1. DRCR Retina Network
Treatment for Center-Involved DME in Eyes with Good Visual Acuity (Protocol V)

2. Financial Disclosures
Funding/Support: Cooperative Agreement with NEI and NIDDK of NIH, U.S. Department of Health and Human Services.
Additional Contributions: Regeneron provided the aflibercept for the study. In addition, Regeneron provided funds to the DRCR Retina Network to defray the study’s clinical-site costs.

3. Anti-VEGF Has Not Been Evaluated In Eyes That Have Center-Involved DME with Good VA (20/25 Or Better)
How should we treat eyes with center-involved DME and visual acuity 20/25 or better?

4. Treatment of DME in ETDRS
Focal/Grid Laser
Observation
Eyes with CI-DME and VA ≥20/25 or better at baseline
N = 120
N = 251
Visual acuity decrease by ≥ 5 letters (one line) at 2 years
27%
40%
~40% of eyes in ETDRS with CI-DME had good VA.

5. Eyes in Protocol I and ETDRS with ≥5 Letter VA Loss
*ETDRS study eyes with CI-DME and VA 20/25 or better at baseline. Protocol I study eyes with CI-DME and VA = 20/32 at baseline
N = 231
% of Eyes
N = 237
N = 246
N = 28
N = 26
N = 28
Months

6. (Add Anti-VEGF if VA drops)? (Add anti-VEGF if VA drops)?
Anti-VEGF Has Not Been Evaluated In Eyes That Have Center-Involved DME with Good VA (20/25 Or Better)
How should we treat eyes with center-involved DME and visual acuity 20/25 or better?
Anti-VEGF?
Focal/Grid Laser
(Add Anti-VEGF if VA drops)?
Observation
(Add anti-VEGF if VA drops)?

7. Study Design Randomized Multicenter Clinical Trial (N = 91 Sites)
≥18 years old with type 1 or type 2 diabetes
Center-involved DME on OCT*
VA letter score 20/25 or better*
No or minimal** prior treatment for DME
Aflibercept
Outcomes
Primary
Proportion of eyes that lost ≥5 letters of VA at 2 years
Secondary
Mean change in VA and CST from baseline at
1 and 2 years
Laser+
(Aflibercept prn)
Observation+
(Aflibercept prn)
*Confirmed at 2 visits 1-28 days apart (screening and randomization)
**No more than 1 laser and/or 4 injections, at least 12 months ago

8. Randomization 702 eyes of 702 participants total
Initiation With
Included in the
Primary Analyses
104 Weeks
Aflibercept
N = 226
N = 205
(94%)*
N = 226
Laser+
(Aflibercept prn)
N = 240
N = 212
(91%)*
N = 240
Observation+
(Aflibercept prn)
N = 236
N = 208
(90%)*
N = 236
*Excluding deaths

9. Study Follow-up Initiation With
Treatment Visit Schedule
Outcome Visit Schedule
Initiation With
Visits q 4 weeks during the first 24 weeks, q 4-16 weeks thereafter.
All participants had visits at 1 and 2 years for outcome assessment.
Aflibercept
Laser+
(Aflibercept prn)
Visits at 8 and 16 weeks followed by q 16-week visits thereafter. If VA/OCT worsen or aflibercept is initiated, visits at q 4, 8, or 16 weeks depending on disease progression and treatment.
Observation+
(Aflibercept prn)

10. Study Treatment Initiation With Aflibercept Laser+ (Aflibercept prn)
Injection at baseline
Evaluation at each visit for re-injection based on protocol criteria
Laser+
(Aflibercept prn)
Focal/grid laser at baseline
Evaluation at each visit for initiating aflibercept based on VA loss*
Retreatment with laser if protocol criteria are met
Observation+
(Aflibercept prn)
No treatment at baseline
Evaluation at each visit for initiating aflibercept based on VA loss*
* VA decrease ≥10 letters at 1 visit or 5-9 letters at two consecutive visits

11. Participant Baseline Characteristics
Initiation With
Aflibercept
N = 226
Laser
N = 240
Observation
N = 236
Age (y), median 59 60
Female
42%
34%
37%
Type 2 Diabetes
93%
92%
89%
HbA1c (%), median
7.6
Race/Ethnicity
White
64%
67%
68%
Black/African American
16%
15%
17%
Hispanic or Latino
14%
11%
Other 6% 4%

