1. Randomized Clinical Trial Jeffrey G. Gross, M.D. for the DRCR Network
Protocol S
Five-Year Outcomes of Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy:
Randomized Clinical Trial
Jeffrey G. Gross, M.D. for the DRCR Network
DRCR.net

3. Financial Disclosures
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

4. Randomized, multi-center clinical trial (55 Sites)
Study Design
Randomized, multi-center clinical trial (55 Sites)
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)

5. Published Two-Year Outcomes
Primary outcome: mean change in VA with ranibizumab no worse than (non-inferior to) PRP at 2 years
Secondary outcomes:
Favored ranibizumab:
Superior mean VA over course of 2 years (AUC)
Less peripheral visual field loss
3-fold decrease in vitrectomies
Decreased development of central-involved DME with vision impairment
Cost effective when DME IS present and causing vision impairment
Favored PRP:
Fewer visits
Fewer injections
Cost effective when DME causing vision impairment IS NOT present initially

6. Visit Completion 394 Eyes Randomized (305 Participants)
Ranibizumab Group
N = 191
PRP
Group
N = 203
Baseline
2-Years
Excluding Deaths
88%
86%
5-Years
Excluding Deaths
69%
65%
5-Years
Overall
61%
61%

7. Ocular Baseline Characteristics at Enrollment
All Eyes Had PDR Per Investigator Determination Prior to Randomization
Ranibizumab
Group
(N = 191)
PRP
(N = 203)
DR Severity Confirmation by Reading Center*
NPDR
10%
13%
Mild to moderate PDR
52%
49%
High risk PDR to advanced PDR
38%
37%
Presence of CI-DME with VA loss**, %
22%
23%
Required ranibizumab at baseline
*Diabetic retinopathy level data were missing for 2 in the ranibizumab group and 4 in the PRP group.
***Eyes with VA letter score ≤ 78 (20/32 or worse) AND OCT CST ≥ machine and gender specific thresholds

8. Mean Number of Injections 5-Year Completers Only
Ranibizumab Group
(N = 117)
PRP
Group
(N = 123)
Year 1
 7.1
2.3 
Year 2
3.3
1.1

9. Mean Number of Injections 5-Year Completers Only
Ranibizumab Group
(N = 117)
PRP
Group
(N = 123)
Year 1
 7.1
2.3 
Year 2
3.3
1.1
Year 3
3.0
0.9
Year 4
2.9
0.6
Year 5
0.4
Cumulative Through 5 Years
19.2
5.4

10. Number of Intravitreous Injections by Year Ranibizumab Group, 5-Year Completers Only

11. Panretinal Photocoagulation
Ranibizumab Group
(N = 191)
PRP Group
(N = 203)
Received PRP During Follow-up, N (%)
26 (14%)
103 (51%)
Received PRP prior to 104 Weeks, N 6%
45%
Received PRP after 104 Weeks, N 8%
15%
Received PRP during Vitrectomy, N 9%
14%
Received PRP outside of Vitrectomy, N 5%
44%

12. Mean Changes in VA From Baseline Over Time - Overall Cohort
Adjusted Mean Difference at 5 Years: +0.6 letters
95% Confidence Interval: (-2.3, +3.5), P = .68
+3.1
+3.0
N = 191
N = 117
N = 203
N = 123

13. Mean Changes in VA From Baseline Over Time for 5-Year Completers Only
5-Year AUC Difference: +1.6 letters
95% Confidence Interval: (0, 3.2), P = .05
+3.3
+1.5
N = 117 of 191
N = 123 of 203
Outlying values were truncated to 3 SD from the mean

14. Visual Acuity at 5-Years
Ranibizumab
(N = 117)
PRP
(N = 123)
Visual Acuity
Mean letter score 80 81
~Snellen Equivalent, Mean
20/25
Median letter score
(25th, 75th percentile) 84
(89, 78)
(89, 77)
~Snellen Equivalent, Median
20/20
(20/16, 20/32)

15. Change in VA Letter Score at 5-Years
Ranibizumab
(N = 117)
PRP
(N = 123)
Adjusted Difference
(95% CI)
≥ 15 letters improvement, %
26%
23% 1%
(-12%, 15%)
≥ 10 letters improvement, %
52%
41% 6%
(-10%, 21%)
≥ 10 letters worsening, % 9%
-3%
(-11%, 5%)
≥ 15 letters worsening, %
-1%
(-7%, 5%)

16. Mean Change in Cumulative Visual Field Total Point Score (30-2 + 60-4) - Overall Cohort
Outlying values were truncated to 3 SD from the mean

17. Mean Change in Cumulative Visual Field Total Point Score (30-2 + 60-4) - Overall Cohort
-330
-527
5-Year Adjusted Mean Difference: 208 dB
95% Confidence Interval (-9, 408), P = .04
N = 81
N = 41
N = 86
N = 38
Outlying values were truncated to 3 SD from the mean

18. Diabetic Retinopathy on Fundus Photographs at 5 Years*
Ranibizumab
(N = 90)
PRP
(N = 93)
Without PDR (≤ level 60), %
43%
37%
With Regressed NV (level 61A), %
28%
33%
With Active NV (≥ level 61B), %
29%
30%
Improved from PDR (≥ level 61) to NPDR (≤level 53)**, %
N/A
Without DR (≤ level 20)*, %
10%
Improved ≥2 steps in DR severity on fundus photos at 5 years**, %
46%
*Observed data only, only include eyes with active NV at baseline as graded by reading center. **Not applicable or cannot determine for PRP group.

