1. The Diabetic Retinopathy Clinical Research Network
Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema
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 

2. Background: Laser Therapy for DME
Focal/grid photocoagulation has been the standard care for DME for the past 25 years
In a randomized, multicenter clinical trial, DRCR.net showed (Protocol B – IVT vs Laser):
Focal/grid photocoagulation in eyes with center-involved DME produces gradual visual acuity improvement of ≥2 lines in about 30% of eyes after 2 years, although approximately 20% of laser treated eyes worsen by ≥2 lines
Other treatment modalities, including anti-vascular endothelial growth factor (VEGF) therapy and steroids, alone or in combination with laser, are under investigation
current standard care

3. Background: Anti-VEGF Therapy for DME
VEGF levels are increased in the retina and vitreous of eyes with diabetic retinopathy
Therapy that inhibits VEGF may represent a useful therapeutic modality which targets the underlying pathogenesis of DME
Prior studies, that were small with short-term follow-up, have reported promising results

4. Background: Intravitreal Triamcinolone for DME
Intravitreal triamcinolone was evaluated previously as a treatment for DME in a randomized trial conducted by DRCR.net (Protocol B – IVT vs Laser):
Results suggested that triamcinolone treatment without laser was not superior to focal/grid photocoagulation
Results suggested that triamcinolone treatment without laser likely was superior to no treatment

5. Study Rationale
To determine if anti-VEGF therapy alone or in combination with laser, or if triamcinolone in combination with laser, might result in improved outcomes compared with laser alone for treatment of DME, the DRCR.net designed a clinical trial to evaluate 3 treatment modalities for DME in comparison with focal/ grid laser:
Intravitreal ranibizumab+prompt (within 1 week) focal/grid laser
Intravitreal ranibizumab + focal/grid laser deferred for at least 24 weeks
Intravitreal triamcinolone+prompt (within 1 week) focal/grid laser

6. Laser-Ranibizumab-Triamcinolone Randomized Clinical Trial for DME:
Study Objective
Evaluate efficacy and safety of 0.5-mg intravitreal ranibizumab plus prompt (within 1 week) or deferred laser (≥24 weeks), or 4-mg intravitreal triamcinolone plus prompt (within 1 week) laser, in comparison with sham plus prompt laser for treatment of diabetic macular edema.

7. Randomized, multi-center clinical trial
Study Design
Randomized, multi-center clinical trial
At least one eye meeting all of the following criteria:
Electronic-ETDRS© best corrected visual acuity letter score of 78 to 24 (~20/32 to 20/320)
Definite retinal thickening due to diabetic macular edema involving the center of the macula on clinical examination
Central subfield (Stratus OCT™) ≥250 µm
Eligible patients were at least 18 years old with type 1 or type 2 diabetes.
Change in VA from baseline to 1 year was adjusted for baseline Visual acuity in stat models
Primary outcome: Change in visual acuity from baseline to 1 year (intent to treat analysis)

8. Follow-up Schedule Baseline to 1 Year 1 Year to 3 Years
Every subject has a follow-up visit at 1 year
Follow-up every 4 weeks
All groups except ranibizumab plus deferred laser group: Additional follow-up visit occurs 3 to 10 days after injection if focal/grid laser also is to be given
Baseline to
1 Year
Every subject has a follow-up visit at 2 years
Follow-up every 4 to 16 weeks depending on treatment group, disease progression, and treatment administered
Triamcinolone plus prompt laser group only: Additional safety visit every 4 weeks after triamcinolone injection
1 Year to
3 Years

9. Study Enrollment and Completion
Eyes Randomized:
N = 854 (691 Participants)
Sham
+Prompt Laser
N = 293
Ranibizumab
+Prompt Laser
N = 187
Ranibizumab
+Deferred Laser
N = 188
Triamcinolone
+Prompt Laser
N = 186
1 Year Visit Completion: 94%*
2 Year Visit Completion: 87%**
* Includes deaths
** Includes deaths and excludes pending and dropped who are not yet in window

10. Baseline Characteristics
Sham
+Prompt
Laser
Ranibizumab
+Deferred
Triamcinolone
Median age 63 62 64
Diabetes type
Type I 9% 6% 8%
Type II
89%
92%
90%
Uncertain 3% 2%
Median E-ETDRS© visual acuity letter score (Snellen equivalent)
65 (20/50)
66 (20/50)
Median OCT CSF thickness (µm)
407
371
382
374

11. Injections/Sham Prior to 1 Year
+Prompt
Laser
N = 274
Ranibizumab
N = 171
+Deferred
N = 178
Triamcinolone
N =176
Maximal possible # of sham/injections
13 sham*
13 drug
9 sham/4 drug
Median number of sham/study drug injections to 1 year
11* 8 9
5 sham/3 drug
AE Precluding Study Drug Injection† NA 2%
15%
Compliance with sham/drug injection when required by protocol
96%
95%
97%
Masked participant with 1 study eye identified correct assignment at 1 year
10%
88%
90%
44%
% of visits where an injection would have otherwise been required based on improvement but was not done due to AE
*Excludes 56 eyes among 163 participants with 2 study eyes unmasked at baseline when assigned ranibizumab + deferred laser.
† % of visits reported; 12% of eyes in the triamcinolone group compared with 3% and 4% in the ranibizumab groups

