DRCR net Dedicated to multicenter clinical research of

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DRCR. net Dedicated to multicenter clinical research of diabetic retinopathy, macular edema and other

DRCR. net Dedicated to multicenter clinical research of diabetic retinopathy, macular edema and other retinal diseases 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 EY 14231, EY 018817

DRCR. net Overview Ø Ø Objective: • The development of a collaborative network to

DRCR. net Overview Ø Ø 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. o Current award 2014 -2018 2

Priority Initiatives Ø Involvement of community-based practices, as well as “academic” or university-based centers.

Priority Initiatives Ø Involvement of community-based practices, as well as “academic” or university-based centers. Ø 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

DRCR. net Status (as of 7/6/17) Active Total 139 333 98 (71%) 214 (64%)

DRCR. net Status (as of 7/6/17) Active Total 139 333 98 (71%) 214 (64%) Investigators 446 1228 Other Personnel 1108 4310 States 33 49 Provinces in Canada 5 5 Sites (Community & Academic Centers) Community Sites 4

Site Locations 5

Site Locations 5

How to Join the Network All retina specialists are welcome to apply Ø E-mail

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

How to Submit a Protocol Idea Go to the public* website: drcr. net Ø

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

Semiannual solicitation of protocol ideas from Investigators submit ideas to CC. Network Chairs /CC

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

Completed DRCR. net Protocols 5/03 1/04 9/04 5/05 2/06 10/06 6/07 2/08 10/08 7/09

Completed DRCR. net Protocols 5/03 1/04 9/04 5/05 2/06 10/06 6/07 2/08 10/08 7/09 3/10 11/10 7/11 4/12 12/12 8/13 4/14 12/14 9/15 5/16 1/17 A - Laser B - IVT C - OCT D - Vitrectomy E - Peribulbar F - PRP G - Subclinical H - Bevacizumab I - LRT for DME J - LRT for DME + PRP K - Laser Response L - Autorefraction M - Diabetes Education N - Vitreous Hemorrhage O - OCT P - Cataract w/Central DME Q - Cataract w/o Central DME R - Topical NSAIDs for DME Recruitment Follow-up T - Anti-VEGF Comparison U - Persistent DME 9

DRCR. net Protocols Enrolling or in Follow-up 2/12 7/12 12/12 5/13 10/13 3/14 7/14

DRCR. net Protocols Enrolling or in Follow-up 2/12 7/12 12/12 5/13 10/13 3/14 7/14 12/14 5/15 10/15 3/16 8/16 1/17 6/17 S - IVR for PDR V - Very Good Vision AA - Ultrawide field Imaging W - PDR/DME Prevention Recruitment Follow-up AB - Vitreous Hemorrhage Genetics • Over 9, 800 DRCR. net Participants to Date Across 2 Protocols 10

What Has Been Learned? Diabetic Macular Edema Treatment Ø Ø Protocol A: Although some

What Has Been Learned? Diabetic Macular Edema Treatment Ø Ø 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 Ø Protocol I: Intravitreal ranibizumab with

What Has Been Learned? Diabetic Macular Edema Treatment Ø 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. • Ø 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 Ø Protocol R: At 1 year

What Has Been Learned? Diabetic Macular Edema Treatment Ø 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. Ø 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 13

What Has Been Learned? Diabetic Retinopathy Treatment Ø Ø Protocol F: Results suggest clinically

What Has Been Learned? Diabetic Retinopathy Treatment Ø Ø 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

What Has Been Learned? Diabetic Retinopathy Treatment Ø Ø Protocol N: The study suggested

What Has Been Learned? Diabetic Retinopathy Treatment Ø Ø 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 15

What Has Been Learned? OCT and Retinal Thickening Ø Ø Ø Protocol C: Although

What Has Been Learned? OCT and Retinal Thickening Ø Ø Ø 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

What Has Been Learned? Optical Coherence Tomography Ø Ø Protocol G: CST (central subfield

What Has Been Learned? Optical Coherence Tomography Ø Ø 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

What Has Been Learned? Optical Coherence Tomography Ø Protocol O: Conversion equations may be

