1. The Diabetic Retinopathy Clinical Research Network
Dedicated to multicenter clinical research of diabetic retinopathy, macular edema and associated conditions
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, EY018817 

2. DRCR.net Overview Objective:
The development of a collaborative network to facilitate multicenter clinical research on diabetic retinopathy, DME and other retinal diseases.
Funding:
National Eye Institute (NEI) and The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-sponsored cooperative agreement initiated September 2002.
Current award

3. Priority Initiatives
Involvement of community-based practices, as well as “academic” or university-based centers.
Collaborate with industry to facilitate investigations and pursue opportunities otherwise not possible and to do so in a manner consistent with the Network’s dedication to academic integrity and optimal clinical trial performance.

4. DRCR.net Status (as of 11/8/16)
Active
Total
Sites
(Community & Academic Centers)
132
318
Community Sites
88 (67%)
204 (64%)
Investigators
423
1183
Other Personnel
1072
4128
States 34 49
Provinces in Canada 5

5. Site Locations

6. How to Join the Network All retina specialists are welcome to apply
Your request will be reviewed and if approved the necessary paperwork will be sent to you

7. How to Submit a Protocol Idea
Go to the public* website: drcr.net
Click on Information for Investigators.
Scroll down to Protocol Idea Form.
form to
It will be reviewed by the Operations Group at the next in-person meeting.
* Forms also available on the study website

8. Protocol Idea Review Process
Semiannual solicitation of protocol ideas from Investigators
Investigators submit ideas to CC.
Network Chair /CC PI conduct initial review for public health importance and potential expedited review.
Operations Group reviews ideas 2x per year for merit and feasibility.
Selected ideas presented to investigators at semiannual meeting
Scientific Advisory Committee
External Individuals
Based on Investigator feedback, ideas are prioritized by EC.
Remind investigators to contribute ideas for PDR studies.
Protocol Idea Review Process
Protocol Development Committee is formed.

9. Completed DRCR.net Protocols

10. DRCR.net Protocols Enrolling or in Follow-up
The exact number of participants is 8,643 as of 3/25/15
Over 9,500 DRCR.net Participants to Date Across 25 Protocols

11. What Has Been Learned? Diabetic Macular Edema Treatment
Protocol A: Although some ophthalmologists considered using a modified macular grid (MMG) photocoagulation technique over the focal photocoagulation technique modified from the ETDRS, this trial showed that at 12 months after treatment, the MMG technique was less effective at reducing OCT measured retinal thickening.
Protocol B: Over 2 years, focal/grid photocoagulation is more effective and has fewer side effects than 1 mg or 4 mg doses of preservative-free intravitreal triamcinolone.
Protocol E: In cases of DME with good visual acuity, peribulbar triamcinolone, with or without focal photocoagulation, is unlikely to be of substantial benefit.
Protocol H: Intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether the treatment was beneficial.

12. What Has Been Learned? Diabetic Macular Edema Treatment
Protocol I: Intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser is more effective through 2 years in increasing visual acuity compared with focal/grid laser treatment alone for the treatment of DME involving the central macula.
Focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better, and possibly worse, for vision outcomes than deferring laser treatment for 24 weeks or more in eyes with DME involving the fovea and with vision impairment.
Protocol K: Sixteen weeks after focal/grid laser for DME in eyes with a definite reduction, but not resolution, of central edema, 23% to 63% likely will continue to improve without additional treatment.

13. What Has Been Learned? Diabetic Macular Edema Treatment
Protocol R: At 1 year in eyes with non-central DME, this study could not identify a difference between topical nepafenac 0.1% and placebo on OCT parameters or visual acuity.
Protocol T*: The 2-year clinical trial compared 3 drugs for diabetic macular edema (DME) and found that gains in vision were greater for participants receiving the drug aflibercept than for those receiving bevacizumab, but only among participants starting treatment with 20/50 or worse vision. At one year aflibercept had superior gains to ranibizumab in this vision subgroup, however a difference could not be identified at 2 years. The 3 drugs yielded similar gains in vision for patients with 20/32 or 20/40 vision at the start of treatment.
*Results appear later in presentation

14. What Has Been Learned? Diabetic Retinopathy Treatment
Protocol F: Results suggest clinically meaningful differences are unlikely in OCT thickness or visual acuity following application of PRP in 1 sitting compared with 4 sittings.
Protocol J: The addition of 1 intravitreal triamcinolone injection or 2 intravitreal ranibizumab injections in eyes receiving focal/grid laser for DME and PRP is associated with better visual acuity and decreased macular edema by 14 weeks. Whether continued long-term intravitreal treatment is beneficial could not be determined from this study.

