Download Ocular Eligibility Criteria - Jaeb Center for Health Research

The Diabetic Retinopathy Clinical
Research Network
A Phase II Evaluation of Topical NSAIDs
in Eyes with Non-Central Involved
DME (Protocol R)
Scott Friedman MD
Protocol Chair
Sponsored by the National Eye Institute,
National Institutes of Health, U.S. Department of Health and Human Services.
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Study Question
 Do topical non-steroidal anti-inflammatory
drugs (NSAIDs) have biological effects on
non-central involved DME?
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Is macular volume influenced by using NSAID
drops in these eyes?
Do these drops reduce the risk of progression to
central-involved DME?
Do these drops reduce the risk of progression of
current non-central DME?
Do these drops increase the chance of resolution
of non-central DME?
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Non-central DME
 Clinical Definition - Retinal thickening due to
DME within 3000µm of, but not involving, the
center of macula
 OCT definition - Retinal thickening due to DME
>2 SD beyond the normal value outside the
central subfield BUT <250 µm in spectral
domain OCT machines within the central
subfield
 Typical Management – observation until
center becomes thickened or until imminent
involvement of center is perceived
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Progression of
Non-center Involved DME
 ETDRS
 22% of study participants with non-center involved
(DME) by color fundus photographs assigned to
deferral of laser progressed to the center of the
macula by 1 year
 Protein Kinase C-β DME Study Group
 1/3 of eyes with non-central DME in the control
group progressed to the central subfield within 1
year
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Rationale for Use of NSAIDs on
Non-central DME
 Possible role of inflammatory markers in DME
 Some topical NSAID medicines reach
posterior segment of the eye
 Observational studies showed some beneficial
effects of topical NSAID eye drops on DME
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Study Objectives
 Primary Objective: Assess effect of topical
NSAIDs on retinal volume compared with
placebo in eyes with non-central DME
 Secondary Objective: Assess effect of topical
NSAIDs on central subfield thickness, and to
compare the progression of non-central to
central DME as determined by spectral domain
OCT, and as determined by color fundus
photographs
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Nepafenac 0.1%(Nevanac®)
 Nepafenac in ocular tissue is converted to active
metabolite, amfenac
 Nepafenac and amfenac inhibit both
cyclooxygenase (COX) I and II enzymes which
catalyze the formation of pro-inflammatory
prostaglandins that contribute to edema
 FDA approved to treat pain and inflammation
associated with cataract surgery
 Dosage: 1 drop, 3 times per day (TID)
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Study Design
Phase II
Multi-center
Randomized
Double-masked
Clinical Trial
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Study Design
Eligibility Criteria Met/Informed Consent
Run-In Phase/Enrollment Visit
30-60 days
Randomization Visit/Baseline
Nepafenac (TID)
Placebo (TID)
4 Months
4 Months
8 Months
8 Months
Primary outcome analysis at 1 year
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Subject Eligibility Criteria
Inclusion
• Age ≥ 18 years
• Diabetes mellitus (type 1 or type 2)
• Successful completion of the run-in
phase during which level of compliance
is more than 80%
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Subject Eligibility Criteria (cont.)
 Exclusion
• Use of systemic corticosteroids or anti-VEGF
therapy.
• Current use of prescription systemic NSAIDs.
• History of auto-immune diseases such as
rheumatoid arthritis.
• Known allergy to any component of the study
drug
• Blood pressure > 180/110 mmHg
• For women of child-bearing potential: pregnant
or lactating or intending to become pregnant
within the next 12 months.
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Ocular Eligibility Criteria
 Inclusion
• BCVA letter score ≥ 74 E-ETDRS (20/32 or better)
• By Clinical exam: Retinal thickening due to DME
within 3000 µm of but not involving the macular
center
• By OCT: Thickened non-central macular
subfields
• Media clarity
• If patient on other drop(s), willingness to comply
with a multi-drop regimen
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Ocular Eligibility Criteria (cont.)
 CSF <250 μm in spectral domain OCT
machines
 Thickened non-central macular subfields on
OCT macular map must meet either one of the
following criteria:
• At least two subfields with thickness above
threshold* in spectral domain OCT machines
• At least one subfield with thickness of at least 15μm
above threshold in spectral domain OCT machines
* Threshold= average normal + 2 standard deviations (SD)
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Ocular Eligibility Criteria (cont.)