12. Laser Treatments Prior to 1 Year
Sham
+Prompt
Laser
Ranibizumab
+Deferred
Laser* (permitted starting at 24-week visit)
Triamcinolone
Median number of laser treatments including baseline 3 2
Proportion of eyes receiving laser at 48-week visit
26%
16% 8%
21%
No, only 1, only 2 or 3 more lasers after baseline
13%,
27%,
31%,
32%,
70%,
20%,
26%,
30%,
40%,
20%
11%
10%, 1%
28%,
15%
* 3 eyes deviated from the protocol and received laser prior to 24 weeks (2 were given laser at the 1 week safety visit and 1 at the 20 week visit).

13. Alternative* Treatments Prior to 1 Year
Sham
+Prompt
Laser
N = 293
Ranibizumab
N = 187
+Deferred Laser
N = 188
Triamcinolone
N = 186
Eyes with alternative treatments
(number of treatments)
14 (25)
1 (1)
Per protocol (failure‡ criteria met) 5 1
Deviations from protocol - clinical care 9
*Alternative treatments include: intravitreal bevacizumab, intreavitreal triamcinolone acetonide, vitrectomy, and intravitreal bevacizumab + intravitreal triamcinolone.
‡Failure is defined as: ≥10 letter loss from baseline, OCT CSF ≥250 µm, DME present on clinical exam that is cause of visual loss, “complete laser” given AND ≥13 weeks since last laser treatment with no improvement since the last laser treatment

14. Alternative* Treatments From 1 Year
and Prior to 2 Years
Sham
+Prompt
Laser
N = 274
Ranibizumab
N = 171
+Deferred
N = 178
Triamcinolone
N = 176
Eyes with alternative treatments*
(number of treatments)
29 (55)
1 (1)
3 (4)
Per protocol (failure‡ criteria met) 20 1 2
Deviations from protocol - clinical care 9
* Alternative treatments include: intravitreal bevacizumab, intravitreal ranibizumab intreavitreal triamcinolone acetonide, vitrectomy, intravitreal bevacizumab + intravitreal ranibizumab, and intravitreal bevacizumab + intravitreal ranibizumab + intravitreal triamcinolone.
‡ Failure is defined as: ≥10 letter loss from baseline, OCT CSF ≥250 µm, DME present on clinical exam that is cause of visual loss, “complete laser” given AND ≥13 weeks since last laser treatment with no improvement since the last laser treatment

15. Visual Acuity

16. Mean Change in Visual Acuity* at Follow-up Visits
FIX LINE TRANSITION
* Values that were ±30 letters were assigned a value of 30
P-values for difference in mean change in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; and triamcinolone+prompt laser=0.31.

17. Change in Visual Acuity (LOCF) at 1 Year*
Change in Visual Acuity (letters)
Sham
+Prompt
Laser
N = 293
Ranibizumab
N = 187
+Deferred
N = 188
Triamcinolone
N = 186
Mean +3 +9 +4
Difference in mean change from Sham +Prompt Laser
[P Value]**
+5.8
[P<0.001]
+6.0
+1.1
[P = 0.31]
Results were similar when using completed visits only. (+3, +9, +10, +4)
*Visits occurring between 308 and 420 days from randomization were included as 1-year visits. When more than 1 visit occurred in this window, data from the visit closest to the 1-year target date were used. For other eyes with out any 1-year data (19 eyes in the sham+prompt laser group, 16 eyes in the ranibizumab+prompt laser group, 10 eyes in the ranibizumab+deferred laser group, and 10 eyes in the triamcinolone+prompt laser group) the last observation carried forward (LOCF) method was used to impute data for the primary analysis.
**Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity

18. Change in Visual Acuity at 2 Years*
Change in Visual Acuity (letters)
Sham
+Prompt
Laser
N = 163
Ranibizumab
N = 106
+Deferred
N = 112
Triamcinolone
N = 103
Mean +2 +7
+10
Difference in mean change from Sham +Prompt Laser
[P Value]**
+5.0
[P = 0.01]
+7.2
[P<0.001]
-1.6
[P = 0.43]
*Visits occurring between 616 and 840 days from randomization were included as 2-year visits
**Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity

19. ≥10 Letter Improvement in Visual Acuity at Follow-up Visits
Visit Week
P values for the difference in proportion of 10 letter improvement in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; triamcinolone+prompt laser = 0.16

