Locations Fakultni nemocnice Kralovske Vinohrady Appetite regulation supplements Dark chocolate sensation, Czech Republic, However, retinopath was tgials found to have an clinival Diabetic retinopathy clinical trials retinopathy progression, so patients assigned to aspirin were pooled with those assigned to placebo. Sponsor: Oxurion. DRCR Retina Network Protocol U This Phase II randomized clinical trial compared treatment with ranibizumab alone and ranibizumab plus intravitreal dexamethasone implant Ozurdex, Allergan in patients with persistent DME.

Diabetic retinopathy clinical trials -

Could I receive a placebo? Products Runcaciguat BAY Accepts Healthy Volunteers No. Where to Participate Loading Locations Locations. Trial Design A Phase 2 randomized, placebo-controlled, double-masked proof-of-concept study to investigate the efficacy and safety of runcaciguat BAY in patients with moderately severe to severe non-proliferative diabetic retinopathy Trial Type : Interventional.

Intervention Type : Drug. Trial Purpose : Treatment. Allocation : Randomized. Assignment : Parallel Assignment. Trial Arms : 2. Secondary Outcome Vision threatening complications at 48 weeks of treatment in the study eye. Timeframe : From first dosing up to 28 days after last dose of study intervention.

Click here to find information for studies related to Bayer products. To find this study enter the ClinicalTrials. gov identifier NCT number or Bayer Study Identifier ID in the search field. Follow Us. Terms of Use. Copyright © Bayer.

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Cataract Therapeutics. Clinical Diagnosis. Dry Eye. Gene Therapy. Dorr C ; Lisa Spuches V ; Lynn M. Kwasniewski V ; Michelle L. Manley V ; Abigail Miller P ; Nicole E. Robarge P ; Stefanie R. DeSantis, BS P ; Teresa M. DeForge P ; and Jeffrey P Barker P. West Monroe, Louisiana: Joseph E. Humble and Raymond Haik PTRS DBA Eye Center Eye Assoc of Northeast Louisiana 3 : Ruben A.

Grigorian, MD I ; Latha M Jois C, P ; Rebecca Morris C, P, V ; Rebecca Webb, BS, CRC C, P, V ; Dusti D Douglas V ; Sharoon David, MBBS P ; and Faith Pena, BS P.

Asheville, North Carolina: Western Carolina Clinical Research, LLC 2 : Cameron McLure Stone, MD I ; McCayla Elise Hall C ; Andrea K. Menzel, COA C ; Monica Hamrick C ; Lea R. Raymer, BS C ; Leslie D. Rickman, COA V ; Julia Crokett Overbey V ; Donna Machen V ; Lisa H.

Hawkins, COA P ; Melissa Smith P ; and Paula A. Price, COT P. Halifax, Nova Scotia: Nova Scotia Health Authority 2 : Alan F. Cruess, MD I ; R. Rishi Gupta, MD, DABO I ; John D.

Dickinson, MD I ; Alec M. Cranston C ; Meggie D. Caldwell C ; Stacey Durling V ; Mitzi Hynes, COT P ; and Trina MacDonnell, OC C , COMT P.

Lubbock, Texas: Texas Retina Associates 2 : Michel Shami, MD I ; Yolanda Saldivar C ; Ashaki Meeks V ; and Glenn R. Gardner, CRA P. Monroeville, Pennsylvania: Retina-Vitreous Consultants, Inc. Olsen, MD I ; Jared E. Knickelbein, MD, PhD I ; Robert L. Bergren, MD I ; Bernard H. Doft, MD I ; Lori A.

Merlotti C ; Julie Walter V ; Lois Stepansky V ; Dawn Diperna P ; and Phyllis P Ostroska P. Palm Desert, California: Southern California Desert Retina Consultants, Inc 2 : Clement K.

Chan, MD I ; Maziar Lalezary, MD I ; Tiana Gonzales C ; Kimberly S. Walther C ; Tonya M Gieser C ; Isela Aldana C, V ; Lenise E. Myers, COA V ; Kristina Pettit P ; and Kenneth M.

Huff, COA P. Pinellas Park, Florida: Southeast Eye Institute, P. dba—Eye Associates of Pinellas 2 : Jason M. Handza, DO I ; Bronson Oudshoff, CCRC C ; Corey T. McGahee, COA P ; Christina Glover P ; nd Annette M. Carey, COA P. Plantation, Florida: Eye Physicians of Florida LLC DBA Fort Lauderdale Eye Institute LLC 2 : Tirso M.

Lara, MD I ; Stuart K. Burgess, MD I ; Noel H. Pereda, MD C, V ; Deborah Davis V ; Adriana Villa V ; Mark Oberlander P ; and Karen Workman P.

Portland, Oregon: Retina Northwest, PC 2 : Apurva K. Patel, MD I ; Paul S. Tlucek, MD I ; Mark A. Peters, MD I ; Colin Ma, MD I ; Brian S Puckett C ; Pualani Smith C ; Stephanie L.

Ho, BA C, P, V ; Margaret E Charpentier V ; Marcia Kopfer, BS, COT V ; and Christine Hoerner P. Sarasota, Florida: Sarasota Retina Institute 2 : Melvin Chen, MD I ; Peggy A.

Jelemensky C, V ; Samantha R. Basham V ; Tara L. Raphael V ; Mark Sneath, COA P ; and Rosa Miller P. Shawnee Mission, Kansas: Retina Associates, PA 2 : Gregory M.

Fox, MD I ; Ryan D. Christensen, MD I ; David S. Dyer, MD I ; Ivan R. Batlle, MD I ; Ravi S. Singh, MD I ; Lexie R. Ainley C ; Karla A. Batlle, BS C ; Amber R. VandeVelde, RN V ; Holly Wyrick V ; Frank T. Yeager P ; and Katherine Pippin P. Southlake, Texas: Jawad A. Qureshi MD, PA DBA Retina Center of Texas 2 : Jawad A.

Qureshi, MD I ; Kruti P. Dajee, MD I ; Johnathan D. Warminski, MD I ; Pualani Smith C, V ; Victoria E. Cowart C ; Andre Watkins P ; Denise Ortiz P ; and Diana Murillo P. Vancouver, British Columbia: University of British Columbia and Vancouver Coastal Health Authority and Eduardo Navajas, MD, PhD 2 : Eduardo Vitor Navajas, MD, PhD I ; Sijia Cao C ; Mira Jovanovic, Msci C, V ; Theresa Wiens, MSc, CCRP C ; Sherry Han, MSc V ; Bryan Harrison P ; Anne-Marie Godfrey P ; and Kelly Grant P.

