

2. Disclosure
Funding/Support: Cooperative Agreement with NEI and NIDDK of NIH, U.S. Department of Health and Human Services.
Additional Contributions: Genentech Inc. provided the ranibizumab and clinical site funding.
A complete list of all DRCR.net investigator financial disclosures can be found at

3. Background Proliferative diabetic retinopathy (PDR):
Left untreated, is a leading cause of blindness
~12,000 to 24,000 new cases of diabetic retinopathy-induced blindness each year*
Without treatment, ~50% of eyes with high-risk PDR experience severe vision loss within 5 years
* CDC: National diabetes fact sheet, 2007 3

4. Background
Panretinal photocoagulation (PRP) has been the treatment for PDR over last 4 decades
Substantially reduces risk of severe vision loss, but . . .
Inherently destructive
Peripheral visual field loss
Night vision loss
Exacerbation of pre-existing DME
Not perfect: 5% severe vision loss (worse than 5/200 at 2 consecutive visits) despite PRP
Anti-VEGF, when given for DME, decreases risk of diabetic retinopathy worsening and increases chance of improved retinopathy level 4

5. Randomized, multi-center clinical trial (55 Sites)
Study Design
Randomized, multi-center clinical trial (55 Sites)
Participants meeting all of the following criteria:
Age ≥18 years with Type 1 or type 2 diabetes
Study eye(s) meeting all of the following criteria (a participant can have 2 study eyes):
PDR
No history of PRP
Best corrected visual acuity letter score ≥24
(~Snellen equivalent 20/320 or better)
Eyes with or without central-involved DME were eligible
Primary Objective: Compare the efficacy and safety of PRP with that of intravitreous ranibizumab (0.5-mg in
0.05 mL) for proliferative diabetic retinopathy (PDR)

6. Primary Question Secondary Question
Is visual acuity using ranibizumab for PDR not worse than treatment with PRP at 2 years?
Non-inferiority margin of 5 letters
Secondary Question
Are there potential benefits of ranibizumab on:
Vision throughout follow-up (area under the curve)
Peripheral vision
Macular edema
Incidence of vitrectomy

7. Follow-up Schedule PRP group: Visits every 16 weeks*
Ranibizumab group: Visits every 4 weeks to assess for PDR treatment
Both groups simultaneously evaluated for DME treatment
Baseline to
1 Year
PRP group: Visits every 16 weeks*
Ranibizumab group: Visits every 4wk to 16wk to assess for PDR treatment
Interval is extended if injections for PDR and DME deferred (“Defer and Extend”)
1 Year to
2 Years
*Eyes with DME could be seen more frequently for DME treatment as needed.

8. PDR Treatment Schedule: Ranibizumab Group – Year 1
6 initial injections q4 weeks
One exception: if no neovascularization (NV) at
4-month or 5-month visit, then injection withheld
Starting at 6-month visit:
Inject if NV improved compared with any previous 3 consecutive visits where injection given
Withhold injections if NV stable over previous 3 consecutive injections
After injection withheld, resume injections if NV worsens

9. PDR Treatment Schedule: PRP Group
Prompt PRP- Initial
1 to 3 sittings within 8 weeks of randomization
Standard laser initial full session = 1200 to 1600 burns
Automated pattern initial full session = 1800 to 2400 burns
Ranibizumab required for eyes with central involved DME and vision loss at baseline.
If the size or amount of NV increased following initial PRP, then additional PRP could be given.

10. DME Treatment Schedule: Ranibizumab or PRP Groups
Eyes in both groups could receive 0.5-mg ranibizumab for DME treatment
At randomization, treatment was required for central DME with visual acuity 20/32 or worse – defined as “Baseline DME” throughout remainder of presentation
Otherwise initiation and retreatment with ranibizumab for DME at follow-up was at investigator discretion
DRCR.net protocol comparing ranibizumab with prompt or deferred focal/grid laser with focal/grid laser (Protocol I) retreatment regimen provided as guideline
Focal/grid laser at investigator discretion

11. Median (Quartiles) No. Visits over 2 years
Randomization
Participants:
N = 304
Eyes: N = 394
Ranibizumab Group
N = 191
PRP Group
N = 203
Baseline
N = 160 (84%)
N = 168 (83%)
2-Years
2-Years
Excluding Death
N = 88%
N = 86%
Median (Quartiles) No. Visits over 2 years
N = 22 (18, 24)
N = 16 (9, 22)