12. Ocular Baseline Characteristics
Initiation With
Aflibercept
N = 226
Laser
N = 240
Observation
N = 236
Prior Treatment for DME
Anti-VEGF 5% 6%
Focal/Grid Laser
12%
10%
Prior PRP 7% 4%
Recent or planned DME treatment in fellow eye*
38%
39%
* Randomization stratification factor

13. Ocular Baseline Characteristics
Initiation With
Aflibercept
N = 226
Laser
N = 240
Observation
N = 236
E-ETDRS VA Letter Score
Mean 85
≥89 (20/16 or better)
20%
24%
22%
88 to 84 (20/20)
46%
38%
42%
83 to 79 (20/25)
34%
36%
OCT CST (µm), mean
(Stratus Equivalent)
306
314

14. Visits Aflibercept Laser Observation Median 11 5 6 7 18 12
Number of Visits
Initiation With
Aflibercept
N = 226
Laser
N = 240
Observation
N = 236
Year 1
N = 210
N = 220
Median 11 5 6
Year 2
N = 205
N = 212
N = 208 7
Cumulative Over 2 Years 18 12

15. Visual Acuity (VA)

16. ≥5-Letter Loss At 2 Years Primary Outcome
Treatment Group Comparisons
Relative Risk CI
P Value
Aflibercept
vs. Laser
0.88
.79
vs. Observation
0.83
Laser vs. Observation
0.95

17. Treatment Group Comparisons
≥10-Letter Loss At 2 Years
Treatment Group Comparisons
Relative Risk CI
P Value
Aflibercept
vs. Laser
1.13
.83
vs. Observation
1.21
Laser vs. Observation
1.08

18. Treatment Group Comparisons
≥5-Letter Gain at 2 Years
Treatment Group Comparisons
Relative Risk CI
P Value
Aflibercept
vs. Laser
1.13
.46
vs. Observation
1.30
.40
Laser vs. Observation
1.15

19. ≥84 Letters (20/20 or Better) at 2 Years
Treatment Group Comparisons
Relative Risk CI
P Value
Aflibercept
vs. Laser
1.11
.15
vs. Observation
1.18
.03
Laser vs. Observation
1.06
.40

20. VA Letter Score at 2 Years
20/25 or Better
86%
84%
86%
N = N = N = 208

21. Mean VA Letter Score At 2 Years
86.0 (20/20)
85.3 (20/20)
84.2 (20/20)
N = 226
N = 240
N = 236
N = 205
N = 212
N = 208
8-Week
1-Year
2-Year
Error bars represent 95% confidence Intervals

22. Mean VA Letter Score Change from Baseline
+2.1
+0.1
1 Year: Adjusted Treatment Group Comparisons
Aflibercept vs. Laser: 2.1 (0.9 to 3.2); P <.001
Aflibercept vs. Observation: 2.2 (1.0 to 3.5); P <.001
Laser vs. Observation: 0.1 (-0.9 to 1.2); P = .82
N = 226
N = 240
N = 236
N = 205
N = 212
N = 208
8-Week
1-Year
2-Year
Error bars represent 95% confidence Intervals

23. Mean VA Letter Score Change from Baseline
+0.9
+0.1
-0.4
2 Years: Adjusted Treatment Group Comparisons
Aflibercept vs. Laser: 1.0 (-0.4 to 2.5); P = .21
Aflibercept vs. Observation: 1.3 (-0.3 to 2.8); P = .14
Laser vs. Observation: 0.2 (-1.0 to 1.5); P = .70
N = 226
N = 240
N = 236
N = 205
N = 212
N = 208
8-Week
1-Year
2-Year
Error bars represent 95% confidence Intervals

24. Mean Change in Letter Score Over 2 Years Treatment Group Comparisons
Mean Change in VA Letter Score Over 2 Years (Area Under the Curve) Exploratory Analysis
AUC
Mean Change in Letter Score Over 2 Years
Treatment Group Comparisons
1.5
0.0
-0.4
Mean
Difference CI
P Value
Aflibercept vs.
Laser
1.9
(1.0, 2.8)
<.001
Aflibercept vs. Observation
2.1
(1.1, 3.1)
Laser vs.
Observation
0.2
(-0.7, 1.0)
.73
Aflibercept
Laser
Observation