15. What Has Been Learned? Diabetic Retinopathy Treatment
Protocol N: The study suggested little likelihood of a clinically important difference between ranibizumab and saline on the rate of vitrectomy by 16 weeks in eyes with vitreous hemorrhage from PDR. Short-term secondary outcomes including visual acuity improvement, increased panretinal photocoagulation completion rates, and reduced recurrent vitreous hemorrhage rates suggest biologic activity of ranibizumab. Long-term benefits remain unknown.
Protocol S*: This study showed that ranibizumab injections are effective in treating proliferative diabetic retinopathy. At two years, vision of the ranibizumab group on average improved by half a line on an eye chart. Vision of the laser group remained unchanged.
*Results appear later in presentation

16. What Has Been Learned? OCT and Retinal Thickening
Protocol C: Although on average there are slight decreases in retinal thickening during the day, most eyes with diabetic macular edema have little meaningful change in OCT central subfield thickening or visual acuity between 8 AM and 4 PM.
Protocol C: Reproducibility of retinal thickness in DME was better for central subfield thickness measurements than for center point measurements. A change in central subfield thickness exceeding 11% is likely to be real.
Protocol G: While subclinical DME may be uncommon, this study suggests that between approximately one-quarter and one-half of eyes with subclinical DME will progress to more definite thickening or be judged to need treatment for DME within 2 years after its identification.

17. What Has Been Learned? Optical Coherence Tomography
Protocol G: CST (central subfield thickness) on Stratus OCT™ in people with diabetes and minimal or no retinopathy are similar to thicknesses reported from a normative database of people without diabetes. CST is greater in men than in women. Studies involving comparisons of retinal thickness to expected norms should consider different mean values for women and men.
Protocol O: Mean CST is ~70 µm thicker when measured with Heidelberg Spectralis OCT as compared with Stratus OCT among individuals with diabetes in the absence of retinopathy or with minimal non-proliferative retinopathy and a normal macular architecture.  CST values ≥320 µm for men and 305 µm for women are proposed as gender-specific thickness levels.

18. What Has Been Learned? Optical Coherence Tomography
Protocol O: Conversion equations may be used to transform CSF values obtained on a SD-OCT to a TD scale for group comparisons. However, the CST conversion equations do not appear to predict TD values for an individual accurately enough to warrant use of these conversion equations confidently in clinical decision-making at the patient level.

19. Recently Published Results

20. Aflibercept, Bevacizumab, or Ranibizumab for DME: Two-year Results
Protocol T
Aflibercept, Bevacizumab, or Ranibizumab for DME: Two-year Results 20

21. Randomized, multi-center clinical trial (89 Sites)
Study Design
Randomized, multi-center clinical trial (89 Sites)
Participants meeting all of the following criteria:
At least 18 years old
Type 1 or type 2 diabetes
Study eye meeting all of the following criteria:
~Snellen equivalent visual acuity 20/32 or worse and 20/320 or better
Central-involved DME on clinical exam
Central subfield thickness (CST) ≥ protocol-defined gender and optical coherence tomography (OCT) machine-specific thresholds
No history of an anti-VEGF treatment for DME in the past 12 months or any other DME treatment in the past 4 months