Baltimore, Maryland: Johns Hopkins University 1 : Sharon D. Solomon, MD I ; Susan Bressler, MD I ; Deborah Donohue C, V ; Lisa K. Levin C ; Mary Frey, BSc, CCRP V ; Russ Distle P ; and Dennis Cain, CRA P. Chicago, Illinois: Northwestern University 1 : Alice T.

Lyon, MD I ; Manjot K. Gill, MD I ; Chisomo Mwale C, V ; Carmen Ramirez C, V ; Crystal Santillanes C, V ; Evan C. Davies C ; Nicole M Seddon C ; Priya M Thakkar, BS C ; Anson Moore V ; Cason Moore P ; Maritza Barragan P ; and Evica Simjanoski, BFA P.

Chicago, Illinois: The Board of Trustees of the University of Illinois 1 : Jennifer I. Lim, MD I ; Felix Y. Chau, MD I ; Jie Sun, MD C ; Tametha Johnson V ; Natasa Stankovic, AAS, COT V ; Ben Martinez V ; Mark Janowicz, BS P ; and Andrea Degillio, CRA, CDOS P. Jacksonville, Florida: University of Florida—Jacksonville 1 : Sandeep Grover, MD I ; Ghulam Shabbir Hamdani, MBBS, MSH, CCRP C ; Bharani Krishna Mynampati A, PhD C, P, V ; Romesh Babaria, MS C, V ; and Jazzmin N Smith C, P.

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Dietzman, BS, CCRC C ; Christopher M. Smith, COA C, V ; Angela M. Adler, BS, CCRC V ; Denise A. Krolnik, MS P ; and Sandie L. Reed, AD P. Minneapolis, Minnesota: Retina Center, PA DBA Retina Center of Minnesota 1 : Abdhish R. Bhavsar, MD I ; Andrea Gilchrist C ; Matt D.

Peloquin, AA V ; Jason R Sweet V ; Denise Vang P ; Erin C. Kinney P ; and Alanna C. Evans P. New York, New York: The New York Eye and Ear Infirmary 1 : Ronald C Gentile, MD I ; Melissa Rivas C, V ; John Bo Soo Choi C, V ; Wanda Carrasquillo-Boyd P ; and Robert Masini P.

Orlando, Florida: Magruder Eye Institute 1 : John T. Lehr, MD I ; Brittany M. Pendarvis C ; Elaine Rodriguez-Roman, OD C ; Mari Delgado C, P, V ; Atira Bramble, COA V ; Robert Atnip V ; Patricia Lynch V ; Martha Eileen Haddox V ; Julian Rodriguez P ; Kyle Dreessen P ; Ashley E Willer P ; Mark Pena P ; and Chase Hutchings, COA P.

Overland Park, Kansas: Mid-America Retina Consultants, PA 1 : William N. Rosenthal, MD I ; Elizabeth N. Heim, BSN, RN C ; Sarah N. Lamaster, RN, BSN C, V ; Courtney J. Dunn P ; R. Scott Varner P ; and Mary C. Stewart, RN P. San Antonio, Texas: Retinal Consultants of San Antonio 1 : Moises A.

Chica, MD I ; Calvin E. Mein, MD I ; Lydia Adams C ; Jenny M Bermea C ; Sara L Cloudt C ; Lita Kirschbaum, COA C ; Victoria Lopez V ; Jonathan San Roman V ; Samantha Bankston P ; Brenda Nakoski P ; and Christopher Sean Wienecke P.

Springfield, Illinois: Springfield Clinic, LLP 1 : Ramanath Bhandari, MD I ; Jennifer Shaw C, P ; Bradley C. Evans, LPN, COA C ; Braden Anderson V ; Gaylan W Moushon, OD V ; Kris Karrick, COA P ; Caitlyn Wessel P ; and Dennis Frye P.

Trumbull, Connecticut: New England Retina Associates, PC 1 : Gregory M. Haffner, MD I ; Andrea L. DeClement C ; Leslie D. Hurst, MS C ; Patricia L Anderson C ; Adriana N. Enxuto V ; Stephanie Esteves V ; and Emily Morse, BS P. Christoforidis, MD I ; Jill Brickman-Kelleher, BS, AAS C ; Sue A.

Bulau C, V ; Patricia H. Fryer V ; and Dennis Haymore P. West Columbia, South Carolina: John A. Wells, III MD DBA Palmetto Retina Center, LLC 1 : John A. Wells, III, MD I ; Tiffany R. Swinford C, V ; Tiffany N. Ogbuewu V ; Robbin Spivey P ; and Ashley Studebaker P.

West Des Moines, Iowa: Wolfe Eye Clinic, PC 1 : Jared S. Nielsen, MD I ; Kyle J. Alliman, MD I ; Tami Jo Woehl C ; Marianne Parker C ; Erin L. Riley C ; Jack Bowers V ; Jamie Spillman V ; Paula L. Bix V ; Spencer D. Ridgway P ; and Lisa M.

Boender P. Data Sharing Statement: See Supplement 3. At that time, the data will be made available to anyone requesting the data. full text icon Full Text. Download PDF Comment. Top of Article Key Points Abstract Introduction Methods Results Discussion Conclusions Article Information References.

Figure 1. Study Flow Diagram. View Large Download. Figure 2. Time From Randomization to Development of Proliferative Diabetic Retinopathy PDR or Center-Involved Diabetic Macular Edema CI-DME. Figure 3. Mean Change in Visual Acuity Through 2 Years. Table 1. Baseline Participant and Study Eye Characteristics.

Table 2. Components of PDR and DME Composite Outcome Met at First Occurrence of Outcome. Table 3. Visual Acuity Outcomes at 2 Years a. Audio Author Interview Randomized Trial of Anti-VEGF to Prevent Proliferative Diabetic Retinopathy PDR and Diabetic Macular Edema DME.

Subscribe to Podcast. Supplement 1. Study Protocol and Statistical Analysis Plan. Supplement 2. eFigure 1. Mean Change in Central Subfield Thickness Over 2 Years eFigure 2. Mean Change in Optical Coherence Tomography Retinal Volume Over 2 Years eTable 1. Subgroup Analysis for the Development of PDR and CI-DME eTable 2.

Change in Diabetic Retinopathy Severity at 2 Years eTable 4. Change in Diabetic Retinopathy Severity at 1 Year eTable 5. Change in OCT Central Subfield Thickness and Retinal Volume at 2 Years eTable 6.

Change in OCT Central Subfield Thickness and Retinal Volume at 1 Year eTable 7. Change in Visual Acuity at 1 Year eTable 8. Subgroup Analysis for Change in Visual Acuity at 2 Years eTable 9. Annual Treatments for PDR and DME eTable Endophthalmitis Cases eTable Ocular Adverse Events of Interest in Study Eyes eTable Systemic Adverse Events of Interest eTable All Systemic Adverse Events eTable All Ocular Adverse Events.