20. ≥15 Letter Improvement in Visual Acuity at Follow-up Visits
Visit Week
P values for the difference in proportion of 15 letter improvement in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; triamcinolone+prompt laser = 0.07

21. ≥10 Letter Worsening in Visual Acuity at Follow-up Visits
Visit Week
P values for the difference in proportion of 10 letter worsening in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser =0.001; triamcinolone+prompt laser = 0.75

22. ≥15 Letter Worsening in Visual Acuity at Follow-up Visits
Visit Week
P values for the difference in proportion of 15 letter worsening in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser = 0.009; ranibizumab+deferred laser = 0.01; triamcinolone+prompt laser = 0.95

23. > 10 Letter Improvement
≥10 Letter Improvement or Worsening in Visual Acuity at Follow-up Visits
> 10 Letter Improvement
> 10 Letter Worsening
N = 799 (52 weeks)
N = 484(104 weeks)
P values for the difference in proportion of 10 letter improvement in visual acuity from sham+prompt laser at the 52-week visit: : ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; triamcinolone+prompt laser = 0.16
P values for the difference in proportion of 10 letter worsening in visual acuity from sham+prompt laser at the 52-week visit: : ranibizumab+prompt laser <0.001; ranibizumab+deferred laser =0.001; triamcinolone+prompt laser = 0.75

24. ≥15 Letter Improvement or Worsening In Visual Acuity at Follow-up Visits
≥15 Letter Worsening
N = 799 (52 weeks)
N = 484 (104 weeks)
P values for the difference in proportion of 15 letter improvement in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; triamcinolone+prompt laser = 0.07
P values for the difference in proportion of 15 letter worsening in visual acuity from sham+prompt laser at the 52-week visit: : ranibizumab+prompt laser = 0.009; ranibizumab+deferred laser = 0.01; triamcinolone+prompt laser = 0.95

25. Visual Acuity Subgroup Analyses

26. Subgroup Analyses
No obvious clinically important difference in results at 1-year primary outcome visit for any of the following subgroups:
Prior treatment for DME
Baseline visual acuity
Baseline OCT-measured central subfield thickening
Baseline level of diabetic retinopathy on photos
Description of edema by ophthalmologist as predominantly focal or predominantly diffuse
In the subset of pseudophakic eyes at baseline (n = 273), visual acuity improvement in the triamcinolone+prompt laser group appeared comparable to the ranibizumab groups 26 26

27. Change in Visual Acuity at 1 Year Stratified by Baseline Visual Acuity

28. Change in Visual Acuity at 1 Year Stratified by Baseline CSF

29. Change in Visual Acuity at 1 Year Stratified by Prior DME Treatment

30. Change in Visual Acuity at 1 Year Stratified by Number of Study Eyes

31. Change in Visual Acuity (LOCF) at 1 Year Stratified by Eyes with Diffuse vs. Focal Edema at Baseline as Graded by Study Ophthalmologist

32. Change in Visual Acuity at 1 Year Stratified by Pseudophakic at Baseline

33. Mean Change in Visual Acuity at Follow-up Visits among Eyes that were Pseudophakic at Baseline*
Visit Week
* Values that were ±30 letters were assigned a value of 30

34. Retinal Thickening

35. Mean Change in Central Subfield Thickening at Follow-up Visits
Visit Week
P values are for the difference in mean change in OCT CSF retinal thickness from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001, ranibizumab+deferred laser <0.001, and triamcinolone+prompt laser <0.001.

36. Central Subfield Thickness <250 µm with at Least a 25 µm Decrease in Thickness from Baseline at Follow-up Visits
Visit Week
P values for difference in proportion in OCT central subfield thickness <250 microns with at least a 25 µm decrease in thickness from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001, ranibizumab+deferred laser = 0.001, and triamcinolone+prompt laser <0.001.

37. Two or More Step Improvement in the Logarithmic Transformation of Optical Coherence Tomography* Data from Baseline
Visit Week
*Logarithmic optical coherence tomography is calculated by taking the log base 10 of the ratio of the central subfield thickness divided by 200 and rounded to the nearest hundredth

38. Change in Retinal Thickening at 1 Year*
Change in OCT Central Subfield Thickeninga
Sham
+Prompt Laser
N = 271
Ranibizumab
N = 171
+Deferred Laser
N = 175
Triamcinolone
N = 173
Mean change from baseline (µm)
-102
-131
-137
-127
Difference in mean change from Sham Prompt+Laser
[P Value]**
-55
[P<0.001]
-49
-52
Thickness <250 µm with at least a 25 µm decrease from baseline
27%
53%
42%
47%
*Visits occurring between 308 and 420 days from randomization were included as 1 year visits. When more than 1 visit occurred in this window, data from the visit closest to the 1 year target date were used.
**Analysis of covariance adjusted for baseline OCT retinal thickness and visual acuity and correlation between 2 study eyes
a Missing data for 22 eyes in the sham+prompt laser group, 16 eyes in the ranibizumab+prompt laser group, 13 in the ranibizumab+deferred Laser, and 13 eyes in the triamcinolone+prompt laser group (includes missing and ungradeable data [3 in sham+prompt laser, 2 in ranibizumab+deferred laser and 2 in triamcinolone+prompt laser]

