Transcript 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.
1
Study Question
 Do topical non-steroidal anti-inflammatory
drugs (NSAIDs) have biological effects on
non-central involved DME?




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?
2
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
3
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
4
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
5
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
6
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)
7
Study Design
Phase II
Multi-center
Randomized
Double-masked
Clinical Trial
8
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
9
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%
10
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.
11
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
12
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)
13
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
14
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
15
16
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
17
Permitted OCT Machines
Only the following spectral domain
OCT machines should be used in this
study
 Zeiss Cirrus
 Heidelberg Spectralis
 Optovue RTVue
18
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
19
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
20
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
21
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
22
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
23
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
25
Safety Outcome
Cornea
•
•
•
•
•
•
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
26
Sample Size
 60 study participants per group
convenience sample size will be recruited
 Total number of eyes is 120 in 120 study
participants
27
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.
28