 Exclusion
• Focal/grid laser within the last 6 months or other treatment for DME
within the last 4 months
• Anticipated need to treat DME during the study
• NSAID eye drops use within the last 30 days or anticipated need for
such drops during the study
• History of PRP within 4 months prior to randomization
• Need for PRP in the 6 months following randomization
• Need for cataract surgery of study eye during the study
• Lipid in the fovea
• History of major ocular surgery within prior 4 months or anticipated
within the next 6 months
• An ocular condition, other than DME, that may affect VA
• YAG capsulotomy within 2 months of randomization
• Severe external ocular infection
• Aphakia
• Vitrectomy for any reason
• Cataract surgery within the prior 1 year
• Uncontrolled glaucoma
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How can investigators know if an
eye meets the protocol definition of
non-central DME?
 The Coordinating Center will provide site an
OCT grid with the threshold values for reference
 Site personnel will enter the thickness value of
each subfield directly into the study website for
eligibility confirmation
 Computer algorithm will determine if eyes meet
protocol criteria for non-central DME
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Study Eye
Both eyes may be evaluated for
eligibility, but only ONE eye will be
enrolled
If both eyes are eligible at the time of
enrollment, study eye will be
selected by investigator and study
participant
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Permitted OCT Machines
Only the following spectral domain
OCT machines should be used in this
study
 Zeiss Cirrus
 Heidelberg Spectralis
 Optovue RTVue
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Run-in Phase
Purpose
 Filtering participants with poor compliance
at the start of the study
Protocol
 All eligibility criteria must be met before
enrollment
 Artificial tears (Tears Naturale Forte®)-1
drop, 3 times per day
 At least 30 days (30-60 days)
 Compliance is assessed at end of run-in
phase before randomization
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Randomization
All eligibility criteria must be
reconfirmed again after run-in phase
Data collected at randomization will
be the baseline data
Study participants must show good
compliance with drops during the
run-in period in order to be eligible
for randomization
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Compliance Assessment and
Randomization Eligibility
Compliance will be assessed by
weighing bottles and comparing to
an expected weight
Study participants will be eligible for
randomization if compliance was
80% or more of expected
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Compliance Assessment
 Digital scales will be provided to sites by the
Coordinating Center
 Each bottle will be weighed prior to
dispending to study participant
 Each bottle will be re-weighed when
participant comes for next visit
 At enrollment, each participant will be
provided with 1 artificial tears bottle
 At randomization and follow up visits each
participant will be provided 6 bottles of
drug/placebo
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Study Testing Procedures
E-ETDRS BCVA/
Eye Exam/
OCT
Enrollment
Randomization
4M
8M
12M
Run-in (30-60
days)
Baseline
±1M
±1M
±1M
X
X
X
X
X
X
Fundus Photo
Blood Pressure
X
X
X
HbA1c
Weighing
Bottles
X
X
X
X
X
X
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Guidelines for DME Treatment
Randomized eye drops
No treatment for DME is given unless
 Central subfield thickness increases to 310 μm or more
 Extenuating circumstances after protocol chair
discussion e.g. rapidly-developing cataract prior to
cataract surgery
Study participants will continue their study treatment
through 12 months regardless of whether treatment for
DME is received
Primary outcome analysis at 1 year
Outcome Measures
Primary Outcome
 Mean change in macular retinal volume
(mm3) between baseline and 12 months
Secondary Outcomes
 Progression of non-central involved DME
 Correlation of progression of DME in OCT
and fundus photographs
 Visual Acuity
 Safety Outcomes
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Safety Outcome
Cornea
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Irritation/burning sensation
Corneal edema
Superficial keratitis
Ulceration
Melting
Note: Corneal complications will be
expeditiously sent for review by the DSMB
Cataract/cataract surgery
Ocular infection/inflammation
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Sample Size
 60 study participants per group
convenience sample size will be recruited
 Total number of eyes is 120 in 120 study
participants
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Thank You on Behalf of Diabetic Retinopathy
Clinical Research Network (DRCR.net)
Dedicated to multicenter clinical research of diabetic
retinopathy, macular edema and associated disorders.
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