22. Main Outcome
Change in visual acuity at 1 and 2 years adjusted for baseline visual acuity using the intent-to-treat principle
Aflibercept
vs.
Bevacizumab
Aflibercept
vs.
Ranibizumab
Bevacizumab
vs.
Ranibizumab
Visits were every 4 weeks during year-1 and 4 to 16 weeks during year-2, depending on treatment course
Starting at the 6-month visit, focal/grid laser treatment was administered if DME persisted and was not improving
Participants unmasked to treatment group following the publication of the primary results: though discouraged, decision could be made at that time to switch to a non-study anti-VEGF agent.
Doses: aflibercept 2.0-mg; bevacizumab 1.25-mg; ranibizumab 0.3-mg

23. Conclusions
Vision gains at 2 years were seen in all 3 groups with ~half the number of injections, slightly decreased frequency of visits, and decreased amounts of laser in the 2nd year
Among eyes with better VA no differences in 2-year vision outcomes identified
Among eyes with worse baseline VA:
Aflibercept, on average, had superior 2-year VA outcomes compared with bevacizumab, although the difference was diminished
The VA difference between aflibercept and ranibizumab that was noted at 1 year had decreased at 2 years.
The implication of the increased rate of APTC events with ranibizumab found in the current study is uncertain due to inconsistency with prior trials, warranting continued evaluation

24. For the full presentation of results click here.

25. DRCR.net Prompt PRP vs Ranibizumab+Deferred PRP for PDR Study
Protocol S
DRCR.net Prompt PRP vs Ranibizumab+Deferred PRP for PDR Study

26. 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

27. Study Design Randomized, multi-center clinical trial
(N = 305 patients, 394 eyes, 55 Sites)
Study eye meeting all of the following criteria – (note: 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

28. Conclusions
Ranibizumab injections for Proliferative Diabetic Retinopathy ….
No worse than (not inferior to) PRP for visual acuity at 2 years
Superior vision over the course of 2 years (area under the curve)
Reduces the incidence of DME
Less peripheral VF loss
Fewer vitrectomies
No major safety differences from PRP identified except one case of endophthalmitis

29. 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
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

30. For the full presentation of results click here.

31. Active Studies
Image: National Eye Institute, National Institutes of Health

32. Protocols Currently Enrolling

33. Protocol AB Intravitreous Anti-VEGF vs. Vitrectomy
for Vitreous Hemorrhage from PDR

34. Study Objectives
Compare visual acuity outcomes over time for the following two treatment regimens:
Prompt Vitrectomy + PRP
Intravitreous Anti-VEGF injections
in eyes presenting with vitreous hemorrhage from PDR causing vision impairment for which intervention is deemed necessary. 34

35. Proposed Study Design
Multi-Center Randomized Clinical Trial
At least one eye that meets the following criteria:
Vitreous hemorrhage
causing vision impairment,
presumed to be from PDR, and
requiring intervention (vitrectomy or anti-VEGF)
Vitrectomy +
PRP
Anti-VEGF
Primary Outcome: Visual Acuity AUC over 6 months
Sample Size: 200 eyes 35

36. Additional Eligibility Criteria
Visual acuity 20/32 or worse and at least light perception
Investigators should use particular caution when considering an eye with visual acuity 20/32 to 20/40 to ensure that the need for vitrectomy and its associated potential benefits outweighs the potential risks
No anti-VEGF treatment within 2 months prior to vitreous hemorrhage onset
No prior vitrectomy
Note: Prior PRP is not a requirement nor an exclusion
No RRD, no TRD involving or threatening the fovea

37. Secondary Outcomes Treatment Group Comparisons
Mean visual acuity at annual visits
Visual acuity Area Under the Curve (AUC) at 12 and 24 months
Percent 20/20 and 20/40 or better at annual visits
Percent 20/200 or worse at annual visits
Rates of recurrent VH on clinical exam
Difference in productivity from WPAI questionnaire
Treatment and follow-up costs

38. Additional Outcomes of Interest
Vitrectomy Group Outcomes
Percent requiring repeat vitrectomy
Rates of post-surgical complications
Retinal detachment/tear
Cataract/cataract surgery
Anti-VEGF Group Outcomes
Number of injections performed
Percent requiring vitrectomy
Percent requiring PRP