What Has Been Learned? Optical Coherence Tomography Ø 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

Recently Published Results 19

Recently Published Results 19

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

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

Study Design Randomized, multi-center clinical trial (89 Sites) Participants meeting all of the following

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 21

Main Outcome Change in visual acuity at 1 and 2 years adjusted for baseline

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

Conclusions Ø Vision gains at 2 years were seen in all 3 groups with

Conclusions Ø 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 Ø Among eyes with better VA no differences in 2 -year vision outcomes identified Ø 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. Ø 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 23 continued evaluation

For the full presentation of results click here. 24

For the full presentation of results click here. 24

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

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

Primary Question Ø Is visual acuity using ranibizumab for PDR not worse than treatment

Primary Question Ø Is visual acuity using ranibizumab for PDR not worse than treatment with PRP at 2 years? • Non-inferiority margin of 5 letters Secondary Question Ø Are there potential benefits of ranibizumab on: • • Vision throughout follow-up (area under the curve) Peripheral vision Macular edema Incidence of vitrectomy 26

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

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 27

Conclusions Ranibizumab injections for Proliferative Diabetic Retinopathy …. Ø No worse than (not inferior

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

Conclusions Ø PRP effective for PDR over last 4 decades; remains effective in 21

Conclusions Ø PRP effective for PDR over last 4 decades; remains effective in 21 st century Ø Ranibizumab for PDR is at least as good as (noninferior 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 Ø Longer follow-up should determine whether effects sustained through 5 years 29

Ø For the full presentation of results click here. 30

Ø For the full presentation of results click here. 30

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

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

Protocols Currently Enrolling 32

Protocols Currently Enrolling 32

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

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

Study Objectives Ø Compare visual acuity outcomes over time for the following two treatment

Study Objectives Ø Compare visual acuity outcomes over time for the following two treatment regimens: 1) 2) 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

Proposed Study Design Multi-Center Randomized Clinical Trial At least one eye that meets the

Proposed Study Design Multi-Center Randomized Clinical Trial At least one eye that meets the following criteria: Ø Vitreous hemorrhage 1. causing vision impairment, 2. presumed to be from PDR, and 3. requiring intervention (vitrectomy or anti-VEGF) Vitrectomy + PRP Anti-VEGF Primary Outcome: Visual Acuity AUC over 6 months Sample Size: 200 eyes 35

Additional Eligibility Criteria Ø Visual acuity 20/32 or worse and at least light perception

Additional Eligibility Criteria Ø Visual acuity 20/32 or worse and at least light perception • Ø Ø No anti-VEGF treatment within 2 months prior to vitreous hemorrhage onset No prior vitrectomy • Ø 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 Note: Prior PRP is not a requirement nor an exclusion No RRD, no TRD involving or threatening the fovea 36

Secondary Outcomes ØTreatment Group Comparisons • Mean visual acuity at annual visits • Visual

Secondary Outcomes ØTreatment 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 37

Additional Outcomes of Interest Ø Vitrectomy Group Outcomes Ø • Percent requiring repeat vitrectomy

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

Study Treatment Overview Ø Anti-VEGF Group • • • Follow-up injections every 4 weeks

Study Treatment Overview Ø 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: o TRD threatening or involving the macula o Rhegmatogenous retinal detachment o 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

Anti-VEGF Group • At least 2 monthly Monthly injections to start and Injections then

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

Study Treatment Overview Ø Vitrectomy Group • Vitrectomy scheduled within 2 weeks of randomization

Study Treatment Overview Ø Vitrectomy Group • Vitrectomy scheduled within 2 weeks of randomization • Performed according to surgeon’s usual routine including +/-: o o o • • 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 41

Vitrectomy Group Vitrectomy PRP Injections Cataract Surgery Injections during follow-up if needed for recurrent

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

Protocol W Intravitreous Anti-VEGF Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes

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

Primary (Short-term) Objective To determine safety and efficacy of anti-VEGF versus observation in eyes

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

Rationale Ø The application of anti-VEGF therapy earlier in the course of disease could