39. Change in Retinal Thickening at 2 Years*
Change in OCT Central Subfield Thickeninga
Sham
+Prompt Laser
N = 152
Ranibizumab
N = 99
+Deferred Laser
N = 100
Triamcinolone
+Prompt
Laser
N = 93
Mean change from baseline (µm)
-133
-144
-170
-95
Difference in mean change from Sham + Laser [P Value]**
-31
[P = 0.01]
-36
[P = 0.004] -3
[P = 0.81]
Thickness <250 µm with at least a 25 µm decrease from baseline
38%
54%
55%
44%
*Visits occurring between 616 and 840 days from randomization were included as 2-year visits. When more than 1 visit occurred in this window, data from the visit closest to the 2-year target date were used.
** Analysis of covariance adjusted for baseline OCT retinal thickness and visual acuity and correlation between 2 study eyes
ª Excluding pending- Missing data for 2 eyes in the sham+prompt laser group, 2 eyes in the ranibizumab+prompt laser group, 2 in the ranibizumab +deferred laser, and 6 eyes in the triamcinolone+prompt laser group; Ungradeable data for 1 in the ranibizumab+prompt laser, 1 in ranibizumab+deferred laser and 2 in triamcinolone+prompt laser

40. Comparison of Visual Acuity and OCT Central Subfield Thickness
Mean Change in Visual Acuity
≥2 Step Improvement in Log OCT
UPDATED

41. Retinopathy

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 = 0.08
P =0.17
Baseline Severity: Severe NPDR or worse
N = 83
N = 121
N = 70
19%
28%
13% 8% 1%
P = 0.03
P = 0.17 42
*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 42

43. Retinopathy Progression During 1 Year of Follow-up
Sham
N = 293
Ranibizumab
N = 375
Triamcinolone
N = 186
Reported vitreous hemorrhage OR received PRP 8% 3%
P Value for comparison with sham --
0.002
0.02
Eyes assigned to the ranibizumab groups or the triamcinolone+prompt laser groups, respectively, appeared less likely to have a vitreous hemorrhage or receive panretinal photocoagulation than the sham+prompt laser group (3% [P=0.002] and 3% , [P=0.02] respectively vs. 8%) during the first year of follow up.

44. Safety

45. Major Ocular Adverse Events During 2-Years of Follow-up
Sham
+Prompt Laser
N = 293
Ranibizumab
+Prompt Laser
N = 187
+Deferred Laser
N = 188
Triamcinolone
+Prompt Laser
N = 186
Number of injections
1833
2140
685
Endophthalmitis*
1 (<1%)
2 (1%)
Pseudoendophthalmitis†
1(<1%)
1 (1%)
Ocular vascular event‡
3 (2%)
Retinal detachment§
Vitrectomy
15 (5%)
4 (2%)
7 (4%)
Vitreous Hemorrhage
27 (9%)
6 (3%)
8 (4%)
When fundus photographs of 10 of the 12 eyes (2 eyes did not have photographs) that received ranibizumab with at least a 10 letter loss at the one year study visit were reviewed, there was no obvious evidence of macular capillary non-perfusion as the cause of visual acuity loss.
VA data for 3 related Endophthalmitiis cases:
Group B Baseline VA=75; 1 year VA=63; 2 year VA=69; lowest VA score=28 at 8 week visit highest VA score baseline (site 89)
Group C Baseline VA=69; 1 year VA=77; lowest VA score= 69 at baseline ; highest VA Score 90 at 48 week visit (site 89)
Group C Baseline VA=70; 1 week safety VA=0; 1 week was last visit (site 191)
VA data for 1 traction retinal detachment case:
Visual acuity had remained stable (within 5 letters) of the baseline visual acuity letter score of 66 (20/50) while ranibizumab was given every 4 weeks through the 24-week visit when focal/grid laser also was applied. Ranibizumab again was given at the 28-week visit and five weeks later, sudden vision loss was reported and a table top detachment involving the central macula was noted at an unscheduled visit with a visual acuity letter score of 48 (20/125). Vitrectomy surgery was delayed for several weeks because of other medical problems; following surgery, the visual acuity letter score remained 0 (<20/800).
*One case unrelated to study drug injection (following cataract extraction) in the sham+prompt laser group; 1 case related to study drug injection and 1 case unrelated to injection (following cataract surgery) in the ranibizumab+prompt laser group; 2 cases related to study drug injection in the ranibizumab+deferred laser group. The 3 cases related to study drug injection in the ranibizumab groups are 0.08% of ranibizumab study drug injections given.
† One case unrelated to the study drug injection (vitreous opacity with hypopyon) and one case related to study drug injection in the triamcinolone group.
‡ Includes 2 central retinal vein occlusions and 4 branch retinal vein occlusions.
§Includes 1 traction retinal detachment with proliferative diabetic retinopathy and prior panretinal photocoagulation at baseline. 45 45