39. Study Treatment Overview
Anti-VEGF Group
Follow-up injections every 4 weeks according to protocol criteria and no PRP unless failure criteria are met
Vitrectomy only permitted prior to 16 weeks if criteria for rescue treatment met:
TRD threatening or involving the macula
Rhegmatogenous retinal detachment
NVG, NVA, progressive NVI, or ghost cell glaucoma
After 16 weeks, vitrectomy may be performed if persistent VH after 2 consecutive 4-week injections 39

40. Anti-VEGF Group
Monthly Injections
At least 2 monthly injections to start and then as needed for VH/PDR
Vitrectomy
After 4 months, vitrectomy may be performed for non-clearing hemorrhage
PRP
If injections not enough to adequately treat the PDR, PRP may be given

41. Study Treatment Overview
Vitrectomy Group
Vitrectomy scheduled within 2 weeks of randomization
Performed according to surgeon’s usual routine including +/-:
Pre-op intravitreous anti-VEGF
Removal of the internal limiting membrane
Use of agents to improve visualization of membranes
Use of intraoperative corticosteroids
Cataract extraction
PRP during surgery is required, unless it is determined to already be “complete”
Anti-VEGF will be permitted during follow-up in certain cases for recurrent hemorrhage
NMB: Why is PRP required at not at investigator discretion?? 41

42. Vitrectomy Group
Vitrectomy
Injections
Cataract Surgery
PRP
Injections during follow-up if needed for recurrent hemorrhage
If cataract becomes visually significant

43. Protocol W
Intravitreous Anti-VEGF Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk

44. Primary (Short-term) Objective
To determine safety and efficacy of
anti-VEGF versus observation in eyes presenting with severe NPDR and no CI-DME for prevention of vision threatening outcomes (DME or PDR)
Observation (sham injections)
Intravitreous anti-VEGF
Primary outcome: Proportion of eyes that develop PDR/PDR-related outcomes or center-involved DME causing visual acuity loss by 2 years 44

45. Rationale
The application of anti-VEGF therapy earlier in the course of disease could help to reduce future potential treatment burden in patients, at the same time resulting in similar or better long-term visual acuity outcomes.
If this study demonstrates that anti-VEGF treatment is effective and safe in the setting of severe NPDR, a new strategy to prevent vision-threatening complications will be available for patients.

46. Composite Primary Outcome: Part 1 – PDR
Development of NV within the 7 modified ETDRS fields on fundus photography or FA, confirmed by Reading Center, or…
NVI, NVA, or NVG on clinical exam, or…
Traction retinal detachment, vitreous hemorrhage, or pre-retinal hemorrhage presumed to be from PDR, documented on fundus photography or FA, or…
PRP, anti-VEGF, or vitrectomy for PDR, images should be obtained prior to treatment 46

47. Composite Primary Outcome: Part 2 – DME
Center-involved DME on clinical exam with ≥10% increase in central subfield thickness from baseline and visual acuity loss from DME
Treatment for DME performed without meeting above criteria (protocol deviation)
Note: An eye will be considered to have met the primary outcome if any one of the above PDR or DME criteria are met

48. Major Inclusion/Exclusion Criteria in Study Eye
Severe NPDR (ETDRS level 53) according to investigator
4-2-1 rule
Severe hemorrhages in at least 4 midperipheral quadrants, or
Definite venous beading in at least 2 quadrants, or
Moderate IRMA in at least 1 quadrant
VA letter score 20/25 or better
No CI-DME using standard OCT thresholds
No history of DME/DR treatment in prior 12 months and <4 prior injections at any time
No prior PRP 48

49. Follow-Up and Treatment Overview
Total duration: 4 years
Primary outcome: 2 years for anatomic outcome – if anatomic benefit through 2 years, continue follow-up through 4 years to determine if VA benefit too
Visits at 1, 2, and 4 months; every 4 months thereafter
Injections (intravitreous or sham) required at each of the above visits through 2 years
Thereafter, evaluate at each visit for retreatment:
If eye is “Mild NPDR” or better, defer injection
If “Moderate NPDR” or worse, injection is required

