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
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 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 www.drcr.net.

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 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)
 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: Favored PRP:
 Superior mean VA over course of 2  Fewer visits
years (AUC)  Fewer injections
 Less peripheral visual field loss  Cost effective when DME causing
 3-fold decrease in vitrectomies vision impairment IS NOT present
 Decreased development of central- initially
involved DME with vision impairment
 Cost effective when DME IS present
and causing vision impairment
 Visit Completion
394 Eyes Randomized
(305 Participants)
Ranibizumab PRP
Baseline Group Group
N = 191 N = 203
2-Years
Excluding Deaths 88% 86%

5-Years
Excluding Deaths 69% 65%

5-Years
Overall 61% 61%

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 Ocular Baseline Characteristics at
Enrollment
Ranibizumab PRP
All Eyes Had PDR Per Investigator Group Group
Determination Prior to Randomization (N = 191) (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
 Mean Number of Injections
5-Year Completers Only
Ranibizumab PRP
Group Group
(N = 117) (N = 123)

Year 1 7.1 2.3

Year 2 3.3 1.1

 Mean Number of Injections
5-Year Completers Only
Ranibizumab PRP
Group Group
(N = 117) (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 2.9 0.4

Cumulative Through 5 Years 19.2 5.4

 Number of Intravitreous Injections by Year
Ranibizumab Group, 5-Year Completers Only
50 None
45
45 1-3
40
40 37 4-6
35 35
35 32 7-9
30
Percentage

30 27 27 28 ≥10
25 26 25
25
20
20 16
14
15
9 10 10
10
5 2 2 2
0 1 1
0
1 2 3 4 5
Year 10
 Panretinal Photocoagulation

Ranibizumab Group PRP Group

(N = 191) (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%

 Mean Changes in VA From Baseline Over
Time - Overall Cohort
15
Ranibizumab
Mean Change in VA Letter Score

Adjusted Mean Difference at 5 Years: +0.6 letters

95% Confidence Interval: (-2.3, +3.5), P = .68 PRP
10

5
+3.1
+3.0
0

-5
0 16 32 52 68 84 104 120 136 156 172 188 208 224 240 260
N = 191 N = 117
N = 203
Visit Week
N = 123
Outlying values were truncated to 3 SD from the mean
 Mean Changes in VA From Baseline Over
Time for 5-Year Completers Only
15
5-Year AUC Difference: +1.6 letters Ranibizumab PRP
Mean Change in VA Letter Score

95% Confidence Interval: (0, 3.2), P = .05

10
+3.3
5

+1.5
0

-5
0 52 104 156 208 260

N = 117 of 191 Visit Week N = 123 of 203

Outlying values were truncated to 3 SD from the mean
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 Visual Acuity at 5-Years
Ranibizumab PRP
(N = 117) (N = 123)

Visual Acuity

Mean letter score 80 81

~Snellen Equivalent, Mean 20/25 20/25

Median letter score 84 84
(25th, 75th percentile) (89, 78) (89, 77)
20/20 20/20
~Snellen Equivalent, Median
(20/16, 20/32) (20/16, 20/32)
 Change in VA Letter Score at 5-Years

Adjusted
Ranibizumab PRP
Difference
(N = 117) (N = 123)
(95% CI)
1%
≥ 15 letters improvement, % 26% 23%
(-12%, 15%)
6%
≥ 10 letters improvement, % 52% 41%
(-10%, 21%)
-3%
≥ 10 letters worsening, % 6% 9%
(-11%, 5%)
-1%
≥ 15 letters worsening, % 6% 6%
(-7%, 5%)
Mean Change in Cumulative Visual Field Total
Point Score (30-2 + 60-4) - Overall Cohort
200
Mean Change in Cumulative Visual Field

Ranibizumab
PRP
0
Total Point Score (dB)

-200

-400

-600

-800
0 52 104
N = 81 N = 41
Visit Week
N = 86 N = 38
Outlying values were truncated to 3 SD from the mean 16
Mean Change in Cumulative Visual Field Total
Point Score (30-2 + 60-4) - Overall Cohort
200
Mean Change in Cumulative Visual Field

Ranibizumab
PRP
0
Total Point Score (dB)