19. DR Adverse Events: Over 5 Years
Ranibizumab
(N = 117)
PRP
(N = 123)
Adjusted Difference
(95% CI)
Any Retinal detachment, % 6%
15%
-9%
(-14%, -4%)
Retinal Detachment involving
Center of the Macula, % 1% 4%
-3%
(-7%, 0%)
Neovascular Glaucoma, % 3%
-2%
(-6%, 2%)
Neovascularization of the Iris, %
(-1%, 3%)
Vitreous Hemorrhage, %
48%
46% 2%
(-6%, 11%)
Vitrectomy, %
11%
19%
-7%
(-14%, -1%)

20. Ocular Adverse Events Ranibizumab (N = 191) PRP (N = 203) P-Value
Number of Injections
3132
981
Endophthalmitis, %
0.03%
Inflammation, % 2% 5%
.05
Retinal Tear, %
<1%
Cataract Surgery, %
16%
19%
.62
Elevated IOP, %
18%
.58
Event defined as occurring at least once through 5 years.

21. Systemic Adverse Events
2 Study Eyes
(N = 89)
Ranibizumab
(N = 102)
PRP
(N = 114)
Global P-Value
Nonfatal Myocardial Infarction 3% 6% 4%
.64
Nonfatal Stroke
.65
Death due to potential vascular cause or unknown cause 7% 2%
.13
Any APTC Event*
13%
18%
11%
.31
Event defined as occurring at least once through 5 years.
*Anti-platelet Trialists’ Collaboration Arterial Thromboembolic Events.

22. Summary: 5-Year Results Visits, Injections, Safety
66% of participants (excluding death) completing 5-year visit
Ranibizumab = 117
PRP = 123
Median number of visits*
Ranibizumab = 43
PRP = 21
Mean number of injections
Ranibizumab = (Mean of 3 per year- Years two through five)
PRP = 5
APTC events appeared similar between groups. No ocular safety concerns were identified.
* Counting participants with one study eye only

23. Summary: 5-Year Results Central Visual Acuity
Mean change in VA letter score at 5 years
Ranibizumab = 3.1±14.3 letters
PRP = 3.0±10.5 letters
+3.1
+3.0
Difference = 0.6 (95% CI: -2.3 to 3.5; P = .68)

24. Summary: 5-Year Results Central Visual Acuity
Mean change in VA letter score over 5 years
Ranibizumab = 3.3±9.5 letters
PRP = 1.5±7.5 letters
+3.3
+1.5
Difference = 1.6 (95% CI: 0 to 3.2; P = .05)

25. Summary: 5-Year Results Peripheral Visual Field*
Mean change in cumulative visual field total point score (HFA )
Ranibizumab = ± 645 dB (N = 41)
PRP = -527 ± 635 dB (N = 38)
Difference = 208 (95% CI: 9 to 408)
In the subgroup of eyes that participated in this ancillary study
-330
-527
Visual field loss present in both groups from years 2 - 5

26. Summary: 5-Year Results Complications
Development of Vision-Impairing DME Among Eyes Without Vision-Impairing (better than 20/32) DME at Baseline
Ranibizumab = 22%
PRP = 38%
Hazard Ratio = 0.4
(95% CI: 0.3 to 0.7)
22%
38%
P < .001

27. Summary: 5-Year Results Complications
Development of Retinal Detachment
Ranibizumab = 7%
PRP = 18%
Hazard Ratio = 0.4
(95% CI: 0.2 to 0.8) 7%
18%
P = .004

28. Conclusions: Five-Year Outcomes
Mean change in VA with ranibizumab similar to PRP at 5 years
Loss to follow-up was relatively high in both groups
Other outcomes:
Favored PRP:
Fewer visits
Fewer injections
Favored ranibizumab:
Decreased development of central-involved DME with vision impairment
Decreased development of retinal detachments
Both Groups:
Substantial VA loss rare (6% in each group)
Visual field loss progressed in both groups in years 2-5; difference between groups diminished
Vitreous hemorrhage in almost 50% of both groups

29. Clinical Relevance of 5-Year Outcomes from DRCR Network Protocol S
These findings support either ranibizumab or PRP as viable treatments for PDR
Patient-specific factors, including anticipated visit compliance, cost, and frequency of visits, should be considered when choosing treatment for PDR.
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30. Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)
Slide-Set Available at
A complete list of all DRCR.net investigator financial disclosures at
Full protocol available on clinicalTrials.gov (NCT )