Supplement 3. Data Sharing Statement. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema.

doi: Wells JA, Glassman AR, Ayala AR, et al; Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. Gross JG, Glassman AR, Jampol LM, et al; Writing Committee for the Diabetic Retinopathy Clinical Research Network.

Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. Sivaprasad S, Prevost AT, Vasconcelos JC, et al; CLARITY Study Group. Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks CLARITY : a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial.

Wilkinson CP, Ferris FL 3rd, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Regeneron Pharmaceuticals Inc. Published February 8, Accessed January 19, World Medical Association.

World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Bressler SB, Edwards AR, Chalam KV, et al; Diabetic Retinopathy Clinical Research Network Writing Committee. Reproducibility of spectral-domain optical coherence tomography retinal thickness measurements and conversion to equivalent time-domain metrics in diabetic macular edema.

National Institutes of Health. NIH policy and guidelines on the inclusion of women and minorities as subjects in clinical research. Accessed April 11, US Food and Drug Administration.

Collection of race and ethnicity data in clinical trials: guidance for industry and Food and Drug Administration staff. Published October 26, Aiello LP, Odia I, Glassman AR, et al.

Comparison of Early Treatment Diabetic Retinopathy Study standard 7-field imaging with ultrawide-field imaging for determining severity of diabetic retinopathy. Gross JG, Glassman AR, Liu D, et al; Diabetic Retinopathy Clinical Research Network.

Five-year outcomes of panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial.

Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Lin DY, Wei LJ, Ying Z. Checking the Cox model with cumulative sums of Martingale-based residuals.

Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Elman MJ, Ayala A, Bressler NM, et al; Diabetic Retinopathy Clinical Research Network.

Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy.

ETDRS report number 9. Baker CW, Glassman AR, Beaulieu WT, et al; DRCR Retina Network. Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial.

Wykoff CC, Nittala MG, Zhou B, et al; Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy Study Group. Intravitreal aflibercept for retinal nonperfusion in proliferative diabetic retinopathy: outcomes from the randomized RECOVERY trial.

Couturier A, Rey PA, Erginay A, et al. Widefield OCT-angiography and fluorescein angiography assessments of nonperfusion in diabetic retinopathy and edema treated with anti-vascular endothelial growth factor. Nicholson L, Crosby-Nwaobi R, Vasconcelos JC, et al.

Mechanistic evaluation of panretinal photocoagulation versus aflibercept in proliferative diabetic retinopathy: CLARITY substudy. Prevention of Severe Nonproliferative Diabetic Retinopathy Progression With More at Stake Than Visual Acuity. Practicality of Prophylactic Aflibercept to Reduce Diabetic Retinopathy Progression.

See More About Diabetic Retinopathy Ophthalmology Diabetes Diabetes and Endocrinology Macular Diseases Retinal Disorders. Select Your Interests Select Your Interests Customize your JAMA Network experience by selecting one or more topics from the list below.

Ocuphire Pharma Inc. announced this week it is screening the first patients in ZETA-1 Diaabeticretinopahty Phase 2 Metabolism-boosting smoothies to evaluate Retinopathg in non-proliferative diabetic Dark chocolate sensation Diabefic Diabetic retinopathy clinical trials mild proliferative diabetic retinopathy mild PDR. According to the company, the effects on diabetic macular edema will be explored as a secondary outcome. A number of retinal centers across the US are active and recruiting eligible diabetic retinopathy patients. The ZETA-1 trial is a randomly assigned, placebo-controlled, double-masked study designed to evaluate the efficacy of APX to improve diabetic retinopathy over 24 weeks.

Diabetic retinopathy clinical trials -

Chambers, MD, Supervisory Medical Officer, Division of Transplant and Ophthalmology Products of the FDA's Center for Drug Evaluation and Research, presented the agency's requirements for approving clinical drug trials in ophthalmology, with particular regard to past clinical trials of DR, and reviewed acceptable endpoints for such trials.

The Food, Drug, and Cosmetic Act of was passed in response to severe adverse events tied to the use of products that had been marketed without prior review. Citing a couple of well-known examples of ophthalmic products, Dr.

Chambers reminded the gathering that the entry of unapproved products into the market can result in disastrous consequences to patients, thus underscoring the primacy of safety concerns in the FDA regulatory process. The Act prohibits the transportation of unapproved drug products across state lines and requires substantial evidence of safety and efficacy for the approval of new drugs.

Chambers explained the distinction between Investigational New Drugs, which are experimental therapies that may be approved for subsets of selected patients through clinical trials, and the standard approval process for new drugs that would essentially approve the drugs for use in all patients.

Ultimately, FDA approval depends on whether a product's benefits outweigh its risks in the intended population for the designated indication as demonstrated in replicated, adequate, and well-controlled studies. Such studies must be carried out by scientific experts with the relevant training and experience required to determine whether the product has the purported effects under the stipulated conditions suggested or proposed in the labeling.

The identity, strength, purity, quality, and dosage form of new drug products must be established and standardized for consideration for approval. The federal code of regulations lists Good Manufacturing Practices, and facilities used to manufacture new drug products must comply with those practices.

Chambers noted that the FDA considers seven factors in deciding whether a given drug study is adequate and well controlled as required by the Act: clear statement of goals; design that incorporates a valid comparison with a control to enable an evaluation of the drug's quantitative effects; assurance that patients included have the condition s for which approval is sought; a method of minimizing bias in assigning patients to treatment and control groups; methods to minimize bias among subjects, observers, and analysts; reliable and well-defined methods of evaluation of subjects' responses; and analysis of results that are adequate to assess the drug's effects.

Currently, ranibizumab and aflibercept injections are approved for the treatment of DR in patients with DME.

In both cases, Dr. Chambers noted, approval was based on replicated, adequate, and well-controlled trials showing a statistically significant greater percentage of patients who improved by two or more steps on the ETDRS grading scale, compared with patients who did not receive treatment.

Chambers explained the reasons behind the approval of the drugs. Because the ETDRS scale is well established and step changes on the scale are associated with changing risks of long-term vision loss higher scores on the scale represent higher risks of vision loss , this outcome measure was found acceptable.

Further, more than one study found statistically significant, clinically meaningful superiority for the drugs in the study population. Chambers noted that approval typically requires more than one trial, given the law's requirement for replicability, but exceptions may be made when a single trial shows overwhelmingly convincing evidence or if the eligible study population is limited.

He hastened to add that the high prevalence of DR means that the FDA is unlikely to approve new drugs for DR based on a single trial. Superiority should be demonstrated over current practice, which is often the standard of care for a particular condition.

