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 

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 2014-2018

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.

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' -- 428 active investigators from vwPersonnel and siterole = 'investigator' and PersStatus = 'Active' and siteid is not null   -- 1116 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'

How to Join the Network All retina specialists in the U.S. and Canada 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

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

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.

Completed DRCR.net Protocols

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

Recently Published Results

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

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)

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

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

Protocols Currently Enrolling

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

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

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

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.

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)

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”

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

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

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

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

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.

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

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

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.

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

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

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

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

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

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

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

Genetics Genes in Diabetic Retinopathy Project

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)

Protocols Currently in Follow-up

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

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.

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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.

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.

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 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 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

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.

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

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

Recently Completed

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

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

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

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

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

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

Other Upcoming Studies

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