Rationale Ø 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 longterm visual acuity outcomes. Ø If this study demonstrates that anti-VEGF treatment is effective and safe in the setting of severe NPDR, a new strategy to prevent visionthreatening complications will be available for patients. 45

Composite Primary Outcome: Part 1 – PDR Ø Development of NV within the 7

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

Composite Primary Outcome: Part 2 – DME Ø Ø Center-involved DME on clinical exam

Composite Primary Outcome: Part 2 – DME Ø Ø 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 47

Major Inclusion/Exclusion Criteria in Study Eye Ø Severe NPDR (ETDRS level 53) according to

Major Inclusion/Exclusion Criteria in Study Eye Ø Severe NPDR (ETDRS level 53) according to investigator 4 -2 -1 rule o o o Ø Ø 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

Follow-Up and Treatment Overview Ø Total duration: 4 years • Ø Ø Ø Primary

Follow-Up and Treatment Overview Ø Total duration: 4 years • Ø Ø Ø 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 49

Genetics Genes in Diabetic Retinopathy Project 50

Genetics Genes in Diabetic Retinopathy Project 50

Genes in Diabetic Retinopathy Project Ø • • Ø Objective To create a repository

Genes in Diabetic Retinopathy Project Ø • • Ø 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 • Ø Previous/current participant in a DRCR. net study Enrollment (Ongoing) • Total enrolled: 2, 084 subjects (as of 7/6/17) 51

Not Enrolling Currently in Follow-up 52

Not Enrolling Currently in Follow-up 52

Protocol T – Follow-up Extension Study A Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab

Protocol T – Follow-up Extension Study A Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for Diabetic Macular Edema 53

Study Design Observational cohort study Eligibility Criteria: Any participant, not known to be deceased,

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 54

Primary Objective Ø Descriptive analyses for the following: • • Types of DME treatments

Primary Objective Ø 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 55 visit

5 Year Visit Examination Procedures Ø Best Corrected Visual Acuity, including refraction Ø IOP

5 Year Visit Examination Procedures Ø Best Corrected Visual Acuity, including refraction Ø IOP measurement Ø Eye Exam Ø Hb. A 1 c Ø OCT Ø Fundus Photos Ø Visit and Treatment Log 56

Protocol V Treatment for Central-involved DME in Eyes with Very Good Visual Acuity 57

Protocol V Treatment for Central-involved DME in Eyes with Very Good Visual Acuity 57

Study Design Randomized, multi-center clinical trial At least one eye meeting all of the

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 58

Outcome Measures Ø Primary Outcome • Ø % with VA loss of ≥ 5

Outcome Measures Ø Primary Outcome • Ø % 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 59

Major Eligibility Criteria Ø Ø Type 1 or 2 diabetes Study Eye: • Central-involved

Major Eligibility Criteria Ø Ø 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 Ø 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 60

Major Exclusion Criteria Ø Systemic • • • Ø History of chronic renal failure

Major Exclusion Criteria Ø Systemic • • • Ø 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 61 months

Follow-Up Schedule Ø Ø Total follow-up through 2 years Visit schedule will vary by

Follow-Up Schedule Ø Ø Total follow-up through 2 years Visit schedule will vary by treatment group and disease progression • • Ø 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 62

Protocol AA Peripheral Diabetic Retinopathy (DR) Lesions on Ultrawide-field Fundus Images and Risk of

Protocol AA Peripheral Diabetic Retinopathy (DR) Lesions on Ultrawide-field Fundus Images and Risk of DR Worsening Over Time 63

Objectives Ø Primary objective • To assess whether evaluation of the retinal far periphery

Objectives Ø 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. 64

Study Design Prospective, observational longitudinal study At least one eye meeting all of the

Study Design Prospective, observational longitudinal study 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 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. 65

Major Eligibility Criteria Ø Enrollment Criteria (one or two study eyes) • Adults with

Major Eligibility Criteria Ø Enrollment Criteria (one or two study eyes) • Adults with Type 1 or type 2 diabetes • NPDR based on clinical exam o Confirmed 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 o 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 o Cirrus: < 290 µm for women; < 305 µm for men o Spectralis: < 305µm for women; < 320 µm for men 66