The use of two steps on the ETDRS scale reduces the chances of assessment artifacts. Chambers reminded the gathering that the FDA is willing to consider both prevention and regression of DR as potential outcome measures, drawing an analogy to infectious diseases. Chambers broadly categorized endpoints as anatomic endpoints, which are often structural; objective endpoints, which use specific instruments; subjective endpoints, which need interpretation; and patient-reported outcomes on single questions or on multiple domains.

The anatomic endpoints that the FDA considers acceptable final—not surrogate—endpoints of drug trials are improvement of DR; prevention of DR progression, cytomegalovirus retinitis progression, or retinal detachment; resolution of cell and flare, or conjunctival redness; and re-epithelialization of cornea with elimination of bacteria.

Among the acceptable objective endpoints are intraocular pressure and improvements in refractive power, pupil size, or tear production.

Chambers listed specific thresholds for each of these objective endpoints while cautioning that being able to measure an endpoint does not render it clinically meaningful.

Among the subjective endpoints that need interpretation are measures of visual function, such as visual acuity, color vision, visual fields, and contrast sensitivity.

Patient-reported outcomes include itching, pain, ocular irritation, ocular dryness, and quality-of-life measures, which is a composite outcome. Chambers noted that none of the currently reviewed patient-reported measures in ophthalmology drug trials have been validated or approved by the FDA.

The agency has issued a guidance document for manufacturers who wish to develop patient-reported outcome measures to support labeling claims. Drugs on accelerated approval must be studied after marketing to verify clinical benefits.

Chambers noted that no ophthalmic drugs have been approved based on surrogate endpoints. In many cases, he added, some surrogate endpoints have been used as final endpoints through labeling for specified populations without requiring final validation. Finally, Dr.

Chambers raised an array of questions that the ophthalmology community might consider in seeking FDA approval of new drugs: Does a candidate treatment reverse DR? Can the time of its effectiveness be determined? Does the treatment cure DR?

How many treatments are necessary? Is the treatment effect long-lasting? These are some of the common criteria that the FDA would consider in approving any new drugs for DR.

Food and Drug Administration approval of new drug products for DR would depend on whether the products' benefits outweigh their risks in the intended population for the designated indication as demonstrated in replicated, adequate, and well-controlled studies, which must be carried out by scientific experts with the relevant training and experience required to determine whether the product has the purported effects under the stipulated conditions suggested or proposed in the labeling.

Both prevention and regression of DR may be considered as potential outcome measures in DR clinical trials. Prior to seeking FDA approval, researchers and drug developers might consider an array of factors for candidate drug products for DR, including the ability of the products to reverse or cure DR, the ability to determine the products' window of effectiveness, the number of treatments required, and the duration of the treatment effect.

Providing an epidemiologic perspective, Dr. Klein, MD, began by explaining the need for accurate estimates of prevalence and incidence of DR. Because prevalence and incidence data are needed to accurately track disease trends, determine necessary patient services and associated costs, design clinical studies, and identify age-, sex-, and race-related disparities in care, data on the prevalence, severity, incidence, and progression of DR must be collected in a systematic manner in population-wide studies.

Among the regional studies of prevalence are the Beaver Dam Eye Study, the Chinese Eye Study, the Los Angeles Latino Eye Study, the New Jersey Study, and the Wisconsin Epidemiologic Study of Diabetic Retinopathy WESDR. The Atherosclerosis Risk in Communities Study is a multicenter study that has provided DR prevalence and incidence data, and the National Health and Nutrition Examination Survey NHANES is a federally sponsored, cross-sectional, nationwide survey of noninstitutionalized, civilian individuals in the United States that also provides DR prevalence and incidence data.

All the above-mentioned studies use the current gold-standard method for diagnosing DR, namely the grading of color stereoscopic film or digital fundus photographs 30° with seven overlapping standard retinal fields.

Klein described the Airlie House classification scheme, a standard method of grading fundus photographs for DR that has been used in gathering prevalence and incidence data.

The classification scheme typically examines the presence and extent of a number of lesions, including retinal microaneurysms, venous loops, and hard and soft exudates, among others. Based on the classification, a severity level for a given individual's eye is assigned, ranging from no DR 10 to PDR 81—85 , depending on the presence of certain lesions and combinations of lesions.

For a given individual, a combined severity score is obtained by assigning greater weight to the more severely affected eye. The severity score reflects ranking on the ETDRS DR severity scale, which is itself based on the Airlie House classification scheme.

The ETDRS severity scale is rank ordered as a series of steps from 1 to 23, and directional step changes on the scale reflect improvement or worsening of DR. The NHANES study, carried out from to , examined fundus photographs of individuals, of whom had diabetes, which was defined either by self-report of a previous diagnosis of diabetes or by a glycated hemoglobin A1c level of 6.

The prevalence measures were statistically weighted to provide a representative prevalence estimate of DR among adults with diabetes who were 40 years of age or older in the United States. The estimated prevalence for DR was In parentheses are the corresponding values for vision-threatening diabetes.

Klein noted that despite the survey's many strengths, NHANES did not include institutionalized individuals and did not distinguish between type 1 and type 2 diabetes; moreover, the area in the fundus photos was less than that captured by seven 30° images. Klein noted that there are no national estimates of incidence or progression of DR, and most available estimates come from old, regional studies.

Klein recalled findings on the year cumulative incidence of DR among patients with type 1 and type 2 diabetes from the WESDR study, carried out from through to through In summary, Dr. Klein noted, the estimated prevalence of PDR and clinically significant DME both appear to be on the wane, likely due to improved clinical management of blood pressure and sugar levels among patients with type 1 and type 2 diabetes.

The estimated prevalence of visual impairment appears to be on the wane among non-Hispanic whites with type 1 diabetes, likely due to earlier detection and treatment of vision-threatening retinopathy.

Demographic changes, such as increasing prevalence of DR among Mexican Americans and African Americans, may explain the increase in visual impairment reported in the NHANES study. Most projections of the worldwide future prevalence of DR are based on the assumption of unchanging risk profiles, clinical management practices, and life expectancies for people with diabetes.

Klein cautioned that such an assumption may lead to erroneous estimates. Klein noted the need for improved worldwide epidemiologic surveillance and screening methods for DR and for the incorporation of new imaging techniques into classification schemes and severity scales.

The to NHANES estimated the prevalence of DR to be The WESDR, the Beaver Dam Eye Study, and the National Health Interview Survey suggest that the EDPRG projections may overestimate the DR disease burden because the estimated prevalence of PDR and clinically significant DME both appear to be on the wane, likely due to improved clinical management of blood pressure and sugar levels among patients with type 1 and type 2 diabetes.

There is a need for improved worldwide epidemiologic surveillance and screening methods for DR and for the incorporation of new imaging techniques into classification schemes and severity scales of DR.