50. Genes in Diabetic Retinopathy Project
Genetics
Genes in Diabetic Retinopathy Project

51. Genes in Diabetic Retinopathy Project
Objective
To create a repository of genetic material and clinical phenotype information as a resource for the research community
The database may provide the opportunity to assess genetic susceptibility and resistance to DR and also variants impacting visually-important biomarkers for ME and neovascularization.
Major Eligibility Criteria
Previous/current participant in a DRCR.net study
Enrollment (Ongoing)
Total enrolled: 1,976 subjects (as of 11/8/16)

52. Not Enrolling Currently in Follow-up

53. Protocol V Treatment for Central-involved DME in Eyes with Very Good Visual Acuity

54. Study Design Randomized, multi-center clinical trial
At least one eye meeting all of the following criteria:
Central-involved DME on OCT (Cirrus/Spectralis only)*
VA letter score 20/25 (Snellen equivalent) or better*
Minimal prior treatment for DME **
Prompt
anti-VEGF
Prompt laser + deferred anti-VEGF
Observation + deferred anti-VEGF
Primary outcome: Proportion of eyes that have lost ≥5 letters of VA at 2 years
*Confirmed at 2 visits (screening and randomization 1-28 days apart)
**No more than 1 laser and/or 4 injections, at least 12 months ago

55. Outcome Measures Primary Outcome Secondary Outcomes
% with VA loss of ≥ 5 letters at 2 years
Secondary Outcomes
Mean change in VA letter score
% with at least 10 and 15 letter VA gain/loss
Visual acuity area under the curve
Mean change in OCT CSF thickness
% with 1 or 2 log step gain or loss on OCT
Number of injections/lasers performed
Worsening/improvement of DR severity level
Low contrast visual acuity
Safety outcomes 55

56. Major Eligibility Criteria
Type 1 or 2 diabetes
Study Eye:
Central-involved DME on clinical exam, confirmed on OCT at two consecutive visits (1-28 days apart)
VA letter score >79 (~20/25 or better) at two consecutive visits (1-28 days apart)
The investigator is comfortable with the eye being randomized to any of the three treatment groups
Minimal history of prior DME treatment
No more than 1 laser, 4 injections at least 12 months ago
Non-study eye:
Investigator must be willing to use (or switch to using) study aflibercept on the non-study eye if needed 56

57. Major Exclusion Criteria
Systemic
History of chronic renal failure requiring dialysis or kidney transplant
Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months
BP > 180/110
Study eye
Macular edema not due to DME (eyes with thickening due to ERM, prior cataract surgery or other non-DME reason should not be enrolled)
PRP in last 4 months or anticipated in next 6 months
History of intravitreal anti-VEGF for an ocular condition other than DME in last 6 months or anticipated in next 6 months

58. Follow-Up Schedule Total follow-up through 2 years
Visit schedule will vary by treatment group and disease progression
Prompt anti-VEGF group: visits every 4 weeks through 24 weeks, then every weeks depending on whether injections are being given
Deferred groups (observation and laser groups): visits at 8 and 16 weeks, then every 16 weeks unless vision and/or OCT are worsening or anti-VEGF is initiated
All participants will have visits at 1 and 2 years

59. Protocol U
Short-term Evaluation of Combination Corticosteroid+Anti-VEGF Treatment for Persistent CI-DME Following Anti-VEGF Therapy

60. Objectives
To assess short-term effects of combination corticosteroid+anti-VEGF therapy on OCT retinal thickness and visual acuity in comparison with that of continued anti-VEGF therapy alone in eyes with persistent DME and visual acuity impairment despite previous anti-VEGF treatment.
To provide more information needed for future conduct of a definitive phase III clinical trial.
Not confirmatory; definitive

61. Study Design
Phase II, multicenter, controlled, participant-masked, clinical trial
Duration of Follow-up
Run-in Phase
12 Weeks
Randomized Phase
24 Weeks
Explain in words, rationale for run-in phase
Purpose
To ensure that enrolled eyes truly have “persistent DME” with decreased visual acuity despite prior anti-VEGF therapy.

