The Diabetic Retinopathy Clinical Research Network Peripheral Diabetic Retinopathy (DR) Lesions on Ultrawide-field Fundus Images and Risk of DR Worsening Over Time 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, EY14229, EY018817 

Background Current standard DRCR.net protocol for digital images for diabetic retinopathy 7-field or 4-field wide angle digital photos Disadvantages of current methods Up to 16 or more flashes per eye Combined images capture ~30% of the retina JKS- edited last bullet point 2

Optomap® System Noncontact SLO technology with ultra- widefield high definition retinal imaging Captures over 80% of retina 200° field Green and red laser wavelengths scan simultaneously Red-free imaging and FA capability 3

Retinal Pathology in the ETDRS 7 Standard Fields

Identification of Additional Retinal Pathology on UWF Image HMA >2A NVE <1/2 Disc Area IRMA >8A HMA >2A

H/Ma = hemorrhages and/or microaneurysms; VB = venous beading; Distribution of Diabetic Retinopathy Lesions (total fields evaluated per lesion = 1020) This graph shows the distribution of diabetic retinopathy lesions. Over 60% of all DR lesions WERE predominantly evident in the retinal area imaged by ETDRS defined fields H/MA H/Ma = hemorrhages and/or microaneurysms; VB = venous beading; IRMA = intraretinal microvascular abnormality; NVE = new vessels elsewhere (Silva, et al. AJO 2012)

H/Ma = hemorrhages and/or microaneurysms; VB = venous beading; Distribution of Diabetic Retinopathy Lesions (total fields evaluated per lesion = 1020) This graph shows the distribution of diabetic retinopathy lesions. Over 60% of all DR lesions WERE predominantly evident in the retinal area imaged by ETDRS defined fields H/MA H/Ma = hemorrhages and/or microaneurysms; VB = venous beading; IRMA = intraretinal microvascular abnormality; NVE = new vessels elsewhere (Silva, et al. AJO 2012)

H/Ma = hemorrhages and/or microaneurysms; VB = venous beading; Distribution of Diabetic Retinopathy Lesions (total fields evaluated per lesion = 1020) Peripheral lesions might have suggested a more severe retinopathy severity in 10% of eyes This graph shows the distribution of diabetic retinopathy lesions. Over 60% of all DR lesions WERE predominantly evident in the retinal area imaged by ETDRS defined fields H/MA H/Ma = hemorrhages and/or microaneurysms; VB = venous beading; IRMA = intraretinal microvascular abnormality; NVE = new vessels elsewhere (Silva, et al. AJO 2012)

Study Rationale If peripheral DR lesions improve our ability to predict DR worsening or improvement, this could: Change patient management: evaluation and follow-up Give new insights into mechanisms for changes in retinal pathology Allow fewer images leading to faster imaging time and greater patient comfort

Peripheral Field Definitions   H/ma’s, venous beading, IRMA, and NVE are evaluated and compared in each ETDRS field and the corresponding UWF field (including the far periphery),  as:  (1) lesion predominantly or only present within ETDRS fields, (2) lesion predominantly or only present outside ETDRS fields, (3) lesion distributed approximately equally in areas imaged and not imaged by ETDRS fields, (4) ETDRS field not gradable, and (5) peripheral UWF field not gradable. (Silva, et al. Ophthalmology 2013)

Study Definitions Ultra-wide field: Fundus photography field that is 100º or more Peripheral Lesions: Lesions located outside of the modified ETDRS 7-standard fields Predominantly Peripheral: Severity of lesion (taking into account # and extent) is greater in the retinal periphery outside the standard ETDRS field than within the ETDRS field.  Uniform Distribution: Severity of lesion (taking into account # and extent) is approximately equivalent both within and outside the ETDRS field H/ma’s, venous beading, IRMA, and NVE are evaluated and compared in each ETDRS field and the corresponding UWF field (including the far periphery),  as:  (1) lesion predominantly or only present within ETDRS fields, (2) lesion predominantly or only present outside ETDRS fields, (3) lesion distributed approximately equally in areas imaged and not imaged by ETDRS fields, (4) ETDRS field not gradable, and (5) peripheral UWF field not gradable.  

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.

Objectives Major Secondary Objectives To evaluate how often UWF photos are comparable to DRCR.net modified 7-field photos To determine whether extent and location of non-perfusion on UWF FA is predictive of rates of DR worsening over time Redefine DR severity grading based on evaluation of the periphery

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 - 53 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.