Sun, MD, MPH, discussed past findings on the progression and regression of DR from major clinical trials, and described the effects of various treatments on the natural history of DR worsening.

One striking observation from recent clinical trials of intravitreous anti-VEGF treatment of DME has been the finding that treatment with anti-VEGF often leads to an amelioration of DR severity in patients. To illustrate the point, Dr. Sun presented an example of color fundus photographs from a patient whose DME was treated with ranibizumab and who also showed a three-step improvement in DR severity on the ETDRS scale after 1 year of monthly treatments.

Such findings have raised the question whether intravitreous anti-VEGF treatment decreases rates of DR worsening and increases rates of DR improvement, and, if so, at what rates and at what minimal course of treatment.

Also of interest is the optimal time point at which anti-VEGF treatment must be initiated to achieve desired DR severity outcomes indicating a potential optimal therapeutic window and the possibility of non—anti-VEGF intravitreous agents that have similarly salutary effects on DR outcomes.

To address the question of the specific effects of anti-VEGF treatment for DME on DR severity, Dr. At baseline, most of the patients enrolled in these trials had moderate to severe NPDR, and after around 2 years of treatment with anti-VEGF agents, showed a decrease in the rates of two-step or more as well as three-step or more worsening of DR on the ETDRS scale.

Figure 3. Trial of ranibizumab for eyes with PDR at baseline. Image courtesy of Jennifer Sun. Figure 3 Trial of ranibizumab for eyes with PDR at baseline. This study suggested that DR severity improvement can be maintained with less frequent injections. Sun presented a case example of an eye with severe NPDR that received ranibizumab and showed a three-step improvement of DR severity after 36 months of continuous monthly therapy, continuing to maintain the improvement at 48 months, despite receiving only four injections between months 36 and The trial also provided clues regarding DR severity outcomes: A sham-treated group that was administered ranibizumab beginning at 24 months for a period of 1 year showed an improvement in DR severity in many patients, but the improvement in this group after 1 year of treatment did not match that seen among the patients originally selected to receive ranibizumab from the beginning of the trial at their 1-year follow-up visit.

The rate of new PDR events is also higher in eyes for which ranibizumab therapy is delayed by 2 years as compared with eyes that receive immediate ranibizumab treatment.

Together, these findings suggest the presence of a therapeutic window for anti-VEGF agents for achieving optimal DR severity outcomes. A delay of 2 or more years in initiating anti-VEGF treatment might lead to worse long-term DR severity outcomes.

Sun presented data from the MEAD study and the DRCR Network protocol B, both showing the beneficial effects of intravitreal steroids on DR severity. The MEAD study showed decreased rates of two-step or more worsening of DR severity on the ETDRS scale for patients who received a dexamethasone implant.

In conclusion, Dr. Sun pointed out that while the ETDRS scale is well established for monitoring DR progression in eyes with baseline NPDR, it is not designed to monitor changes in PDR.

Thus, she emphasized the need to develop new outcome measures for evaluating such changes in clinical trials and additional needs to determine how endpoints based on visual function are associated with DR in the early stages of the disease, as well as how such endpoints vary with DR severity over time.

Landmark clinical trials have shown not only a clear benefit for anti-VEGF agents in DR treatment but also that sustained improvement of DR can occur rapidly.

There is evidence that improvements in DR severity obtained with initial monthly dosing can be maintained in many eyes with less frequent injections of anti-VEGF drugs. The presence of a therapeutic window for anti-VEGF agents to achieve optimal DR severity outcomes underscores the importance of timely intervention, and a delay of 2 or more years in initiating anti-VEGF treatment might lead to worse long-term DR severity outcomes.

Results from several clinical trials suggest that steroids, like anti-VEGF drugs, might be effective in improving DR severity and reducing PDR-related outcomes. Sun focused her second presentation on future perspectives in DR treatment, underscoring the recurring theme that a focus on the early stages of the disease may be increasingly important in future clinical trial designs and endpoints.

Given recent advances in DR treatment, trends in better systemic clinical management of diabetes, improved patient education, and the high prevalence of diabetes worldwide, it would be reasonable to project an increasing trend in the number of patients with mild DR in the coming decades.

Recent reports of improvements in blood glucose control in small numbers of type 1 diabetes patients who received a bionic pancreas bode well for the future treatment of diabetes-related complications, including DR. Further, technological advances in retinal imaging, such as adaptive optics scanning laser ophthalmoscopy and optical coherence tomography angiography, which are currently largely used as research tools, could potentially allow earlier detection of DR and intervention to minimize or prevent the risk of vision loss.

Other advances have already reached clinics: Telemedicine programs currently allow the remote detection and diagnosis of DR for patients in the United States Veterans Health Administration and Indian Health Service IHS , the United Kingdom, and other countries.

The Joslin Vision Network, a telemedicine arm of the Beetham Eye Institute, together with the IHS, deploys 94 health care facilities across 25 U. states to perform annual screening of more than 16, patients. Some regional and national screening programs for DR both in the United States and in Europe now use automated retinal image grading systems to supplement their teleophthalmology efforts.

Dozens of ongoing DR clinical trials are exploring an array of agents that act through various molecular pathways. To ease the burden on patients and physicians of the current regimen of frequent, often monthly anti-VEGF treatments, a range of alternative sustained-release drug delivery systems are currently being explored or in development, including encapsulated cell techniques, drug conjugation in biodegradable vehicles, hydrogel contact lenses, and refillable port delivery systems, to name a few examples.

Despite the low frequency of adverse events, such as vision-threatening endophthalmitis associated with intravitreal injections, the need for noninvasive drug delivery, such as topical application, exists.

Further, individualized treatments tailored to the intravitreal biochemistry of patients is currently being explored, and preliminary studies of intravitreal biomarkers in animal models suggest a potential role for the synergistic effects of combined therapeutic agents in improving certain anatomic endpoints.

Sun noted that the coming decades are likely to witness improved understanding of disease biology, development of novel drugs and delivery systems, development of precise tools to classify patients based on risk profiles, and further improvements in systemic control of patients' blood glucose levels.

Sun urged the gathering to engage in a discussion centered on evaluating potential treatments and outcome measures for early-stage DR while continuing to pursue improved treatments for advanced DR. She also emphasized the need to define, update, and clarify anatomic and functional outcomes in clinical trials that the FDA would deem acceptable and to identify and validate biomarkers that would enable analysis of the natural history of DR progression.

Several clinical trials of novel drug delivery systems are currently being tested to ease the burden of monthly injections of anti-VEGF drugs for DR. The need to evaluate potential treatments and outcome measures for early-stage DR is as pressing as the need to pursue improved treatments for advanced DR.