25. Central Subfield Thickness (CST)

26. Mean Change in OCT CST from Baseline
1 Year: Adjusted Treatment Group Comparisons
Aflibercept vs. Laser: -22 (-34 to -11); P <.001
Aflibercept vs. Observation: -28 (-41 to -15); P <.001
Laser vs. Observation: -6 (-17 to 6); P = .34
-25
-30
-50
8-Week
1-Year
2-Year
N = 226
N = 240
N = 236
Visit
N = 205
N = 212
N = 208
Error bars represent 95% confidence Intervals

27. Mean Change in OCT CST from Baseline
2 Year: Adjusted Treatment Group Comparisons
Aflibercept vs. Laser: -12 (-24 to 1); P = .07
Aflibercept vs. Observation: -13 (-27 to 1); P = .07
Laser vs. Observation: -1 (-13 to 11); P = .82
-42
-41
-48
8-Week
1-Year
2-Year
N = 226
N = 240
N = 236
Visit
N = 205
N = 212
N = 208
Error bars represent 95% confidence Intervals

28. DME Treatment

29. Time to First Aflibercept Injection (Laser and Observation Groups)
Laser vs. Observation Hazard Ratio: (95% CI, ) P = .01
Cumulative Probability, %
36%
28%
26%
13%
Weeks
# of Eyes at Risk
N = 236
N = 157
N = 132
N = 240
N = 202
N = 156

30. Aflibercept Treatment for DME
Number of Injections
Initiation With
Aflibercept
N = 226
Laser
N = 240
Observation
N = 236
Year 1
N = 210
N = 220
Median (IQR) 6
Year 2
N = 205
N = 212
N = 208 1
Cumulative Over 2 Years 8
Note: Injection adherence was 98% in each group.

31. Aflibercept Treatment for DME (Eyes receiving at least one injection)
Initiation With
Aflibercept
N = 226
Laser
N = 240
Observation
N = 236
Cumulative Over 2 Years*
N = 205
N = 56
N = 76
Median 8 7 9
* 2 year completers only

32. Number of Injections Over 2 Years
Aflibercept (N=205)
Laser (N=212)
Observation (N=208)
* 2 year completers only

33. Aflibercept Treatment for DME
Initiation With
Aflibercept
N = 226
Laser
N = 240
Observation
N = 236
Indication for first injection, N
Decrease of ≥10 Letters - 37 44
Decrease of 5 to 9 letters at two consecutive visits 19 34

34. Safety

35. Ocular Adverse Events Aflibercept Laser Observation Initiation With
P Value
Endophthalmitis
>.99
Any retinal detachment
<1%
.32
Cataract surgery 2%
.94
Vitreous hemorrhage 4% 3%
.66
Ocular inflammation
.21
IOP elevation 8% 6%
.02

36. APTC* Systemic Adverse Events
Initiation With
Aflibercept
N = 226
Laser
N = 240
Observation
N = 236
P Value
Nonfatal myocardial infarction
<1%
.75
Nonfatal stroke 2% 3%
.84
Death due to potential vascular or unknown cause 4% 1%
.19
Any event 7% 5%
.28
*APTC = Antiplatelet Trialists’ Collaboration

37. Summary
In this cohort of individuals with center-involved DME and good visual acuity (> 20/25):
No difference in rates of 1 or more lines of VA loss at 2 years among eyes initiating management with aflibercept, laser or observation
All three management strategies resulted in mean VA at 2 years of 20/20
Proportion of eyes 20/20 or better was significantly greater with aflibercept (77%) than observation (66%)
Proportion of eyes 20/25 or better was similar in each group (~85%)
Majority of eyes in laser group (~3/4) and observation group (~2/3) did not receive aflibercept during study

38. Discussion
Study did not compare monotherapies; study did compare 3 different management strategies
Eyes were followed carefully; aflibercept was initiated in the laser and observation groups if vision decreased by 1 line at 2 consecutive visits or 2 or more lines at 1 visit.
Changes on OCT did not trigger aflibercept initiation
Primary outcome was loss of 5 or more letters (≥1 line)
Likely clinical relevant in eyes with good vision
Unlikely due to chance variation

39. Conclusion
Among eyes with CI-DME and good VA, no significant difference in VA loss at 2 years whether eyes were initially managed with aflibercept, or with laser photocoagulation or observation and given aflibercept only if VA worsened.
Given the costs and risk associated with interventions, observation without treatment unless VA worsens may be a reasonable strategy for these eyes.

40. CW Baker and coauthors
Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial