1. The Diabetic Retinopathy Clinical Research Network
Peripheral Diabetic Retinopathy (DR) Lesions on Ultrawide-field Fundus Images and Risk of DR Worsening Over Time
Protocol Version 2.0
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 

2. 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

3. 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

4. Retinal Pathology in the ETDRS 7 Standard Fields

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

6. 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)

7. 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)

8. 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)

9. 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

10. 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)

11. 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.

12. 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.

13. 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
To determine if retinal vascular characteristics are associated with kidney and cardiovascular complications

14. Study Design Prospective, observational longitudinal study
At least one eye meeting all of the following criteria:
NPDR based on clinical exam (Confirmed ETDRS level on 7-field photos, without the use of ultrawide-field imaging)
No CI-DME on clinical exam or OCT
No history of PRP or vitrectomy, and PRP not anticipated for next 6 mos.
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.

15. 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

16. 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
Secondary analysis also includes
Evaluation of risk factors for correlation with eGFR, albumin-creatinine ratio and cardiovascular events

17. Outcomes (Cont.) 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
Correlation between baseline NPDR level and eGFR and urine albumin-creatinine ratio and between baseline NPDR level and cardiovascular events

18. 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 on 7-field photos
No history of PRP or vitrectomy and PRP is not anticipated for next 6 months
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

19. 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.

20. 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 systemic drug therapy or drug therapy that affects the study eye.
Individual is expecting to move out of area of clinical center to area not covered by another clinical center during next 24 months.

21. Schedule of Study Visit and Examination Procedures
Visit Window
Baseline
Annual Visits
1 yr yr yr yr
Best Corrected Visual Acuity x
Eye Exam
7- Field Fundus Photos
UWF Photos
UWF FA
OCTa
Bloodb and Urinec collection BP
a Macular and choroidal thickness scans b Blood collection must occur before any intravitreous injection c Urine must be collected before FA

22. Schedule of Phone Calls: Medical Conditions Assessment
Visit Window
Baseline
Annual Visits
1-4 Years
Phone Calls at 6, 18, 30, and 42 months (± 1 mo)
Medical Conditions Assessment x
Medical Conditions Assessment:
Collected in person at baseline and each annual visit
Collected during a phone call at months 6, 18, 30 and 42 (± 1 month) (*Note – can be collected in person if the patient is in the clinic for a usual care visit during the phone call window)
Asks about medical conditions and events including cardiovascular events

23. 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 (macular AND choroidal thickness)
Measurement of blood pressure
Blood and Urine collection
Medical conditions assessment
Within 21 Days of Enrollment:
ETDRS protocol 7 modified-field fundus photography in both eyes
UWF images
UWF FA

24. 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)

25. 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.

26. 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

27. 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

28. 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).

29. 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, intravitreal anti-VEGF or steroid treatment, or vitrectomy is performed, the study procedures (protocol refraction and VA as well as imaging procedures as performed for 1 year visit) should be performed.
After treatment, study participants will continue to follow-up as per original study schedule through full 4 years.

30. 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

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

32. 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.

33. ***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

34. 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

35. Thank You