Thus, biomarkers, endpoints, and trial designs must be explored to better understand the natural history of DR progression. Rorer, MD, Chief Ophthalmic Medical Officer of the FDA's Division of Ophthalmic and Ear, Nose, and Throat Devices within the Center for Devices and Radiological Health, Office of Device Evaluation, provided the FDA's perspectives on evaluating the performance of diagnostic medical devices used in clinical trials of DR, including those used to measure trial outcomes.

Examples of diagnostic devices are imaging systems, nonimaging in vivo diagnostic devices, devices that provide anatomic measures, devices that measure subject function, or algorithms that yield a composite, subject-specific output. Based on their potential risk to patients, devices are grouped into and regulated by the FDA as three classes.

Class I devices have a simple design, pose low risk to patients, and are subject to the lowest level of regulation, such as general controls e. Class II devices have a more complex design, pose a greater potential risk to patients, must meet a higher standard, such as special controls e.

Clearance does not imply that the FDA has reviewed clinical evidence supporting all potential clinical uses of the device. Class III devices have a complex design, pose the highest level of risk, are subject to the highest level of regulation, and hence require premarket approval through the premarket approval PMA application process.

In , when the FDA and NEI convened to discuss clinical trial endpoints for DR, visual acuity charts and fundus cameras were the main diagnostic devices used in DR therapeutic trials.

Around the same time, optical coherence tomography OCT and electronic visual acuity charts were put forth as promising diagnostic devices for measuring structural and functional outcomes, respectively, in future DR trials. Also available around this time were devices such as contrast sensitivity charts, perimeters, color vision testers, SLO, electroretinograms, and visual-evoked potentials.

To be useful in early therapeutic intervention trials for DR, a diagnostic device must be capable of detecting changes that occur early in the natural history of DR. Diagnostic device performance should support such an indication for use.

Other advances to assess blood flow, perfusion, and oxygenation in the retina include Doppler, stroboscopic fundus cameras, optical coherence angiography, and retinal oximeters, the latter two of which had not been FDA cleared or approved at the time of the workshop.

Metabolic imaging, which measures changes in reflectance or fluorescence elicited by light stimulation during disease-related metabolic stress, is another technique on the horizon that might help detect metabolic changes prior to the onset of irreversible cell damage in DR; retinal metabolic imaging had not been cleared or approved by the FDA as of the workshop.

Many health-related mobile applications are now available on the market. The majority of these applications do not meet the definition of a medical device, and thus the FDA does not regulate them. Some mobile applications apps , however, may meet the definition of medical devices, but owing to their low potential risk to patients, the FDA will not enforce requirements under the Federal Food, Drug, and Cosmetics Act for such devices.

The FDA exercises regulatory authority over only those mobile apps that are medical devices and whose function could pose safety risks to patients.

The February FDA guidance document on mobile medical applications MMAs elaborates these considerations. The FDA has a Web page dedicated to MMAs. Next, Dr. Rorer described paths to bringing diagnostic devices for DR to the market. Substantial equivalence depends on comparing the intended use and indications for use, technological characteristics, and performance measures of the devices.

When assessing the clinical performance of a diagnostic device for a particular indication for use, it is important for the device to be studied in the same context of that use—for the same purpose, on the intended patient population, by similar users, in the same type of clinical setting.

Rorer noted other considerations when designing studies for assessing the performance of diagnostic devices, using the case of imaging devices for illustration. When the device output includes qualitative output such as images, masked graders using preestablished criteria should assess the images obtained with the predicate and new devices in the same retinal location and in the same eye using equivalent parameters.

Numerous pairs of images from subjects across the intended population should be assessed, including subjects with various forms of pathology and those who are disease free. Assessments should include image quality as well as the identification of relevant pathology.

Devices that provide quantitative measurements should be evaluated for agreement, defined by how one device model's output compares with another's agreement is distinct from accuracy except when the device is compared with a gold standard ; bias, defined as the estimate of systematic measurement error defined as the mean difference between the measured value and the reference value and expressed as difference in measurement units or percent difference ; and precision, defined as an estimate of random measurement error and reflecting the closeness between repeated, independent measurements on the same eye under the specified testing conditions.

Variability related to devices, operators, settings, and patient alignment can affect precision. Repeatability and reproducibility are precision measures that vary with testing conditions, which must be clearly described. Rorer noted that agreement, bias, and precision measures can be either constant or variable across the measurement range of the device.

Further, these measures of device performance may not be identical for healthy subjects and those with pathology. These measures can also vary with image quality. Thus, appropriate measurement validation studies should be carried out. Clinical decision limits, which allow discrimination between different health states of subjects, must be established before conducting pivotal diagnostic clinical performance studies.

Once the limits are established, a pivotal diagnostic clinical performance study may be performed. Such a study compares the reported diagnosis or referral decision with the clinical reference standard, that is, the best available method for establishing the true status of a subject with respect to a target condition, and uses a different population of subjects than that used to determine clinical decision limits.

Clinical reference standards may be individual methods or combinations of methods, can evolve over time, and are typically established by evidence of current practice from medical and regulatory communities.

Therefore, any report of diagnostic device performance should always include the definition of the clinical reference standard used.

Rorer encouraged the gathering to solicit input and feedback from the FDA on proposed preclinical testing and clinical trial design through the presubmission program prior to embarking on studies and during early stages of device development.

This program provides investigators and manufacturers an opportunity to meet with the FDA. Rorer concluded the talk with a call to action, highlighting the need for well-characterized diagnostic devices with low bias and imprecision for detecting early-stage DR. She added that diagnostic device performance must be carefully considered when the devices are incorporated into therapeutic trials, especially for evaluating endpoints.

Prior to conducting a pivotal clinical trial to support the approval of a new therapeutic intervention for DR, it would be prudent to ensure that the performance of any diagnostic device planned for use during the course of the trial e.

In order to develop and market new medical products for the earlier treatment of DR, well-characterized diagnostic devices with low bias and imprecision for detecting early-stage DR are needed. Panel Discussion: Clinical Trial Designs for NPDR, PDR, and DME.

Ferris opened the panel discussion with a query regarding approaches to develop personalized treatments for DR, given the current federal focus on precision medicine and the fact that almost half of patients treated with anti-VEGF drugs for DR do not respond to the treatment.

To put this finding in perspective, Dr. Ferris observed that almost all patients with AMD who are treated with anti-VEGF drugs respond to the drugs but require long-term treatment.

Aiello acknowledged the query as an important one, underscoring the fact that current research efforts in the post-VEGF era would potentially allow researchers to use biomarkers to identify responders and nonresponders to anti-VEGF drugs among patients. Though the need for such studies is clear, methods to operationalize biomarker tracking remain to be established.