Major Eligibility Criteria Cont. Ø No substantial non-diabetic intraocular pathology • including AMD or

Major Eligibility Criteria Cont. Ø No substantial non-diabetic intraocular pathology • including AMD or other conditions that could lead to ocular neovascularization Ø Pupillary dilation is adequate for DRCR. net protocol 7 std fld acquisition (at least 4 mm or wider) Ø No known substantial media opacities that would preclude successful imaging Ø Primary intraocular pathology is DR Ø No Hx of major ocular surgery within prior 4 months or anticipated within the next 6 months following study enrollment. 67

Outcomes Ø Longitudinal Analysis • Relative risk of 2 or more step worsening of

Outcomes Ø 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: o Type of peripheral lesions o Location of peripheral lesions o Extent of peripheral or posterior non-perfusion on FA o Presence or absence of peripheral lesions o Whether DR severity level is different within 7 modified fields compared with UWF images 68

Outcomes (Cont. ) Ø Secondary outcomes include • Evaluation of risk factors for progression

Outcomes (Cont. ) Ø 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. Ø 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 69

Protocols In Development 70

Protocols In Development 70

Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab + Deferred Aflibercept for Treatment of

Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab + Deferred Aflibercept for Treatment of Central-Involved Diabetic Macular Edema (DME) 71

Background Ø Aflibercept treatment in Protocol T resulted in better VA, on average, for

Background Ø Aflibercept treatment in Protocol T resulted in better VA, on average, for eyes with worse baseline VA than bevacizumab Ø 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 Ø Cost is an issue 72

Background Ø Real Life Application: • Compare starting with bevacizumab and switching to aflibercept

Background Ø 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? o Cost savings o Visual outcomes 73

Study Objective Ø To compare the efficacy of intravitreous aflibercept with intravitreous bevacizumab +

Study Objective Ø To compare the efficacy of intravitreous aflibercept with intravitreous bevacizumab + deferred aflibercept if needed in eyes with CI DME and moderate vision loss. 74

Proposed Study Design Multi-Center Randomized Clinical Trial At least 1 eye that meets all

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 o Cirrus: ≥ 290 µm for women; ≥ 305 µm for men o 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 Prompt Aflibercept Bevacizumab with Deferred Aflibercept Primary Outcome: Mean change in VA over 2 years, area under the curve adjusted for baseline visual acuity 75

Treatment Groups 1. 2. 0 mg intravitreous aflibercept 2. 1. 25 mg intravitreous bevacizumab

Treatment Groups 1. 2. 0 mg intravitreous aflibercept 2. 1. 25 mg intravitreous bevacizumab + deferred intravitreous aflibercept if eye meets switch criteria Sample size: Approximately 312 eyes 76

Follow-up Schedule Ø Duration of follow-up: 2 years Ø Follow-up visits occur q 4

Follow-up Schedule Ø Duration of follow-up: 2 years Ø Follow-up visits occur q 4 weeks up to 1 year visit Ø Study eyes in both groups will be evaluated for injection at each visit according to the same retreatment protocol. Ø 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 Ø After 1 year, visits occur q 4 to 16 weeks depending on disease progression and treatment administered Ø All participants will have follow-up visits at 1 and 2 years 77

Follow-up Schedule Visits q 4 weeks At 12 weeks, potential to switch 1 st

Follow-up Schedule Visits q 4 weeks At 12 weeks, potential to switch 1 st Year Visits q 4 weeks as long as injections given. (Otherwise visits q 4 to 16 weeks*) 2 nd 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. 78

Other Upcoming Studies Ø Ø Ø PROMINENT-EYE The Effect of Photobiomodulation on DR Automated

Other Upcoming Studies Ø Ø Ø PROMINENT-EYE The Effect of Photobiomodulation on DR Automated DR Detection Algorithms 79

The Diabetic Retinopathy Clinical Research Network Thank you 80

The Diabetic Retinopathy Clinical Research Network Thank you 80