62. Randomization Phase (6 months)
Study Overview
Week 0
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
SHM
SHM
VGF
VGF
VGF
VGF
VGF
VGF
Week 0
Week 4
Week 8
Week 12
Week 0
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Group A: Sham + Ranibizumab
VGF
VGF
VGF
Assess Eligibility For
Randomization
Group B: Dexamethasone+ Ranibizumab
Enrollment
VGF
VGF
VGF
VGF
VGF
VGF
Dex
Dex
Run-In Phase (3 months)
Randomization Phase (6 months)

63. Major Eligibility Criteria
Age ≥18 years
Type 1 or type 2 diabetes
At least 1 eye meeting study eye eligibility criteria
No history of chronic renal failure requiring dialysis or kidney transplant
BP <180/110
No history of cardiac event
or stroke within 1 month
prior to enrollment

64. Major Study Eye Eligibility Criteria
At least 3 injections of anti-VEGF drugs (aflibercept, bevacizumab, or ranibizumab) within the prior 20 weeks (5 months)
Visual acuity letter score ≤78 and ≥24 (20/32 to 20/320)
Central-involved DME on clinical exam
OCT CSF thickness above gender and OCT-machine specific thresholds:
Zeiss Cirrus: ≥290 in women; ≥305 in men
Heidelberg Spectralis: ≥305 in women; ≥320 in men
No previous history of glaucoma or steroid intraocular pressure response in either eye

65. Efficacy Outcomes at 24 Weeks
Primary:
Mean change in visual acuity letter score adjusted for baseline (randomization)
Secondary:
Visual Acuity
% of eyes with ≥10 and ≥15 letter increase or decrease
Area under the curve (AUC) from baseline
OCT
Change in CSF thickness adjusted for baseline
% ≥2 logOCT step gain or loss in CSF
CSF thickness < spectral-domain value equivalent to 250 microns on Zeiss Stratus
AUC from baseline
Diabetic Retinopathy worsening or improvement on clinical exam

66. Protocol AA Peripheral Diabetic Retinopathy (DR) Lesions on Ultrawide-field Fundus Images and Risk of DR Worsening Over Time

67. Objectives Primary objective
To assess whether evaluation of the retinal far periphery on UWF images improves our ability to assess DR and predict rates of DR worsening over time as compared with evaluation only of the area within the 7 standard ETDRS fields.
Please define predominance as a footnote or asterisk

68. Study Design Prospective, observational longitudinal study
At least one eye meeting all of the following criteria:
NPDR based on clinical exam (Confirmed ETDRS level on 7-field photos)
No CI-DME on clinical exam or OCT
No history of PRP or vitrectomy
No intravitreal Tx over prior 12 mos. and not anticipated for next 6 mos.
Annual Visits for 4 years
Primary outcome: Relative risk of 2 or more step worsening of DR severity over 4 years in groups with and without any predominantly peripheral lesions on UWF images at baseline.

69. Major Eligibility Criteria
Enrollment Criteria (one or two study eyes)
Adults with Type 1 or type 2 diabetes
NPDR based on clinical exam
Confirmed ETDRS level on 7-field photos
No history of PRP or Vitrectomy
No intravitreal treatment over prior 12 months and not anticipated for next 6 months
Enrollment will be limited to only 50% of the cohort with any prior intravitreal anti-VEGF or steroid for DME.
No DME in the central subfield on clinical exam or OCT
Cirrus: < 290 µm for women; < 305 µm for men
Spectralis: < 305µm for women; < 320 µm for men

70. Major Eligibility Criteria Cont.
No substantial non-diabetic intraocular pathology
including AMD or other conditions that could lead to ocular neovascularization
Pupillary dilation is adequate for DRCR.net protocol 7 std fld acquisition (at least 4mm or wider)
No known substantial media opacities that would preclude successful imaging
Primary intraocular pathology is DR
No Hx of major ocular surgery within prior 4 months or anticipated within the next 6 months following study enrollment.