12. Baseline Characteristics
Ranibizumab
Group
(N = 191)
PRP
(N = 203)
Age (yrs) – Median 52 51
Women
43%
45%
Race
White
52%
50%
Type 2 diabetes
73%
76%
Duration of Diabetes (yrs) 18 17
Median HbA1c (%)
8.6
8.9

13. Ocular Baseline Characteristics
Ranibizumab
Group
(N = 191)
PRP
(N = 203)
Mean visual acuity letter score (~Snellen Equivalent)
75.0
(20/32)
75.2
20/25 or better
46%
20/32 to 20/40
34%
33%
20/50 to 20/100
16%
17%
20/125 to 20/320 5% 4%

14. Ocular Baseline Characteristics
Ranibizumab
Group
(N = 189)
PRP
(N = 201)
Mean OCT CST* (µm)
262
249
< 250 µm
66%
67%
250 to 349 µm
19%
26%
≥ 350 µm
15% 7%
Presence of central-involved DME with VA loss**
22%
23%
Required ranibizumab at baseline
*OCT values are Stratus equivalents
**Eyes with visual acuity letter score ≤ 78 (20/32 or worse) AND OCT CST ≥ machine and gender specific thresholds

15. Ocular Baseline Characteristics
Ranibizumab
Group
(N = 189)
PRP
(N = 199)
Diabetic Retinopathy Severity by Reading Center
NPDR†
10%
13%
Mild to moderate PDR
52%
49%
High risk PDR to advanced PDR
38%
37%
† There were 46 eyes (12%) for which NV was not identified by the reading center on the submitted color images or quality precluded identification. In 29 of these cases (63%), subsequent review of additional images (e.g. FA) confirmed NV, leaving 17 (4%) of 394 subjects with no photographic documentation of PDR.

16. Treatment For Proliferative Diabetic Retinopathy

17. PRP Group Baseline PRP Completed initial full PRP 98%
Overall
(N = 203)
Completed initial full PRP
98%
Performed in 1 Sitting
54%

18. PRP Group Additional PRP
Overall
(N = 203)
Eyes given additional PRP
(after completing initial full PRP)
45%
Distribution of timing to additional PRP
From completion of initial full PRP:
median time to additional PRP
~7 months

19. # of Ranibizumab Injections Eyes Without Baseline DME
Ranibizumab Group
# of Ranibizumab Injections
Eyes With Baseline DME
(N = 36)
Eyes Without Baseline DME
(N = 133)
Prior to 1-year Visit (Max possible = 13)
Median 9 7
Mean
8.9
6.9
Prior to 2-year visit (Max possible= 26) 14 10
13.3
10.1
Note: 97% of protocol-required injections for PDR were given

20. Ranibizumab Group Received PRP for PDR
Overall
N = 191
Received PRP* before 2 years
12 (6%)
*1 met failure criteria, 1 with Protocol Chair approval, 1 without Chair approval, 8 during vitrectomy (e.g., via endolaser), and 1 by non-study physician

21. Treatment For Diabetic Macular Edema

22. PRP Group Ranibizumab Treatment for DME
Timing of first ranibizumab injection for DME
Overall
(N = 203)
Never
47%
Baseline
35%
Follow-up
18%

23. # of Ranibizumab Injections for DME Eyes without baseline DME
PRP Group:
# of Ranibizumab Injections for DME
Eyes with baseline DME
(N = 42)
Eyes without baseline DME
(N = 135)
Prior to 1-year Visit (Max = 13)
Median 5
Mean
5.7
1.4
Prior to 2-year Visit (Max = 26) 9
9.1
2.2

24. Additional Treatment for DME
Ranibizumab Group
PRP
Group
Focal/grid laser 8%
10%
Received 1 or more alternative treatment
<1% 2%

25. Efficacy

26. Visual Acuity

27. Mean Change in Visual Acuity
Outlying values were truncated to 3 SD from the mean

28. Mean Change in Visual Acuity
Outlying values were truncated to 3 SD from the mean

29. Mean Change in Visual Acuity
2-Year Adjusted Mean Difference: +2.2 letters
95% Confidence Interval: (-0.5, +5.0)
(Meets pre-specified non-inferiority criterion: lower bounds of the 95% CI of -0.5 letters was greater than the non-inferiority limit of -5.0 letters)
Outlying values were truncated to 3 SD from the mean

30. Mean Change in Visual Acuity Area under the Curve Analysis
Area under the curve (AUC) analysis: Pre-planned secondary outcome

