1. DRCR.net
Improve the lives of individuals with retinal pathology by performing high quality collaborative clinical research that leads to a better understanding of retinal diseases and advances their treatment
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
The DRCR.net supports the identification, design, and implementation of multicenter clinical research initiatives focused on retinal disorders. Principal emphasis is placed on clinical trials, but epidemiologic outcomes and other research may be supported as well.
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 10/18/18)
Active
Total
Sites (Community & Academic Centers)
155
362
Community Sites
106 (68%)
234 (65%)
Investigators
509
1,343
Other Personnel
1,225
6,465
States 37 49
Provinces in Canada 8 11
--Active Sites
select SiteID, SiteName
from tblSites
where DRCRStatus = 'Active'
order by SiteID
--active community sites
select *
where recdelete =0
and sitestatus = 'active'
and SiteType = 'Private'
active investigators
from vwPersonnel
and siterole = 'investigator'
and PersStatus = 'Active'
and siteid is not null
active other personnel
and isnull(siterole,'') <> 'investigator'
-- 36 active states
select distinct SiteState
and sitestate is not null
and SiteCountry = 'USA'
-- 3 active provinces in canada
select distinct siteprovince
and siteprovince is not null
and SiteCountry = 'Canada'

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

6. 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 every six months.
* Forms also available on the study website

7. Submit ideas to drcrnet@jaeb.org
Initial review for public health importance and potential expedited review.
Operations Group reviews ideas 2x per year for merit and feasibility. Submitter joins via phone to present idea.
Designated ideas presented to investigators at semiannual meeting
Protocol Idea Review Process
Based on Investigator feedback, ideas are prioritized by EC.
Protocol Development Committee is formed.

8. Completed DRCR.net Protocols

9. DRCR.net Protocols Enrolling or in Follow-up
select *
from ufn_GetPtData_Ver1(null)
where ptconsideredinstudy = 1
order by ptid

10. 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.

11. 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.

12. 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.

13. What Has Been Learned? Diabetic Macular Edema Treatment
Protocol U: Although its use is more likely to reduce retinal thickness and increase intraocular pressure, the addition of intravitreous dexamethasone to continued ranibizumab therapy does not improve visual acuity at 24 weeks more than continued ranibizumab therapy alone among eyes with persistent DME following anti-VEGF therapy.

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.

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. Access to Publications and Presentations
Publications and Presentations can be found on the public website or on the study website (log in required)

20. Recently Published Results

21. Randomized Clinical Trial
Protocol S
Five-Year Outcomes of Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy:
Randomized Clinical Trial

22. Randomized, multi-center clinical trial (55 Sites)
Study Design
Randomized, multi-center clinical trial (55 Sites)
Study eye(s) meeting all of the following criteria (a participant can have 2 study eyes):
PDR
No history of PRP
Best corrected visual acuity letter score ≥24
(~Snellen equivalent 20/320 or better)
Eyes with or without central-involved DME were eligible
Primary Objective: Compare the efficacy and safety of PRP with that of intravitreous ranibizumab (0.5-mg in 0.05 mL) for proliferative diabetic retinopathy (PDR)

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

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

25. Protocols Currently Enrolling

26. Protocol AC Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab + Deferred Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (DME)

27. 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

28. 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

29. 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.

30. Study Design At least 1 eye that meets all of the following criteria:
Multi-Center Randomized Clinical Trial
(312 Eyes, 260 Participants)
At least 1 eye that meets all of the following criteria:
VA letter score ≤ 68 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: ≥ 305 µm 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 (Aflibercept if needed)
Aflibercept
Primary Outcome: Mean change in VA over 2 years
(AUC)

31. Bevacizumab (Aflibercept if needed)
Treatment Groups
Aflibercept
Bevacizumab (Aflibercept if needed)
2.0-mg
intravitreous
aflibercept
Centrally repackaged 1.25-mg bevacizumab
Switched to intravitreous aflibercept if eye is not “successful”

32. Study Treatment Overview
At randomization, study eyes will receive an intravitreous injection according to their assigned treatment group
After the initial injection, each eye will be treated according to the retreatment protocol (Protocol T retreatment criteria)
Bevacizumab will be provided by DRCRnet and will have a study drug number
Aflibercept will be from your clinic stock

33. Early Switching Criteria
Concept: 3-5 bevacizumab injections and eye has not improved and vision is still poor
Details: At the 3, 4, and 5 month visit, study eyes assigned to the bevacizumab (aflibercept if needed) group will switch from bevacizumab injections to aflibercept injections the first time all of the following criteria are met at 2 consecutive visits:
OCT CST is above the following cutoffs:
Cirrus: ≥290 µm in women or ≥305 µm in men
Spectralis: ≥ 305 µm in women or ≥320 µm in men
OCT CST has not improved at least 10% from prior visit
VA has not improved 5 letters from prior visit
VA is 20/50 or worse

34. Additional Switching Criteria
Concept: At least 6 bevacizumab injections, eye is no longer improving and VA is at least mildly reduced
Details: Beginning at the 6 month visit, study eyes that have not already switched to aflibercept will switch the first time all of the following criteria are met at 2 consecutive visits:
OCT CST is above the following cutoffs:
Cirrus: ≥290 µm in women or ≥ 305 µm in men
Spectralis: ≥ 305 µm in women or ≥320 µm in men
OCT CST has not improved at least 10% from prior visit
VA has not improved at least 5 letters from prior visit
VA is 20/32 or worse

35. The Switch
Eyes assigned to the bevacizumab group that meet the switch criteria will receive 2 initial monthly injections of aflibercept, then will continue with aflibercept injections throughout study according to the Protocol T retreatment regimen

36. The Switch
If bevacizumab injections are deferred because of success according to the initial retreatment protocol and then the eye worsens, injections will resume using bevacizumab.
Then the eye will be switched to aflibercept using the same criteria listed previously, following two consecutive bevacizumab injections.