71. Outcomes Longitudinal Analysis
Relative risk of 2 or more step worsening of DR severity over 4 years in the groups with and without predominantly peripheral lesions on UWF images at baseline.
Secondary analysis - additional risk factors including:
Type of peripheral lesions
Location of peripheral lesions
Extent of peripheral or posterior non-perfusion on FA
Presence or absence of peripheral lesions
Whether DR severity level is different within 7-modified fields compared with UWF images

72. Outcomes (Cont.) Secondary outcomes include
Evaluation of risk factors for progression to PDR, improvement of DR, improvement, worsening, or development of DME, and development of VH
Assess if characteristics of DR on UWF photos and UWF FA are associated with evidence of end organ damage in the kidney or cardiovascular system.
Cross Sectional Analysis at Baseline
Level of agreement between DR or DME severity as graded on UWF vs DRCR.net protocol images
% and type of peripheral lesions identified on UWF images not seen on DRCR.net protocol images
% of time peripheral lesions seen on UWF images outside the 7 std flds could change level of ETDRS DR severity

73. Protocols In Development

74. Aflibercept Compared with Bevacizumab+Deferred Aflibercept in Eyes with Central-Involved DME

75. Background
Aflibercept treatment in Protocol T resulted in better VA, on average, for eyes with worse baseline VA than bevacizumab
However, bevacizumab was effective for many eyes with worse VA at baseline.
Approximately 2/3 of bevacizumab-treated eyes had >10 letter improvement at 2 years
Almost half had resolution of DME at 2 years
Cost is an issue 75

76. Background Real Life Application:
Compare starting with bevacizumab and switching to aflibercept if needed vs. starting with aflibercept?
What are the implications of insurance companies mandating this approach or patients choosing this approach?
Cost savings
Visual outcomes 76

77. Study Objective
To compare the efficacy of intravitreous aflibercept with intravitreous bevacizumab + deferred aflibercept if needed in eyes with CI DME and moderate vision loss. 77

78. Proposed Study Design
Multi-Center Randomized Clinical Trial
At least 1 eye that meets all of the following criteria:
VA letter score ≤ 69 and ≥ 24 (≈20/50 to 20/320)
Ophthalmoscopic evidence of CI-DME
Central-involved thickening on OCT
Cirrus: ≥ 290 µm for women; ≥ 305 µm for men
Spectralis: ≥ 305µm for women; ≥ 320 µm for men
No history of anti-VEGF treatment for DME in past 12 months and no history of any other treatment for DME in past 4 months
No history of major ocular surgery within prior 4 months or anticipated within next 6 months
Bevacizumab with Deferred Aflibercept
Prompt Aflibercept
Primary Outcome: Mean change in VA from baseline to 2 years adjusted for baseline VA 78

79. Treatment Groups 2.0 mg intravitreous aflibercept
1.25 mg intravitreous bevacizumab + deferred intravitreous aflibercept if eye is not “successful” with bevacizumab
Sample size: Approximately eyes

80. Follow-up Schedule Duration of follow-up: 2 years
Follow-up visits occur q 4 weeks up to 1 year visit
Study eyes in both groups will be evaluated for injection at each visit according to the same retreatment protocol.
Beginning at the 12 week visit, study eyes in the bevacizumab treatment group that meet switch criteria at 2 consecutive visits will switch to aflibercept
After 1 year, visits occur q 4 to 16 weeks depending on disease progression and treatment administered
All participants will have follow-up visits at 1 and 2 years

81. Follow-up Schedule 1st Year 2nd Year Visits q 4 weeks
Visits q 4 weeks as long as injections given. (Otherwise visits q 4 to 16 weeks*)
At 12 weeks, potential to switch
1st Year
2nd Year
* The first two times an injection is deferred, the subject will return in 4 weeks for re-evaluation. If deferral continues, the subject will return in 8 weeks for re-evaluation before beginning the every 16 week schedule.

82. Other Upcoming Studies
Randomized Trial of Fenofibrate versus Placebo for Prevention of Diabetic Retinopathy Worsening
The Effect of Photobiomodulation on DR
Automated DR Detection Algorithms

83. The Diabetic Retinopathy Clinical Research Network
Thank you 83