31. Mean Change in Visual Acuity Subset that Completed 2 Yrs
N = 160 of 191
N = 168 of 203

32. Mean Change in Visual Acuity: Eyes “Baseline DME”
+7.9
N = 42
N = 33
N = 37

33. Mean Change in Visual Acuity Eyes Without “Baseline DME”

34. Mean Change in Visual Acuity Stratified by Baseline DME
+1.8
- 0.5
N = 42
N = 33
N = 147
N = 126
N = 46
N = 37
N = 155
N = 130
*Outlying values were truncated to 3 SD from the mean

35. ≥10 Letter Score Improvement*
*Baseline VA 20/32 or worse

36. ≥10 Letter Score Worsening
P= #

37. ≥15 Letter Score Worsening
2-Year Adjusted Difference: -2%
95% Confidence Interval: (-8%, +3%)
N = 191
N = 160
N = 203
N = 168

38. Peripheral Visual Field Outcomes 2-Year Visit
Humphrey Visual Field
Ranibizumab
Group
(N = 58)
PRP
(N = 57)
Cumulative Point Score Change from Baseline
Mean
-23
-422
Difference (P-Value)
372 dB (P<0.001)
Mean Deviation Change from Baseline
-0.08
-2.50
2.2 (P< 0.001)

39. Optical Coherence Tomography Central Subfield Thickness

40. Central Subfield Thickness Change: 2-Year Visit
Ranibizumab
Group
PRP
Mean Change (µm)
-47 -3
Adjusted Difference (P-value)
-45 µm (P < 0.001)
Eyes with “Baseline DME”
-153
-48
-54 µm (P = 0.006)
Eyes without “Baseline DME”
-18
+10
-31 µm (P < 0.001)

41. Proportion of Eyes Developing Center Involved DME with Vision Impairment
2-Year Adjusted Difference: 19%
95% Confidence Interval: (10% to 28%)
P-value < 0.001
For Heidelberg Spectralis defined as central subfield thickness ≥305 for women and ≥320 for men with visual acuity letter score 78 or less (approximate Snellen equivalent 20/32 or worse). For Zeiss Cirrus and Optovue RTVue, defined as central subfield thickness ≥290 for women and ≥305 for men with visual acuity letter score 78 or less (20/32 or worse). For Zeiss Stratus defined as central subfield thickness ≥250 with visual acuity letter score 78 or less (20/32 or worse).

42. Diabetic Retinopathy

43. Complications of PDR Ranibizumab Group (N = 191) PRP Group (N = 203)
P-value
Any retinal detachment 6%
10%
0.08
Neovascular glaucoma 2% 3%
0.50
Iris neovascularization 1%
0.96
Vitreous hemorrhage
27%
34%
0.09
Vitrectomy 4%
15%
< 0.001
PDR = proliferative diabetic retinopathy

44. Diabetic Retinopathy: 2-Year Visit
Ranibizumab Group
(N = 142)
Prompt PRP Group
(N = 148)
P-value
Fundus Photos Graded by Reading Center*
0.41
No PDR
35%
30% -
Regressed NV
23%
24%
Active NV
42%
46%
* Only includes eyes with active NV at baseline

45. Diabetic Retinopathy Improvement: Ranibizumab Group
(Note: Cannot determine for PRP Group)
Ranibizumab Group
2-Year Visit
N = 142
Eyes improving 2 or more steps in DR severity on fundus photos
47%
Note: An eye with PRP cannot improve beyond level 60. It can be worse than 60 if active NV is present but cannot be better than 60; therefore assessing improvement is not possible.

46. Safety

47. Ocular Adverse Events*
Ranibizumab Group
N = 191
PRP Group
N = 203
P-value
Endophthalmitis
0.5% 0% --
Inflammation 1% 4%
0.02
Retinal Tear
Cataract Surgery 2% 6%
0.06
Elevation in IOP 9%
13%
0.16
‡‡Elevated intraocular pressure was defined as an increase in intraocular pressure of 10 mmHg or more from baseline at any visit, an intraocular pressure of 30 mmHg or more at any visit, the initiation of medication to lower intraocular pressure that was not in use at baseline, or glaucoma surgery.
¥Inflammation included the presence of inflammatory cells or flare in the anterior chamber, choroiditis, episcleritis, iritis, and the presence of vitreal cells.
*Event defined as occurring at least once through 2 years.