-200
-330
-400
-527
-600
5-Year Adjusted Mean Difference: 208 dB
95% Confidence Interval (-9, 408), P = .04
-800
0 52 104 156 208 260
N = 81 N = 41
Visit Week
N = 86 N = 38
Outlying values were truncated to 3 SD from the mean 17
Diabetic Retinopathy on Fundus Photographs
at 5 Years*
Ranibizumab PRP
(N = 90) (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
33% N/A
NPDR (≤level 53)**, %
Without DR (≤ level 20)*, % 10% N/A
Improved ≥2 steps in DR severity on
46% N/A
fundus photos at 5 years**, %

*Observed data only, only include eyes with active NV at baseline as graded by reading center. **Not applicable or cannot
determine for PRP group.
 DR Adverse Events: Over 5 Years
Adjusted
Ranibizumab PRP
Difference
(N = 117) (N = 123)
(95% CI)
-9%
Any Retinal detachment, % 6% 15%
(-14%, -4%)
Retinal Detachment involving -3%
1% 4%
Center of the Macula, % (-7%, 0%)
-2%
Neovascular Glaucoma, % 3% 4%
(-6%, 2%)
1%
Neovascularization of the Iris, % 3% 1%
(-1%, 3%)
2%
Vitreous Hemorrhage, % 48% 46%
(-6%, 11%)
-7%
Vitrectomy, % 11% 19%
(-14%, -1%)
 Ocular Adverse Events
Ranibizumab PRP
P-Value
(N = 191) (N = 203)

Number of Injections 3132 981

Endophthalmitis, % 0.03% 0
Inflammation, % 2% 5% .05
Retinal Tear, % <1% 0
Cataract Surgery, % 16% 19% .62
Elevated IOP, % 16% 18% .58

Event defined as occurring at least once through 5 years.

 Systemic Adverse Events
Global
2 Study Eyes Ranibizumab PRP
P-
(N = 89) (N = 102) (N = 114)
Value
Nonfatal Myocardial
3% 6% 4% .64
Infarction
Nonfatal Stroke 3% 6% 6% .65
Death due to potential
vascular cause or 7% 7% 2% .13
unknown cause
Any APTC Event* 13% 18% 11% .31

Event defined as occurring at least once through 5 years.

*Anti-platelet Trialists’ Collaboration Arterial Thromboembolic Events.
 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 = 19 (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 22
 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
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Mean Change in VA Letter

Difference = 0.6 (95% CI: -2.3 to 3.5; P = .68) Ranibizumab

10 PRP
Score

5
+3.1
+3.0
0

-5
0 16 32 52 68 84 104 120 136 156 172 188 208 224 240 260
Visit Week
Outlying values were truncated to 3 SD from the mean 23
 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
15
Ranibizumab PRP
Mean Change in VA Letter Score

Difference = 1.6 (95% CI: 0 to 3.2; P = .05)

10 +3.3

5 +1.5

-5
0 52 104 156 208 260
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Visit Week
 Summary: 5-Year Results
Peripheral Visual Field*
 Mean change in cumulative visual field total point score (HFA 30-2 + 60-4)
 Ranibizumab = -330 ± 645 dB (N = 41)
 PRP = -527 ± 635 dB (N = 38)  In the subgroup of eyes that
Difference = 208 (95% CI: 9 to 408) participated in this ancillary study

200
Visual field loss present in both groups from years 2 - 5 Ranibizumab
0
PRP
-200
-330
-400
-527
-600
Visit Week
-800
0 52 104 156 208 260
 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%
P < .001
 Hazard Ratio = 0.4
(95% CI: 0.3 to 0.7)
38%

22%

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

18%

7%

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 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:
Favored ranibizumab:  Fewer visits
 Decreased development of central-  Fewer injections
involved DME with vision impairment
 Decreased development of retinal Both Groups:
detachments  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
Clinical Relevance of 5-Year Outcomes from
DRCR Network Protocol S
 These findings support either ranibizumab or PRP as
viable treatments for PDR

What’s in
your toolbox?

 Patient-specific factors, including anticipated visit compliance, cost, and frequency of

visits, should be considered when choosing treatment for PDR.
 Thank You on Behalf of Diabetic
Retinopathy Clinical Research Network
(DRCR.net)
Slide-Set Available at www.drcr.net

A complete list of all DRCR.net investigator

financial disclosures at www.drcr.net.

Full protocol available on clinicalTrials.gov

(NCT01489189)
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