46. Elevated Intraocular Pressure/Glaucoma During 2-Years of Follow-up
Sham
+Prompt
Laser
N = 293
Ranibizumab +Prompt Laser
N = 187
Ranibizumab
+Deferred Laser
N = 188
Triamcinolone +Prompt Laser
N = 186
Increase ≥10 mmHg from baseline 8% 9% 6%
42%
IOP ≥30 mmHg 3% 2%
27%
Initiation of IOP-lowering meds at any visit* 5%
28%
Number of eyes meeting ≥1 of the above
11% 7%
50%
Glaucoma surgery**
<1% 1%
Similar results observed in pseudophakic eyes (11%, 18%, 9%, and 50%)
*Excludes eyes with IOP lowering medications at baseline
**Includes 2 filter and 2 cilliary body destruction 46 46

47. Cataract Surgery During 2-Years of Follow-up
Sham
+Prompt
Laser
Ranibizumab
+Deferred Laser
Triamcinolone
+Prompt Laser
Phakic at baseline
N = 192
N = 131
N = 134
N = 124
Eyes that had cataract surgery
12%
13%
55% 47 47

48. Cumulative Probability of Cataract Surgery Over 2-Years
59%
P <0.001 for both Ran and Tri comparisons to Sham
14%
14% 4 8 12 16 20 24 48

49. Number of Deaths Sham N = 130 Ranibizumab N = 375 Triamcinolone
7 (5%)
15 (4%)
6 (3%)
*Study participants with 2 study eyes are counted in their injection group.

50. Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’ Collaboration through 2-Years
Sham‡
N* = 130
Ranibizumab
N* = 375
Triamcinolone
N* = 186
Non-fatal myocardial infarction 3% 1%
Non-fatal cerebrovascular accident-ischemic or hemorrhagic (or unknown) 6% 2%
Vascular death (from any potential vascular or unknown cause†) 5%
Any APTC event
12%
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.
‡One participant had a non-fatal myocardial infarction and a non-fatal stroke (only counted once in the any cardiovascular event row)
†Four of the vascular deaths in the sham group, 1 of the vascular deaths in the ranibizumab group, and 1 of the vascular deaths in the triamcinolone group were from an unknown cause 50 50

51. Discussion

52. Intravitreal Ranibizumab Summary
Intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser had superior VA and OCT outcomes compared with focal/grid laser treatment alone.
~50% of eyes had substantial improvement (≥10 letters) while ~30% gained ≥15 letters
Substantial visual acuity loss (≥10 letters) was uncommon
Results were similar whether focal/grid laser was given starting with the first injection or it was deferred >24 weeks 52 52

53. Intravitreal Ranibizumab Summary
If ranibizumab is to be given as it was in this study, the data indicate a need to follow eyes continuously undergoing this treatment
Additional ranibizumab and/or laser were needed in most eyes through ≥2 years, even if ‘success’ criteria were met early in the course of treatment. 53 53

54. Intravitreal Ranibizumab Treatment Protocol
Results are based on rigorous adherence to a detailed retreatment protocol on a web-based real-time data entry system that provided feedback to the treating physician regarding the treatment to be prescribed at each follow-up visit.
The underlying rationale of the treatment algorithm is to continue treatment, as needed, until stabilization or lack of further improvement is noted. 54 54

55. Intravitreal Ranibizumab Treatment Protocol
Once a retreatment is withheld, the algorithm is designed to identify when there is a need to re-initiate treatment.
The goal was to avoid substantial vision loss while also avoiding a regimen which requires monthly treatments regardless of the clinical course.
The impact of different retreatment approaches or use of other anti-VEGF drugs (such as bevacizumab) in clinical practice cannot be determined from this study. 55 55

56. Intravitreal Ranibizumab Conclusion
Ranibizumab as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. 56 56

57. Intravitreal Triamcinolone Summary
Intravitreal triamcinolone combined with focal/grid laser did not result in superior VA outcomes compared with laser alone.
Intravitreal triamcinolone did result in a greater reduction in retinal thickening at 1 year but not 2 years compared with laser alone.
In an analysis limited to pseudophakic eyes, the triamcinolone group’s outcome for VA appeared to be of similar magnitude to that of the 2 ranibizumab groups.
IOP results for pseudophakic eyes in Group D were similar to IOP in overall cohort. Among the subgroup of 62 pseudophakic eyes at baseline in the triamcinolone+prompt laser group, 30 (48%) had one or more of the ocular hypertension events described above, compared with 10 (10%) and 15 (14%) among the 101 and 110 pseudophakic eyes at baseline in the sham+prompt laser and ranibizumab groups, respectively. 57 57 57