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 the progression to PDR, improvement of DR, improvement, worsening, or development of DME, and development of VH 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

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 - 53 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.

Major Exclusion Criteria Hx chronic renal failure requiring dialysis or kidney transplant. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to enrollment or plans to do so in the next 4 months. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to enrollment. These drugs should not be used during the study. Participation in investigational trial within 30 days of enrollment that involved treatment with any drug that has not received regulatory approval for indication being studied. Individual is expecting to move out of area of clinical center to area not covered by another clinical center during next 24 months.

Schedule of Study Visit and Examination Procedures Visit Window Baseline Annual Visits 1-4 Years Best Corrected Visual Acuity x Eye Exam 7- Field Fundus Photos UWF Photos UWF FA xa OCT HbA1c BP a1 and 4 years only

Baseline Testing Procedures Day of Enrollment: Refraction followed by E-ETDRS visual acuity testing using the refraction obtained in both eyes Ocular exam in both eyes OCT on both eyes Measurement of blood pressure Within 21 Days of Enrollment: ETDRS protocol 7 modified-field fundus photography in both eyes UWF images UWF FA HbA1c within 3 weeks of enrollment

Image Acquisition Procedures The 200º UWF images should be obtained first (acquired after pupillary dilation). Check pupil dilation prior to imaging If not 5 mm, consider reapplying dilating drops Images obtained on each eye (12 total images) 2 central fixation 200° 1 superior 200° 1 inferior 200° 1 nasal 200° (Baseline only) 1 temporal 200° (Baseline only)

FA Acquisition Yes No One Study Eye? Study eye is transit eye. Fellow eye images taken afterwards. Mid and late phase images also on study eye first Right eye is transit eye and all right eye images taken first unless taking left eye first will increase image quality.

FA Image Acquisition (16 total images) Early phase (starting at 15 sec) 3 200° central fixation images study eye 3 200° central fixation images fellow eye Late phase (starting at 4 min) 1 central fixation image study eye 1 superior steered 1 inferior steered                1 nasal steered 1 temporal steered Followed by the same on the fellow eye

Enrollment Form Before submitting, investigator MUST Confirm eligibility Confirm patient’s willingness to accept follow-up schedule and protocol requirements Make sure patient has been properly informed of potential risks/benefits via consent process

Predominantly Peripheral Lesions NOT Predominantly Peripheral Lesions Sample Size Predominantly Peripheral Lesions NOT Predominantly Peripheral Lesions Within each group above ~40% w/ mild NPDR(ETDRS levels 35) ~40% w/ moderate or moderately severe NPDR (ETDRS levels 43-47) ~20% w/ severe NPDR (ETDRS level 53).

Treatment for PDR or DME Tx of DR and/or DME is at investigator discretion (including initiation of PRP or anti-VEGF). Prior to the 1st time PRP is performed or intravitreal anti-VEGF or steroid treatment is administered, the study procedures (protocol refraction and VA as well as imaging procedures as performed for 1 year visit) should be performed. After PRP or intravitreal treatment, study participants will continue to follow-up as per original study schedule through full 4 years.

UWF Reading Center Joslin Diabetes Center will Grade UWF photos, UWF FA, and 7-field photos for the study Provide training and quality feedback as needed JKS- changed pictures

Collaboration Optos® Company Loan 15 machines Machine training/software support JDRF – providing funding for first 2 years of study ~$500,000

Stay Out of Trouble: Use the Computer! All visits must be entered in real time! Menu includes required exams and visit reminders. Forms include visit specific instructions (i.e. required on study eye only or both eyes) Contact CC prior to any deviations from protocol.

***CRITICAL*** Investigator AND Coordinator Role Enrolling the Correct Participants Educate patient with a thorough ICF process so that they understand: Time commitment Assess likelihood that patient will adhere to protocol; annual visit for 4 YEARS Listen to the coordinator Verify patient has reliable means of transportation to study site Consider travel distance and patient’s other health conditions

Certification Requirements Site Specific IRB approval of protocol and ICF UWF Technician certification (performed on site by Optos) Investigator/Coordinator Protocol Q+A (80% correct or higher) Protocol acceptance form Competing studies form (investigator only) Protocol review teleconference w/in 2 months Coordinator Mock informed consent

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