The Diabetic Retinopathy Clinical Research NetworkThe Diabetic Retinopathy

Clinical Research NetworkPeripheral 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 

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BackgroundBackground

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

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Optomap® System Optomap® System

• Noncontact SLO technology with ultra-widefield high definition retinal imaging

• Captures over 80% of retina

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• Green and red laser wavelengths scan simultaneously

• Red-free imaging and FA capability

200° field

Retinal Pathology in the ETDRS 7 Standard Fields

Retinal Pathology in the ETDRS 7 Standard Fields

NVE <1/2 Disc Area

HMA >2A

IRMA >8A

HMA >2A

Identification of Additional Retinal Pathology on UWF Image

Identification of Additional Retinal Pathology on UWF Image

H/Ma = hemorrhages and/or microaneurysms; VB = venous beading; IRMA = intraretinal microvascular abnormality; NVE = new vessels elsewhere

Distribution of Diabetic Retinopathy Lesions(total fields evaluated per lesion = 1020)

Distribution of Diabetic Retinopathy Lesions(total fields evaluated per lesion = 1020)

(Silva, et al. AJO 2012)

H/MA

H/Ma = hemorrhages and/or microaneurysms; VB = venous beading; IRMA = intraretinal microvascular abnormality; NVE = new vessels elsewhere

Distribution of Diabetic Retinopathy Lesions(total fields evaluated per lesion = 1020)

Distribution of Diabetic Retinopathy Lesions(total fields evaluated per lesion = 1020)

(Silva, et al. AJO 2012)

H/MA

H/Ma = hemorrhages and/or microaneurysms; VB = venous beading; IRMA = intraretinal microvascular abnormality; NVE = new vessels elsewhere

Distribution of Diabetic Retinopathy Lesions(total fields evaluated per lesion = 1020)

Distribution of Diabetic Retinopathy Lesions(total fields evaluated per lesion = 1020)

(Silva, et al. AJO 2012)

H/MA

Peripheral lesions might have suggested a more severe retinopathy severity in 10% of eyes

Study RationaleStudy 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

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Peripheral Field DefinitionsPeripheral Field Definitions

1010(Silva, et al. Ophthalmology 2013)

Study DefinitionsStudy 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

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ObjectivesObjectives

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.

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ObjectivesObjectivesMajor 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

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At least one eye meeting all of the following criteria:• NPDR based on clinical exam (Confirmed ETDRS level 35 - 53

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

Study DesignStudy DesignProspective, observational longitudinal study

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.

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.

OutcomesOutcomes Longitudinal Analysis

• Relative risk of 2 or more step worsening of DR severity over 4 years in the groups with and without predominantly peripheral lesions on UWF images at baseline.

• Secondary analysis - additional risk factors including: o Type of peripheral lesionso Location of peripheral lesions o Extent of peripheral or posterior non-perfusion on

FAo Presence or absence of peripheral lesions o Whether DR severity level is different within 7-

modified fields compared with UWF images1515

Outcomes (Cont.)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

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Outcomes (Cont.)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

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Major Eligibility CriteriaMajor Eligibility Criteria Enrollment Criteria (one or two study eyes)

• Adults with Type 1 or type 2 diabetes

• NPDR based on clinical exam

o Confirmed ETDRS level 35 - 53 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

o Enrollment will be limited to only 50% of the cohort with any prior intravitreal anti-VEGF or steroid for DME.

• No DME in the central subfield on clinical exam or OCT

o Cirrus: < 290 µm for women; < 305 µm for men

o Spectralis: < 305µm for women; < 320 µm for men1818

Major Eligibility Criteria Cont.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.

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Major Exclusion CriteriaMajor 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. 2020

Schedule of Study Visit and Examination Procedures

Schedule of Study Visit and Examination Procedures

a Macular and choroidal thickness scansb Blood collection must occur before any intravitreous injection c Urine must be collected before FA

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Visit Window Baseline Annual Visits 1 yr 2 yr 3 yr 4 yr

Best Corrected Visual Acuity x x x x x

Eye Exam x x x x x

7- Field Fundus Photos x

UWF Photos x x x x x

UWF FA x x x

OCTa x x x x x

Bloodb and Urinec collection x x x x x

BP x x x x x

Schedule of Phone Calls:Medical Conditions Assessment

Schedule of Phone Calls:Medical Conditions Assessment

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 2222

Visit Window BaselineAnnual Visits

1-4 Years

Phone Calls at 6, 18, 30, and 42 months (± 1 mo)

Medical Conditions Assessment x x x

Baseline Testing ProceduresBaseline 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 2323

Image Acquisition ProceduresImage 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)

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FA AcquisitionFA Acquisition

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One Study Eye?

Right eye is transit eye

and all right eye images taken first

unless taking left eye first will increase

image quality.

Study eye is transit eye. Fellow eye

images taken afterwards. Mid and late

phase images also on study

eye first

Yes No

FA Image Acquisition(16 total images)

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

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Enrollment FormEnrollment 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

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Sample SizeSample Size

Within each group aboveo ~40% w/ mild NPDR(ETDRS levels 35) o ~40% w/ moderate or moderately severe NPDR (ETDRS

levels 43-47) o ~20% w/ severe NPDR (ETDRS level 53).

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Predominantly Peripheral

Lesions

Predominantly Peripheral

Lesions

NOT Predominantly

Peripheral Lesions

NOT Predominantly

Peripheral Lesions

Treatment for PDR or DMETreatment 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.

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UWF Reading CenterUWF 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

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CollaborationCollaboration

Optos® Company 1. Loan 15 machines

Machine training/software support

JDRF – providing funding for first 2 years of study• ~$500,000

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Stay Out of Trouble: Use the Computer!

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.

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***CRITICAL***Investigator AND Coordinator Role Enrolling the Correct Participants

***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 coordinatorVerify patient has reliable means of

transportation to study siteConsider travel distance and patient’s other

health conditions3333

Certification Requirements 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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Thank You