58. Intravitreal Triamcinolone Conclusion
In pseudophakic eyes, intravitreal triamcinolone with prompt focal/grid laser may be equally effective as ranibizumab at improving visual acuity and reducing retinal thickening, but is associated with an increased risk of intraocular pressure elevation.
IOP results for pseudophakic eyes in Group D were similar to IOP in overall cohort. Among the subgroup of 62 pseudophakic eyes at baseline in the triamcinolone+prompt laser group, 30 (48%) had one or more of the ocular hypertension events described above, compared with 10 (10%) and 15 (14%) among the 101 and 110 pseudophakic eyes at baseline in the sham+prompt laser and ranibizumab groups, respectively. 58 58 58

59. Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)
52 clinical study sites
Study participants who volunteered to participate in this trial
DRCR.net Data and Safety Monitoring Committee
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.
DRCR.net investigators and staff 59

60. Additional Slides 60 60

61. Study Enrollment and Completion
854 study eyes (691 study participants) from 52 clinical sites
Treatment Groups
Sham+prompt laser: N= 293
Ranibizumab+prompt laser group: N= 187
Ranibizumab+deferred laser: N= 188
Triamcinolone+prompt laser: N= 186
1 year visit completion rate* = 95%
Including deaths = 94%
2 year visit completion rate† = 91%
Including deaths = 87%
*1-year analysis window +/- 8 weeks; N=799 completed of 841 (Excludes deaths)
† 2-year analysis window +/- 16 weeks; N=484 completed of 534 (Excludes deaths, pending, and dropped participants who are not yet in window)

62. Study Enrollment and Completion
Eyes Randomized: N = 854
(691 Participants)
Sham
+Prompt Laser
N = 293
Ranibizumab
+Prompt Laser
N = 187
Ranibizumab
+Deferred Laser
N = 188
Triamcinolone
+Prompt Laser
N = 186
1 Year Visit
Completed=274 (94%)
Completed=171 (91%)
Completed=178 (95%)
Completed=176 (95%)
Pending=91
Pending=56
Pending=55
Pending=63
Completed=163
Completed=106
Completed=112
Completed=103
2 Year Visit

63. Protocol B: VA and OCT CSF Results at 1 and 2 Years
Laser
1 mg
4 mg
Change in VA at 1 Year
N = 286
N = 230
N = 221
Mean change from baseline (letters) +1
Change in VA at 2 Years (primary outcome)
N = 272
N = 220
N = 204 +2 -2 -4
Change in OCT CSF at 1 Year
N = 278
N = 225
N = 213
Mean change from baseline (microns)
-98
-55
-93
Change in OCT CSF at 2 Years
N = 178
N = 162
-139
-86
-77
Comparison of protocol B primary VA/OCT results to the protocol I results
LOCF 2 year results are +1 for laser, -2 for 1mg, and -4 for 4 mg 63 63

64. Protocol I: VA and OCT CSF Results at 1 and 2 Years
Sham
+Prompt
Laser
Ranibizumab
+Deferred
Triamcinolone
Change in VA at 1 Year (LOCF)
N = 293
N = 187
N = 188
N = 186
Mean change from baseline (letters) +3 +9 +4
Change in VA at 2 Years
N = 163
N = 106
N = 112
N = 103 +2 +7
+10
Change in OCT CSF at 1 Year
N = 271
N = 171
N = 175
N = 173
Mean change from baseline (microns)
-102
-131
-137
-127
Change in OCT CSF at 2 Years
N = 152
N = 99
N = 100
N = 93
-133
-144
-170
-95
Comparison of protocol B primary VA/OCT results to the protocol I results
The mean change (not LOCF) for 1 year is +3 in Sham, +9 in Ran+Prompt, +10 in Ran +Deferred, +4 in Triamconolone 64 64

65. Additional Information on Injections/Sham Prior to 1 Year
+Prompt
Laser
N = 274
Ranibizumab
N = 171
+Deferred
N = 178
Triamcinolone
N = 176
Success criteria* at 16-week study visit and no injection
31 (11%)
47 (25%)
41 (22%)
38 (20%)
No more injections through 1 year of 16-week successes*†
13 (42%)
17 (36%)
15 (37%)
10 (27%)
% of eyes meeting success criteria* at 1-year study visit
32%
64%
52%
56%
% of eyes with letter score >84 (~>20/20) at 1-year study visit 8%
13%
11%
*VA letter score ≥84 (~20/20 or better) or OCT CSF <250 microns
†Excludes 56 eyes among 163 participants with two study eyes unmasked at baseline when assigned ranibizumab+deferred laser