In particular, the small numbers of nonresponders in past clinical trials of anti-VEGF drugs would render clinical studies of treatment response challenging. That said, Dr.

Chambers noted that in the absence of additional treatment options for patients, personalizing treatment for small groups of patients poses a circular challenge, at least from an FDA labeling perspective.

Jampol raised a question regarding the FDA's views of the use of OCT as a tool to measure endpoints in clinical studies of DR, and Dr. Chambers responded that OCT measurements of retinal thickness changes are currently not approved endpoints because of insufficient data on retinal thickness changes and their effects on visual function; the extent and time period of clinically relevant changes in DR have not been established conclusively.

Given that DME can be seen as the final outcome of a number of cellular pathways, Dr. Ferris noted the need for clinical studies to identify biomarkers in early stages of the natural history of DR.

Chambers noted that a preliminary clinical study to identify responders might conceivably precede the actual trial of a therapeutic agent for the predefined responder population for which labeling is being sought. On a related note, Dr. Helen Nickerson raised the idea of exploring the future use of patients' electronic medical records to collect information on potential prognostic biomarkers in early stages of NPDR.

Sun raised a question regarding the conditions under which the FDA would accept secondary, as opposed to primary, outcomes in trials; and Dr.

Chambers responded that even if an outcome measure is not predefined, an evaluation of whether the outcome is a true, clinically meaningful result or due to chance would underlie the FDA's decision on approval of the drug treatment. Jampol asked under what conditions recent techniques such as wide-field fluorescein angiography, which can provide information about the retinal periphery, would be accepted for use in monitoring treatment response in therapeutic clinical studies.

Chambers responded that the wide availability of a technique is a factor considered in the FDA approval of the technique for measuring any given endpoint in drug trials, but that a more important factor is the clinical relevance of the endpoint measured by the technique as deemed by a majority of ophthalmologists.

Sun also raised the question of using incremental changes in measures such as visual acuity to monitor progression in early stages of the disease, but Dr. Chambers emphatically noted that given the future goal of balkanization of patient populations based on treatment response, the use of substantial changes in small populations of patients is more likely to be approved in future trials rather than the use of incremental changes in large numbers of patients.

Danis, MD, discussed alternate outcome variables in DR clinical trials. He noted that anatomic endpoints can be used to stratify patients according to disease severity and monitor disease progression and treatment response. They can serve as surrogate outcomes if validated in clinical studies.

To develop anatomic endpoints for eventual clinical use, proof-of-concept studies, single-center pilot studies, and large clinical trials must be carried out. These endpoints must show a strong, specific, and sensitive association with the outcome of interest; must be longitudinally studied in multiple populations; must be capable of being repeatable and reproducibly measured; and must generate normative data for future trials.

Currently, there are no FDA-approved surrogate anatomic endpoints for DME. Hence the need for alternate endpoints. Jaffe, MD, presented an example of a color fundus photo of a patient with NPDR and DME who improved following treatment as demonstrated by fundus photos and eye charts. The goal would be to use OCT to measure a corresponding resolution of DME and restoration of macular anatomy through changes in retinal thickness per volume as a surrogate endpoint in a trial.

Given that OCT is noninvasive, rapid, widely available, and quantitative, and allows cross-sectional and topographic evaluations over time, it would be an ideal technique to measure such an anatomic endpoint.

In past clinical trials, OCT has been used as a secondary endpoint to demonstrate a biological effect of drugs and has been correlated with visual function.

Jaffe presented an example of a trial of laser photocoagulation and the intravitreal steroid drug triamcinolone for DME in 69 eyes that were followed for 2 years; OCT measurements of decreases in retinal thickness demonstrated the drug's biological effect.

Together, these findings suggest that OCT is a valuable tool for the measurement of alternate anatomic endpoints in trials.

On a population level, cross-sectional studies and clinical trials have shown that OCT measures of retinal thickness are correlated with visual acuity. On a patient level, small studies have shown correlation between retinal thickness and visual acuity, but the correlation is far from perfect.

Part of the problem, Dr. Jaffe noted, is the increasing resolution of OCT instruments, which have progressively revealed structural details previously hidden from view, posing a challenge for correlational studies.

The development of software to perform automated segmentation of the different retinal layers allows the definition of boundaries between retinal layers for comparison as well as the quantification of multiple retinal layers and edema.

Comparison of such automated segmentation with that performed by expert graders at reading centers has validated such software. Jaffe presented an example of OCT images from a patient with DME in a clinical trial who had been treated with a steroid drug.

While the OCT images showed an improvement in DME over time, there was no corresponding improvement in visual acuity.

Automated segmentation revealed disruptions in the fine structure of different retinal layers that could not be observed in the OCT images without segmentation. Further, studies have revealed correlation between visual acuity and disruptions in the outer retinal layers, namely, the photoreceptor external limiting membrane and ellipsoid zone, as well as disruptions in the inner retinal layers.

Thus, by establishing a threshold of disrupted surface area for a given retinal microstructure, it would be possible to monitor worsening or improvement of the disruption over time using automated segmentation. Jaffe discussed the potential of OCT angiography, a focus of increasing attention among ophthalmologists.

The technique involves the acquisition of a series of B scans at a fixed retinal location; and changes in the contrasts of the OCT images, such as hyperreflectivity, correspond to retinal blood flow.

The retinal layers containing hyperreflective spots can be segmented to define OCT slabs, and dense-volume scans of the slabs can reveal deep structural details in layers of the vascular network at high resolution, including the perifoveal arcade, superficial capillary plexus, deep capillary plexus, choriocapillaris, Sattler's layer, Haller's layer, and the choroid Fig.

Figure 4. Open-label extension study of ranibizumab. Figure 4 Open-label extension study of ranibizumab. Danis noted that retinal specialists often observe DR lesions outside the seven standard photographic fields used in the ETDRS grading of fundus photos in DR, and raised the question of the relevance of these peripheral lesions as prognostic biomarkers of DR Fig.

Previous studies using ultrawide imaging have revealed substantial prevalence of such peripheral lesions and suggested that inclusion of these lesions may indicate increased severity on the ETDRS scale in some eyes.

For example, one study of eyes followed over more than 3 years using ultrawide imaging found that eyes with mostly peripheral lesions had a 5-fold increased risk of two-step DR progression over 3 years, and the absence of mostly peripheral lesions reduced the risk of DR worsening over 3 years by two-thirds Silva PS, et al.

IOVS ;ARVO E-Abstract He also noted that ultrawide-field imaging for DR severity is a widely available technique that remains to be widely adopted in clinical trials. A commercial SLO for ultrawide-field imaging from Optos, a United Kingdom—based manufacturer, is now available in hundreds of clinics worldwide, and the use of the device is being tested in ancillary projects to clinical trials.

