JCHR

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Study Objective

1. To assess whether evaluation of the retinal far periphery on UWF images improves the 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.

 

This objective will be accomplished through the following specific analyses:

1. Assessment of whether any predominance versus no predominance of diabetic retinopathy lesions (see definition section 1.7) in any field of the retinal periphery (lesions located primarily outside versus primarily within the 7 standard ETDRS fields) on UWF images is associated with rates of DR worsening over time
2. Redefining diabetic retinopathy severity grading level based on the status of the periphery and assessing whether differences in severity level assessment between grading with or without inclusion of peripheral findings is associated with rates of DR worsening over time.
3. Evaluating how often mydriatic 200º UWF digital photographs are comparable to mydriatic DRCR.net protocol modified 7-field stereoscopic digital photographs for the grading and assessment of DR, and whether grading of the UWF photographs can be reliably used as an outcome variable in future clinical trials.
4. Determining whether extent and location (peripheral versus posterior) of nonperfusion on UWF fluorescein angiograms is associated with baseline DR and DME severity as well as rates of DR and DME worsening over time

 

Secondary Objective:

To explore whether the prevalence and severity of diabetic nephropathy or cardiovascular disease at baseline and the incidence of these findings over time (4 years) is associated with

• The severity and location (within and peripheral to the standard ETDRS 7 fields) of classic non-proliferative diabetic retinopathy lesions including hemorrhages and microaneurysms, venous beading, intraretinal microvascular anomalies, and neovascularization) identified on UWF FA and UWF fundus photos.

• The extent of peripheral non-perfusion on UWF fluorescein angiography

 

 

  Definitions

1.      Ultrawide field: Fundus photography field that is 100º or more

2.      Peripheral Lesions: Lesions located outside of the modified ETDRS 7-standard fields

3.      A lesion (each of the following lesions is graded separately:  hemorrhages/microaneurysms, venous beading, intraretinal microvascular abnormalities and neovascularization elsewhere) is predominantly peripheral in a specific field (fields 3-7 graded separately) if more than 50% of the lesions are in the retinal periphery compared with within the modified ETDRS fields taking into account the number and extent.   

4.      A lesion is uniformly distributed in a specific field if the severity of lesion (taking into account number and extent) is approximately equivalent both within and outside the ETDRS field

5.      An eye has predominantly peripheral lesions if any one of the lesions graded in any field is predominantly peripheral.

 

  Study Design and Synopsis of Protocol

A.    Study Design

Prospective, observational longitudinal study

 

B.     Major Eligibility Criteria

·         Age >=18 years.

·         Type 1 or type 2 diabetes

·         Ability to cooperate with imaging procedures

·         At least one eye with each of the following:

a.       No known substantial media opacities that would preclude successful imaging

b.      No history of panretinal (scatter) photocoagulation (PRP) and PRP is not anticipated for 6 months following study enrollment.

c.       Eyes that have not previously received treatment with intravitreal agents over the prior 12 months and treatment is not anticipated for the next 6 months

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

                                                            ii.      Macular edema involving the central subfield on OCT or clinical exam is an exclusion

d.      Non-proliferative diabetic retinopathy (ETDRS level 35- level 53) on clinical exam and based on modified 7 field ETDRS grading, without the use of ultrawide-field imaging.   

Participants may have 1 or 2 study eyes.

 

C.    Sample Size

At least 350 participants are expected to be enrolled in this study.  At least 175 participants with predominantly peripheral lesions and at least 175 participants without predominantly peripheral lesions will be enrolled.  In order to achieve a minimum of 175 participants in each of these primary cohorts, over enrollment of one of the groups may be necessary.  Within each primary cohort, participant enrollment will be stratified so that there will be approximately 70 eyes (~40%) of the cohort with mild NPDR (ETDRS levels 35), approximately 70 eyes (~40%) with moderate or moderately severe NPDR (ETDRS levels 43-47) and approximately 35 eyes (~20%) with severe NPDR (ETDRS level 53).  Throughout the study, the distribution of DR severity levels will be evaluated and enrollment may be tailored to add balance between the strata.  In addition, to ensure sufficient numbers in each retinopathy severity group as outlined above, over enrolment of a retinopathy severity group may be necessary.  Retinopathy levels will be based on the ETDRS 7-modified field photographs.  Primary analyses will be adjusted for baseline level of retinopathy based on the modified 7 field grading. 

   

D.    Protocol Summary

The participant cohort will consist of individuals with type I and type II diabetes with NPDR (ETDRS level 35- level 53) based on modified 7 field ETDRS grading and without central involved DME in at least one eye.

Visits will occur annually for a total of four years.  During each study visit, participants will receive a comprehensive dilated eye examination and will have 200º mydriatic UWF fundus images taken using the Optos system for each eye. Modified 7 standard field color digital photographs will be acquired following a DRCR.net protocol at baseline only to be compared with Optos images.  Ultrawide-Field fluorescein angiography will also be obtained at baseline, 1 year, and 4 years.  The DRCR.net protocol images will be obtained by a study imager certified by the DRCR.net for that imaging protocol.  The images will be sent to the DRCR.net Coordinating Center (uploaded through the website as available) and sent to the reading center for further evaluation.

 

E.     Schedule of Study Visit and Examination Procedures

 

	Baseline	1 year ± 2 month	2 year ± 3 month	3 year ± 3 month	4 year ± 3 months
Visit and Visit Window						Phone Call 6, 18, 30, and 42 months (± 1 mo)
Best corrected visual acuity	X	X	X	X	X
Eye Exam	X	X	X	X	X
DRCR.net 7- modified field Fundus Photographya	X
UWF Imagingb	X	X	X	X	X
UWF Fluorescein Angiographyb	X	X			X
Spectral Domain OCTc	X	X	X	X	X
Blood collection (HbA1c/eGFR)d,	X	X	X	X	X
BP	X	X	X	X	X
Urine Samplee	X	X	X	X	X
Medical Conditions  Assessment	X	X	X	X	X	X

1. a. lyses will be performed on the comparison between 7 modified fields and the UWFAnalyses will be performed on the comparison between DR severity grading from 7 modified fields and the UWF at the baseline visit.  If the two modalities are not sufficiently comparable within the 7 fields, 7 field photos will also be obtained annually.
2. DddfjlsUWF Imaging, FA, and OCT must also be performed prior to the initiation of PRP, any intravitreal treatment with anti-VEGF or steroid agentsFA iFSfd, or vitrectomy
3. Includes macular thickness and choroidal thickness scans
4. Blood collection must occur prior to any intravitreous injection
5. Must be obtained prior to fluorescein angiography.  Albumin and creatinine will be measured.

 

 

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