66. Additional Information On Injections/Sham to 2 Years
+Prompt
Laser
N = 274
Ranibizumab
N = 171
+Deferred
N = 178
Triamcinolone
N = 176
% of eyes meeting failure criteria* at 1-year study visit 4% 2% 1%
Maximal # of drug injections prior to 2 years
n/a 25 8
Median drug injections prior to 1 year 9 3
Median drug injections prior to 2 years 11 13 4
* Failure is defined as: VA 10 or more worse than baseline, OCT CSF ≥250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND ≥13w since last laser treatment with no improvement since the last laser treatment

67. Injection Protocol up to 48-Week Visit
Treatment
Injection Protocol up to 48-Week Visit
All subjects are given an injection/sham* on the day of randomization
Every group receives an injection/sham* at each 4-week interval visit through the 12-week visit
At 16 and 20-week visits, injection/sham* is at investigator discretion if visual acuity ≥84 or OCT CSF <250
Between 24 and 48 weeks, the study eye is evaluated using retreatment criteria† at each 4-week interval visit for injection/sham*
†The retreatment criteria for evaluation: 1) reinjection with randomized treatment at investigator discretion if VA>84 or OCT CSF <250; 2) injection if VA<84 and evidence of improvement (OCT CSF thickness decreased by 10% or more OR VA improved 5 or more letters); 3) treated at investigator discretion if failure criteria‡ met; 4) reinjection with randomized treatment at investigator discretion if failure criteria not met but no evidence of improvement.
‡Failure is defined as: VA 10 or more worse than baseline, OCT CSF >=250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND ≥13w since last laser treatment with no improvement since the last laser treatment
*Both ranibizumab groups receive true injection. Sham group receives sham injection. Triamcinolone group receives: true injection if one has not been given in the prior 15 weeks, sham otherwise.
†The retreatment criteria for evaluation: 1) reinjection with randomized treatment at investigator discretion if VA>84 or OCT CSF <250; 2) injection if VA<84 and evidence of improvement (OCT CSF thickness decreased by 10% or more OR VA improved 5 or more letters); 3) treated at investigator discretion if failure criteria‡ met; 4) reinjection with randomized treatment at investigator discretion if failure criteria not met but no evidence of improvement.

68. Injection Protocol at and After 1-Year Visit
Treatment
Injection Protocol at and After 1-Year Visit
Sham injections are discontinued for Groups A and D
For Groups B and C, the study eye is evaluated for ranibizumab injection using retreatment criteria at each 4-week interval visit
For Group D, the study eye is evaluated for triamcinolone injection using retreatment criteria at each 16-week interval visit
 †The retreatment criteria for evaluation: 1) reinjection with randomized treatment at investigator discretion if VA>84; 2) injection if VA<84 and evidence of improvement (OCT CSF thickness decreased by 10% or more OR VA improved 5 or more letters); 3) treated at investigator discretion if failure/futility criteria‡ met; 4) reinjection with randomized treatment at investigator discretion if failure criteria not met but no evidence of improvement.
‡Failure/futility is defined as: VA letter score <84, OCT CSF >=250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND either 1) ≥13w since last laser treatment with no improvement since the last laser treatment and VA 10 or more worse than baseline OR 2) ≥ 29w since last laser with no improvement since the last laser treatment

69. Treatment Laser Protocol
The 3 non-deferral groups (ranibizumab, triamcinolone, and sham) receive initial laser 3-10 days after the baseline injection
Retreatment is given 3 to 10 days after each injection (or at the time of visit if an injection is not given) unless laser already given within 13 wks, maximum laser already given, or CSF <250
The ranibizumab + deferred laser group does not receive laser prior to 24 weeks
At 24-week or later visits, laser is given if CSF decreased <10% (or increased) and VA improved <5 (or worsened) from the last 2 consecutive injections and between the last 2 consecutive injections and macular edema needing laser still present

70. DRCR.net Retreatment Algorithm Flowcharts

71. Intravitreal Injection Treatment at 16 to 48 Weeks (Following 4 Intravitreal or Sham Injections Every 4 Weeks Through Week 12)
*Failure/futility is defined as: Visual acuity letter score <84 (~20/20), OCT central subfield ≥250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND either 1) ≥13 weeks since last laser treatment with no improvement since the last laser treatment and visual acuity 10 or more letters worse than baseline, OR 2) >29 weeks since last laser with no improvement since the last laser treatment.
†Improvement is defined as: OCT central subfield thickness decreased by ≥10% or visual acuity letter score improved by ≥5.

72. Treatment at and after the 52-Week Follow-Up Visit
SHAM+PROMPT LASER GROUP (A)
*Failure/futility is defined as: Visual acuity letter score <84 (~20/20), OCT central subfield ≥250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND either 1) ≥13 weeks since last laser treatment with no improvement since the last laser treatment and visual acuity 10 or more letters worse than baseline, OR 2) >29 weeks since last laser with no improvement since the last laser treatment.
†Improvement is defined as: OCT central subfield thickness decreased by ≥10% or visual acuity letter score improved by ≥5.
±Note: In general an injection should be given if there is edema to treat.
§ Complete laser: Direct treatment to all microaneurysms within areas of macular edema and grid treatment to all other areas of macular edema.
¥Edema threatening the center of the macula: Edema on clincal exam within 500 microns of the foveal center or edema associated with lipid within 500 microns of the foveal center of 1 disc area of edema within 1 disc area of the foveal center.