37. Failure Criteria
For study eyes in both treatment groups, when failure criteria is met, treatment is up to investigator discretion
Treatment with focal/grid laser will not be permitted in the study eye(s) during the study. If the failure criteria are met, treatment (including laser) is up to investigator discretion.
are, not is

38. Protocol AG Randomized Clinical Trial Assessing the Effects of Pneumatic Vitreolysis on Vitreomacular Traction

39. Study Objective Primary Secondary
To compare the proportion of eyes with foveal VMT (symptomatic VMA) release on OCT after PVL with gas injection vs. observation (sham injection) in eyes with VMT without an associated macular hole
Secondary
To evaluate visual function outcomes at 24 weeks after gas injection is performed compared with observation.

40. Multi-Center Randomized Clinical Trial Observation (Sham injection)
Study Design
Multi-Center Randomized Clinical Trial
(124 Eyes)
At least 1 eye that meets all of the following criteria:
Vitreomacular adhesion on OCT ≤3,000 µm
Reading center confirmation required for eligibility
Best corrected ETDRS visual acuity equivalent of 20/32 to 20/400
Decreased visual function attributed to VMT
No macular or lamellar hole
Prompt Vitrectomy not required
PVL
(Injection of C3F8 gas)
Observation (Sham injection)
Primary Outcome: Proportion of eyes with VMT release on OCT without rescue vitrectomy at 24 weeks

41. Study Design Primary outcome visit Informed Consent, Baseline Testing
Dropped Ineligible
Reading Center Review
Dropped Ineligible
Randomization
Observation (Sham Injection)
Injection of C3F8 Gas (0.3 mL)
1 week
1 week
4 weeks
4 weeks
12 weeks
12 weeks
Primary outcome visit
24 weeks
24 weeks

42. Protocol AH Single-Arm Study Assessing the Effects of Pneumatic Vitreolysis on Macular Hole

43. Rationale for Single-Arm Study
Eyes with MH need treatment, therefore randomization to a sham arm would be inappropriate
Vitrectomy results in nearly 100% hole closure making it an unnecessary (and expensive) control group choice
Even if this proposed study finds that PVL is only moderately successful, physicians and patients may decide to attempt PVL in the office first, before proceeding with more costly, invasive surgery
Thus, even without a control group, the results from this study will provide data of value for physicians and patients to make informed decisions about treatment course

44. Study Objective
To obtain estimates for the proportion of eyes with macular hole closure of the inner retinal layers for eyes with VMT and full-thickness macular holes treated with PVL

45. Multi-Center Single-Arm Study PVL (Injection of C3F8 gas)
Study Design
Multi-Center Single-Arm Study
(50 Eyes)
At least 1 eye that meets all of the following criteria:
Full-thickness macular hole ≤250 microns at the narrowest point, confirmed by central reading center
Vitreomacular adhesion on OCT ≤3,000 microns, confirmed by central reading center
Best corrected ETDRS visual acuity equivalent of 20/25 to 20/400
PVL (Injection of C3F8 gas)
Primary Outcome: Proportion of eyes with macular hole closure of the inner retinal layers at 8 weeks without rescue treatment

46. Informed Consent, Baseline Testing Injection of C3F8 Gas (0.3 mL)
Study Design
Informed Consent, Baseline Testing
Dropped Ineligible
Reading Center Review
Dropped Ineligible
Injection of C3F8 Gas (0.3 mL)
1 week
4 weeks
Primary outcome visit
8 weeks
24 weeks

47. Genetics Genes in Diabetic Retinopathy Project

48. 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: 2,350 subjects (as of 10/18/18)

49. Protocols Currently in Follow-up

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

51. 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.

52. Study Design At least one eye that meets the following criteria:
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

53. 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

54. 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

55. 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

56. 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

57. 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

58. 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

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

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

61. 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

62. 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.

63. 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

64. 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

65. 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

66. 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

67. Protocol T – Follow-up Extension Study
A Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for Diabetic Macular Edema

68. Study Design Observational cohort study Eligibility Criteria:
Any participant, not known to be deceased, who was randomized in the Protocol T main study at clinical sites that are currently active in the DRCR.net.
One follow-up visit approximately 5 years after randomization in T

69. Primary Objective Descriptive analyses for the following:
Types of DME treatments since last T visit
Frequency of DME treatments since last T visit
Treatments for diabetic retinopathy since last T visit
Visual acuity outcomes at 5 years
Mean change in VA, proportion of eyes with 2 or 3 or more letter gain/loss, distribution of VA at 5 yrs
DME outcomes at 5 years
Mean change in OCT, proportion of eyes with OCT < gender and machine specific cutoffs
Diabetic retinopathy outcomes at 5 years
APTC events occurring in participants since last T visit

70. 5 Year Visit Examination Procedures
Best Corrected Visual Acuity, including refraction
IOP measurement
Eye Exam
HbA1c
OCT
Fundus Photos
Visit and Treatment Log

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

72. 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.

73. 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.

74. 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

75. 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.

76. 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

77. 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

78. Recently Completed

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

80. 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

81. 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

82. 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

83. 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

84. 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

85. Other Upcoming Studies

86. DRCR.net
Thank you