48. Systemic Adverse Events ATPC Events*
One Study Eye
2- Study Eyes
N = 89
Ranibizumab Group
N = 102
PRP Group
N = 114
Non-fatal MI 2% 3%
Non-fatal stroke 1% 4%
Vascular/
Unknown Death
<1%
Any ATPC event
P = 0.80 8% 9% 6%
††Vascular events were defined according to the criteria of the Antiplatelet Trialists’ Collaboration.
*Anti-platelet Trialists` Collaboration defined events. Occurring at least once
through 2 years.

49. Pre-Specified Systemic Adverse Events*
One Study Eye
2- Study Eyes
N = 89
Ranibizumab Group
N = 102
PRP Group
N = 114
P-value
Death (any cause) 4% 6%
0.70
Hospitalization
42%
47%
35%
0.20
Serious adverse event
43%
48%
37%
0.26
Hypertension
16%
25%
18%
0.23
*Occurring at least once through 2 years

50. MedDRA Systems (P value < 0.05)
N = 26 Systems
One Study Eye
% Per Participant
2- Study Eyes
N = 89
Ranibizumab Group
N = 102
PRP Group
N = 114
P-value
Cardiac
13%
18% 5%
0.01
Endocrine
20%
25%
11%
0.02
Infections/ infestations
28%
27%
14%
Respiratory
35%
46%
30%
0.04
Skin
24%
0.03
Surgical 8%
16%

51. Discussion DRCR.net Protocol S (PRP vs. Ranibizumab for PDR):
Treatment with 0.5-mg ranibizumab met primary non-inferiority outcome for VA being no worse than PRP
Summary of Ranibizumab group results vs. PRP:
Mean change in VA from baseline to 2-years with ranibizumab no worse than with PRP
Superior mean visual acuity over course of 2-years (area under the curve analysis)
Superior mean visual field outcomes
Decreased occurrence of vitrectomies
Decreased development of central involved DME
PRP rarely given for failure or futility of ranibizumab

52. Discussion
No systemic safety concerns with ranibizumab identified among pre-specified major safety outcomes
Increased frequency of adverse events defined by cardiac, endocrine, respiratory, infections/infestations, skin and surgical conditions MedDRA systems in ranibizumab groups could be real, due to chance, or due to ascertainment bias (more visits in ranibizumab group)
Interpretation of systemic safety difficult since large proportion of PRP group received ranibizumab per protocol for DME

53. Discussion
Rates of endophthalmitis or other injection-related serious adverse events were very low

54. Discussion
Key aspects of study design related to interpretation of results
Participant retention through two years (87% of those who had not died) lower than desired
However, no obvious baseline differences between groups for completers and non-completers that would suggest bias
Participants and clinicians were not masked  
However, high adherence to PDR treatment protocol
Primary outcome assessors were masked
Unknown if similar outcomes with 0.3-mg ranibizumab or other anti-VEGF agents (bevacizumab or aflibercept)

55. Advantages of PRP Typically able to be completed in one or two visits
Often long-lasting effect requiring no additional treatment
However, study suggests approximately 45% given additional PRP after initial full PRP was completed
From completion of initial full PRP, median time to additional PRP ~7 months
May cost less than ranibizumab injections
No risk of endophthalmitis
No risk of systemic exposure to anti-VEGF

56. Advantages of Ranibizumab
Mean change in VA from baseline to 2-years no worse than with PRP
Superior mean visual acuity over course of 2-years (area under the curve analysis)
Superior mean visual field outcomes
Decreased chance of vitrectomies
Decreased chance of developing DME
PRP rarely given for futility or failure
Unknown if similar outcomes with 0.3-mg ranibizumab or other anti-VEGF agents (bevacizumab or aflibercept)

57. Potential Impact of DME when Initiating Treatment of PDR
Presence of DME may influence the relative benefit of ranibizumab over PRP
When DME is present and treatment with an anti-VEGF agent is planned, PRP may be unnecessary in most cases provided that the patient is expected to be compliant with follow-up
When DME is not present, ranibizumab is more effective than PRP in preserving central and peripheral visual function, on average, but cost, follow-up compliance, and patient preference need to be considered

58. Conclusions
PRP effective for PDR over last 4 decades; remains effective in 21st century
Ranibizumab for PDR is at least as good as (non-inferior to) PRP for visual acuity at 2 years
Ranibizumab is an effective treatment alternative to PRP for PDR
No substantial safety concerns for at least 2 years
May be the preferred initial treatment approach for some patients, for example, those who have both PDR and DME.
Longer follow-up should determine whether effects sustained through 5 years

59. Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)
A complete list of all DRCR.net investigator financial disclosures and many of these slides can be found at
Full protocol available on clinicalTrials.gov (NCT ) 59