73. Treatment at and after the 52-Week Follow-Up Visit
RANIBIZUMAB+PROMPT LASER GROUP (B)
*Failure/futility is defined as: Visual acuity letter score <84 (~20/20), OCT central subfield ≥250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND either 1) ≥13 weeks since last laser treatment with no improvement since the last laser treatment and visual acuity 10 or more letters worse than baseline, OR 2) >29 weeks since last laser with no improvement since the last laser treatment.
†Improvement is defined as: OCT central subfield thickness decreased by ≥10% or visual acuity letter score improved by ≥5.
±Note: In general an injection should be given if there is edema to treat.
§ Complete laser: Direct treatment to all microaneurysms within areas of macular edema and grid treatment to all other areas of macular edema.
¥Edema threatening the center of the macula: Edema on clincal exam within 500 microns of the foveal center or edema associated with lipid within 500 microns of the foveal center of 1 disc area of edema within 1 disc area of the foveal center.

74. Treatment at and after 52 Week Follow-Up Visit
RANIBIZUMAB+DEFERRED LASER GROUP (C)
*Failure/futility is defined as: Visual acuity letter score <84 (~20/20), OCT central subfield ≥250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND either 1) ≥13 weeks since last laser treatment with no improvement since the last laser treatment and visual acuity 10 or more letters worse than baseline, OR 2) >29 weeks since last laser with no improvement since the last laser treatment.
†Improvement is defined as: OCT central subfield thickness decreased by ≥10% or visual acuity letter score improved by ≥5.
±Note: In general an injection should be given if there is edema to treat.
§ Complete laser: Direct treatment to all microaneurysms within areas of macular edema and grid treatment to all other areas of macular edema.
¥Edema threatening the center of the macula: Edema on clincal exam within 500 microns of the foveal center or edema associated with lipid within 500 microns of the foveal center of 1 disc area of edema within 1 disc area of the foveal center.

75. Treatment at and after the 52-Week Follow-Up Visit
TRIAMCINOLONE+PROMPT LASER GROUP (D)
*Failure/futility is defined as: Visual acuity letter score <84 (~20/20), OCT central subfield ≥250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND either 1) ≥13 weeks since last laser treatment with no improvement since the last laser treatment and visual acuity 10 or more letters worse than baseline, OR 2) >29 weeks since last laser with no improvement since the last laser treatment.
†Improvement is defined as: OCT central subfield thickness decreased by ≥10% or visual acuity letter score improved by ≥5.
±Note: In general an injection should be given if there is edema to treat.
§ Complete laser: Direct treatment to all microaneurysms within areas of macular edema and grid treatment to all other areas of macular edema.
¥Edema threatening the center of the macula: Edema on clincal exam within 500 microns of the foveal center or edema associated with lipid within 500 microns of the foveal center of 1 disc area of edema within 1 disc area of the foveal center.

76. Laser Treatment at and after the 16-Week Follow-Up Visit
(Following Focal/Grid Laser Treatment at 1 Week in Groups A, B, and D)
*Failure/futility is defined as: Visual acuity letter score <84 (~20/20), OCT central subfield ≥250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND either 1) ≥13 weeks since last laser treatment with no improvement since the last laser treatment and visual acuity 10 or more letters worse than baseline, OR 2) >29 weeks since last laser with no improvement since the last laser treatment.
†Improvement is defined as: OCT central subfield thickness decreased by ≥10% or visual acuity letter score improved by ≥5.
±Note: In general an injection should be given if there is edema to treat.
§ Complete laser: Direct treatment to all microaneurysms within areas of macular edema and grid treatment to all other areas of macular edema.
¥Edema threatening the center of the macula: Edema on clincal exam within 500 microns of the foveal center or edema associated with lipid within 500 microns of the foveal center of 1 disc area of edema within 1 disc area of the foveal center.

77. Visual Acuity Change at 1 Year

78. Visual Acuity ≥10 or ≥15 Letter Improvement or Worsening at 1 Year

79. Visual Acuity Improvement at 1 Year

80. Visual Acuity Loss at 1 Year
N = 293
N = 187
N = 188
N = 186

81. Visual Acuity Improvement at 2 Years

82. Visual Acuity Loss at 2 Years
Change all font to arial
N = 163
N = 106
N = 103
N = 112

83. ≥10 Letter Visual Acuity Improvement/Worsening among Eyes Not Pseudophakic and Eyes that were Pseudophakic at Baseline
Eyes not Pseudophakic at Baseline
Eyes Pseudophakic at Baseline