The SLO has a field of capture of up to ° and a reasonable pixel resolution for microstructures, and previous studies have shown agreement between the grading performed using fundus photos and SLO images for DR severity.

Thus, Dr. Danis mentioned that the pilot studies might allow refinement of the prognostic ability of the ETDRS grading scale using the peripheral lesion data. A 5-year study of DR severity that compares the standard seven-field fundus imaging and ultrawide-field imaging using Optos SLO is anticipated under the aegis of the DRCR Network.

Figure 5. Automated segmentation and dense-volume scans can reveal fine structural details in retinal layers. Image courtesy of Glen Jaffe. Figure 5 Automated segmentation and dense-volume scans can reveal fine structural details in retinal layers.

Based on previous studies that showed an association between the location and area of nonperfusion in the retinal periphery and DR severity and the risk of onset of PDR, Dr. Danis suggested that fluorescein angiography of the peripheral fundus might have prognostic value in clinical studies.

Parameters such as area of nonperfusion in the periphery could be reproducibly measured using segmentation programs and SLO, suggesting that vascular nonperfusion might serve as a potential clinical trial endpoint for DR. Another potential endpoint-related technique is OCT angiography, which provides images of unparalleled resolution and contrast.

Segmentation of digital images can help generate vascular density maps, and Doppler and phase signals can be used to measure blood flow, resulting in quantitative measures of vasculature using OCT angiography.

One commercial instrument is currently available in around clinics and must be validated in proof-of-concept studies before the technique can be considered for clinical trials.

Another technique that might hold potential for use in clinical trials is adaptive optics SLO, a noninvasive technique to track erythrocyte aggregates in retinal blood capillaries.

Jaffe noted that in addition to ongoing collaborations between reading centers and the DRCR Network, there is a need for more partnerships with industry. The new imaging techniques must be tested in current and future prospective trials to establish structure—visual function correlations.

Such trials might yield anatomic surrogates of visual function. The potentially superior prognostic value of such endpoints might help refine current DR severity scales.

Validation of an anatomic endpoint requires concerted effort in multiple clinical trials to demonstrate a sensitive and specific association with functional outcomes.

Ultrawide-field fundus imaging holds promise to add additional prognostic information regarding DR progression, which may refine the sensitivity of the ETDRS scale in clinical trials. Change in retinal capillary nonperfusion area over time as measured with ultrawide-field fluorescein angiography to quantitatively measure peripheral capillary nonperfusion is another potential endpoint of high clinical relevance for clinical research because of its relationship with progression to PDR and possibly DME.

Applications of new technology such as OCT angiography and adaptive optics SLO imaging to the study of DR and DME are in early development but may provide useful metrics to monitor and predict disease progression.

Larsen, MD, DMsc, discussed clinically significant measures of visual function that might predict long-term changes in visual acuity.

Among the potential endpoints for DR clinical trials that are directly relevant to patients are best-corrected visual acuity, standard visual fields in photopic and scotopic modes, contrast sensitivity, glare sensitivity, color vision, dark adaptation, and practical tests such as maze navigation.

The potential surrogate endpoints include electroretinograms, visual-evoked potentials, and frequency-doubling perimetry. Larsen noted that the long-term predictive value and robustness of several of these potential endpoints must be validated for use in DR clinical trials.

He presented data from a Swedish study showing visual field deterioration over a 5-year period in patients with diabetes. Still other studies have shown that diabetic patients with NPDR show abnormal frequency-doubling perimetry and poor sensitivity to dark adaptation.

Larsen also presented evidence from an array of studies showing that glycemia can act as a confounder in studies of psychophysical measures such as ERG amplitude and dark adaptation. Studies involving insulin pump therapy for people with diabetes have shown a slow improvement in dark adaptation and ERG measures, and the duration of the glycemic history appears to influence the rate of improvement.

Other confounders of visual field studies include lens aging and cataract surgery. Larsen proposed visual field studies as a strong candidate for a potential endpoint in clinical trials, given the known clinical relevance of the endpoint and the different ways in which it can be refined.

Visual field examination, a method with accepted clinical relevance, is a promising candidate endpoint for early intervention studies in DR. Confounders of this endpoint that should be taken into account include glycemia, glycemic history, lens aging, and cataract surgery. Joussen, MD, PhD, described the need for endpoints that would help predict clinical outcomes at each stage in the development process, from preclinical models to patient-relevant endpoints.

Joussen stressed the need to combine molecular, structural, and functional data in computational models and machine-based learning to develop patient-relevant endpoints for DR. Advances in imaging techniques have allowed a detailed characterization of retinal pathology in patients with DR.

For example, wide-angle angiography has revealed ischemia in the retinal periphery in many patients; and the presence of hyperreflective spots in OCT, which may represent early markers of inflammation, has been reported in patients with diabetes before overt clinical signs of DR begin to appear.

Further, activated microglial cells, nervous system cells that respond to inflammation, have been found in the retina of patients with diabetes. Optical coherence tomography and SLO have been used to determine the extent of macular edema in patients with DME and to characterize retinal blood vessels.

Interframe analysis of OCT angiography data can provide useful information about retinal blood flow contrasts, and OCT angiography can be used to detect microaneurysms, improve capillary visualizations, and derive three-dimensional reconstructions of the microvasculature of the retina and the choroid.

Doppler OCT can be used to visualize the pulsatile nature and dynamics of the bidirectional flow of blood in arteries and veins. Retinal oxymetry has been used to measure light absorbance and oxygen saturation in blood vessels of patients with PDR before and after treatment.

Phase-variance OCT, which measures neuronal potentials, can be used to distinguish retinal and choroidal blood vessels from nerves. However, many of these endpoints and imaging modalities remain to be validated for clinical use in substantial studies. Given that diabetes is a complex disease with several potential comorbidities such as stroke, cardiovascular disease, diabetic nephropathy, and diabetic neuropathy, Dr.

Joussen emphasized the need to focus on common molecular pathways underlying DR and its frequent comorbidities. The 2-year cumulative probability of developing PDR was The mean SD change in VA from baseline to 2 years was not significant, Eyes with moderate to severe NPDR treatment with periodic aflibercept decreased the development of PDR or vision-reducing CI-DME.

However, through 2 years, preventive aflibercept did not confer VA benefit compared with observation plus treatment with aflibercept only after development of PDR or vision-reducing CI-DME. Create account Log in. Main Page. Getting Started.

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Francesc March de Ribot, MD, PhD. All authors and contributors:. Leo A. Kim, MD, PhD , Koushik Tripathy, MD AIIMS , FRCS Glasgow , Francesc March de Ribot, MD, PhD.

Assigned editor:. Koushik Tripathy, MD AIIMS , FRCS Glasgow.

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