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 associated conditions.  Funding: National Eye Institute (NEI) and The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-sponsored cooperative agreement initiated September 2002. o Current award 2014-2018 2

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. 3

4. DRCR.net Status (as of 4/6/16) 4 ActiveTotal Sites (Community & Academic Centers) 128310 Community Sites 85 (66%)199 (64%) Investigators4161146 Other Personnel10373940 States3348 Provinces in Canada44

5. 5 Site Locations

6. How to Join the Network  All retina specialists are welcome to apply  E-mail drcrnet@jaeb.org  Your request will be reviewed and if approved the necessary paperwork will be sent to you 6

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.  E-mail form to drcrnet@jaeb.org  It will be reviewed by the Operations Group at the next in-person meeting. * Forms also available on the study website 7

8. 8 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. Scientific Advisory Committee Selected ideas presented to investigators at semiannual meeting Based on Investigator feedback, ideas are prioritized by EC. Protocol Development Committee is formed. External Individuals Protocol Idea Review Process

9. Completed DRCR.net Protocols 9

10. DRCR.net Protocols Enrolling or in Follow-up 10 Over 9,400 DRCR.net Participants to Date Across 24 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. 11

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. 12

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 nepafenc 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 *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. 14

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. 15 *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. 16

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. 17

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. 18

19. Recently Published Results 19

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

21. Study Design 21 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 Randomized, multi-center clinical trial (89 Sites)

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 2 nd 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 23

24. For the full presentation of results click here.here 24

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

26. Primary 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 26

27. Study Design 27 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 Randomized, multi-center clinical trial (N = 305 patients, 394 eyes, 55 Sites)

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 28

29. Conclusions  PRP effective for PDR over last 4 decades; remains effective in 21 st 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 29

30.  For the full presentation of results click here.here 30

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

32. Protocols Currently Enrolling 32

33. Protocol V Treatment for Central-involved DME in Eyes with Very Good Visual Acuity 33

34. 34 Prompt laser + deferred anti-VEGF Observation + deferred anti-VEGF 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 Study Design Randomized, multi-center clinical trial 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

35. Outcome Measures  Primary Outcome  % 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 35

36. 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 o 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 36

37. 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 37

38. 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 4 - 16 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 38

39. Protocol U Short-term Evaluation of Combination Corticosteroid+Anti-VEGF Treatment for Persistent CI-DME Following Anti- VEGF Therapy 39

40. 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. 40

41. Study Design  Phase II, multicenter, controlled, participant-masked, clinical trial  Duration of Follow-up 41 Run-in Phase 12 Weeks Randomized Phase 24 Weeks Purpose To ensure that enrolled eyes truly have “persistent DME” with decreased visual acuity despite prior anti-VEGF therapy.

42. Study Overview 42 Week 0 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Week 0 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Week 0Week 4Week 8 Week 12 VGF Enrollment SHM VGF Dex VGF SHM Dex Group A: Sham + Ranibizumab Group B: Dexamethasone+ Ranibizumab Run-In Phase (3 months) Randomization Phase (6 months) Assess Eligibility For Randomization

43. 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 43

44. 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 44

45. Efficacy Outcomes at 24 Weeks 45  Primary: Mean change in visual acuity letter score adjusted for baseline (randomization)  Secondary: Visual Acuity o % of eyes with ≥10 and ≥15 letter increase or decrease o Area under the curve (AUC) from baseline OCT o Change in CSF thickness adjusted for baseline o % ≥2 logOCT step gain or loss in CSF o CSF thickness < spectral-domain value equivalent to 250 microns on Zeiss Stratus o AUC from baseline Diabetic Retinopathy worsening or improvement on clinical exam

46. Protocol W Intravitreous Anti-VEGF Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk 46

47. Primary (Short-term) Objective Observation (sham injections) 47 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) 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

48. 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. 48

49. 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 49

50. 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 50

51. Major Inclusion/Exclusion Criteria in Study Eye  Severe NPDR (ETDRS level 53) according to investigator 4-2-1 rule o Severe hemorrhages in at least 4 midperipheral quadrants, or o Definite venous beading in at least 2 quadrants, or o 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 51

52. 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 52

53. Genetics Genes in Diabetic Retinopathy Project 53

54. 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: 1,886 subjects (as of 4/27/16) 54

55. Not Enrolling Currently in Follow-up 55

56. Protocol AA Peripheral Diabetic Retinopathy (DR) Lesions on Ultrawide-field Fundus Images and Risk of DR Worsening Over Time 56

57. 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. 57

58. 58 At least one eye meeting all of the following criteria: NPDR based on clinical exam (Confirmed ETDRS level 35 - 57 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 Study Design Prospective, observational longitudinal study 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.

59. Major Eligibility Criteria  Enrollment Criteria (one or two study eyes) Adults with Type 1 or type 2 diabetes NPDR based on clinical exam oConfirmed ETDRS level 35 - 57 on 7-field photos No history of PRP or Vitrectomy No intravitreal treatment over prior 12 months and not anticipated for next 6 months oEnrollment 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 oCirrus: < 290 µm for women; < 305 µm for men oSpectralis: < 305µm for women; < 320 µm for men 59

60. 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. 60

61. 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: oType of peripheral lesions oLocation of peripheral lesions oExtent of peripheral or posterior non-perfusion on FA oPresence or absence of peripheral lesions oWhether DR severity level is different within 7- modified fields compared with UWF images 61

62. 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 62

63. 63 Protocols In Development

64. Protocol AB Intravitreous Anti-VEGF vs. Vitrectomy for Vitreous Hemorrhage from PDR 64

65. Study Objectives 65  Compare visual acuity outcomes over time for the following two treatment regimens: 1)Prompt Vitrectomy + PRP 2)Intravitreous Anti-VEGF injections in eyes presenting with vitreous hemorrhage from PDR causing vision impairment for which intervention is deemed necessary.

66. Proposed Study Design At least one eye that meets the following criteria :  Vitreous hemorrhage 1.causing vision impairment, 2.presumed to be from PDR, and 3.requiring intervention (vitrectomy or anti-VEGF) Multi-Center Randomized Clinical Trial Primary Outcome: Visual Acuity AUC over 6 months 66 Vitrectomy + PRP Vitrectomy + PRP Anti-VEGF Sample Size: 400 eyes

67. 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 67

68. Secondary Outcomes 68  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

69. 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 69

70. 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 70

71. Anti-VEGF Group 71 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

72. 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 72

73. Cataract Development  Investigators will evaluate lens changes throughout the course of follow-up  Surgery should be considered (or referral for possible cataract surgery) when a lens change is thought to be visually significant based on the investigator’s judgment  Reimbursement for cataract surgery will be available for participants with financial hardship 73

74. Vitrectomy Group 74 VitrectomyInjectionsCataract Surgery PRP Injections during follow-up if needed for recurrent hemorrhage If cataract becomes visually significant

75. The Diabetic Retinopathy Clinical Research Network Thank you 75