Transcript 1 month - Jaeb Center for Health Research

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
1
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
2
Optomap® System
• Noncontact SLO
technology with ultrawidefield high definition
retinal imaging
200° field
• Captures over 80% of
retina
•
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
Distribution of Diabetic Retinopathy Lesions
(total fields evaluated per lesion = 1020)
100%
2%
80%
30%
4%
26%
27%
34%
13%
60%
40%
68%
61%
69%
66%
H/MA
HMA
VB
IRMA
NVE
20%
0%
Uniform distribution
Outside ETDRS fields
Within ETDRS fields
H/Ma = hemorrhages and/or microaneurysms; VB = venous beading;
IRMA = intraretinal microvascular abnormality; NVE = new vessels elsewhere
(Silva, et al. AJO 2012)
Distribution of Diabetic Retinopathy Lesions
(total fields evaluated per lesion = 1020)
100%
2%
80%
30%
4%
26%
27%
34%
13%
60%
40%
68%
61%
69%
66%
H/MA
HMA
VB
IRMA
NVE
20%
0%
Uniform distribution
Outside ETDRS fields
Within ETDRS fields
H/Ma = hemorrhages and/or microaneurysms; VB = venous beading;
IRMA = intraretinal microvascular abnormality; NVE = new vessels elsewhere
(Silva, et al. AJO 2012)
Distribution of Diabetic Retinopathy Lesions
(total fields evaluated per lesion = 1020)
100%
2%
80%
30%
4%
26%
27%
34%
13%
60%
Peripheral lesions might have suggested a
68% retinopathy
69% in 10%66%
61% severity
more severe
of eyes
40%
20%
0%
H/MA
HMA
Uniform distribution
VB
IRMA
Outside ETDRS fields
NVE
Within ETDRS fields
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
9
Peripheral Field Definitions
(Silva, et al. Ophthalmology 2013) 10
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
11
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.
12
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
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and cardiovascular complications
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, 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.
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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:
o Type of peripheral lesions
o Location of peripheral lesions
o Extent of peripheral or posterior non-perfusion on
FA
o Presence or absence of peripheral lesions
o Whether DR severity level is different within 7modified fields compared with UWF images
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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.)
 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 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 men 18
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 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.
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Schedule of Study Visit and
Examination Procedures
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
OCTa
x
x
x
x
x
Bloodb and Urinec collection
x
x
x
x
x
BP
x
x
x
x
x
x
a
Macular and choroidal thickness scans
Blood collection must occur before any intravitreous injection
c Urine must be collected before FA
b
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Schedule of Phone Calls:
Medical Conditions Assessment
Visit Window
Medical Conditions Assessment
Baseline
Annual
Visits
1-4 Years
Phone Calls at
6, 18, 30, and 42
months (± 1 mo)
x
x
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
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cardiovascular events
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
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• UWF FA
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)
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FA Acquisition
One Study Eye?
Yes
Study eye is
transit eye.
Fellow eye
images taken
afterwards.
Mid and late
phase images
also on study
eye first
No
Right eye is
transit eye
and all right
eye images
taken first
unless taking
left eye first
will increase
image quality.
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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 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 Size
Predominantly
Peripheral
Lesions
NOT
Predominantly
Peripheral
Lesions
 Within each group above
o ~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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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.
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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
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Collaboration
 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!
 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
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
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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