Download DRCR.net Protocol V - Jaeb Center for Health Research

The Diabetic Retinopathy
Clinical Research Network
Treatment for Central-involved DME in
Eyes with Very Good Visual Acuity
(DRCR.net Protocol V)
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DRCR.net Overview
 Objective:
• Collaborative network to facilitate
multicenter clinical research of diabetic
retinopathy, DME and associated
conditions
 Funding:
• National Eye Institute (NEI) and The
National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK)-sponsored
cooperative agreement initiated September
2002.
o Current award 2014-2018
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DRCR.net Status
(as of 1/6/14)
Active
Total
119
179
80 (67%)
120 (67%)
Investigators
Other Personnel
363
979
786
2746
States
37
41
Sites
(Community & Academic Centers)
Community Sites
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Current Clinical Question
What is the best treatment strategy for
eyes with central-involved (CI) DME and
good visual acuity?
Possible treatment approaches in clinical
practice include:
• Initiating intravitreal anti-VEGF promptly
• Initiating focal/grid laser promptly
o If VA worsens, begin anti-VEGF
• Observing
o If DME worsening on OCT, begin anti-VEGF or laser
o If VA worsens, begin anti-VEGF
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What do we already know?
In the DRCR.net LRT for DME Study
(Protocol I), ranibizumab + deferred or
prompt laser for CI-DME provided VA
outcomes superior to prompt focal/grid
laser alone
However…
• Only eyes with VA letter score ≤78 (20/32 or
worse) were enrolled
• Anti-VEGF has not been evaluated in eyes that
have CI-DME with VA 20/25 or better
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What do we already know?
 In the ETDRS – eyes with CI-DME that started
with 20/25 or better vision and lost 5 or more
letters at 2 years:
o Focal laser  27%
o Observation  40%
 However….
• OCT not available to closely follow improvement or
worsening of DME
• Clinical characteristics of the cohort may have
changed since the time of the ETDRS
• Deferred Anti-VEGF as a rescue treatment not
evaluated as part of treatment approach
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Available 2 Year Data Summary
ETDRS
Focal
ETDRS
Observation
Eyes with VA ≥20/25 or better
at baseline
Protocol I
Ranibizumab
+ Deferred
Laser
VA = 20/32 at
baseline
N = 118
N = 246
N = 28
Visual Acuity Decrease by
Letter Score of 5 or More
27%
40%
4%
Visual Acuity Decrease by
Letter Score of 10 or More
13%
25%
0
-1 (-5, 2)
-3 (-10, 1)
5 (1, 9)
VA Change from Baseline
Median (25th , 75th)
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ETDRS and Protocol I Data*:
Percent
with
VA
loss
≥
5
letters
45
ETDRS Laser Group
40
ETDRS Observation Only
N = 110
35
DRCR.net I Ranibizumab+deferred
laser
Percent
30
N = 113
N = 118
25
N = 231
N = 237
20
15
N = 246
10
N = 28
N = 26
5
0
0
4
8
12
Months
18
20
*ETDRS study eyes with CI-DME and VA 20/25 or better at baseline. Protocol I study
eyes with CI-DME and VA = 20/32 at baseline
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Study Questions
 In eyes with good VA, is deferring anti-VEGF
similar, better, or worse than prompt anti-VEGF
for long-term visual acuity outcomes?
• If similar or better, how long can you defer
anti-VEGF?
• What % never need anti-VEGF?
 If deferring anti-VEGF, is it better to observe or
give focal/grid laser?
• Does one provide better VA outcomes?
• Does one allow for fewer anti-VEGF
injections?
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Study Questions
 If prompt anti-VEGF is better, does it have
enough of a benefit to warrant risks of repeated
intravitreal injections?
• How many injections are needed to maintain
20/20 vision?
• Are fewer injections needed in the long run
than if you wait until after VA or OCT decline to
initiate anti-VEGF?
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Study Design
Randomized, multi-center clinical trial (N=702)
At least one eye meeting all of the following criteria:
• Central-involved DME on OCT (Cirrus/Spectralis only)*
• VA letter score 20/25 or better*
• No or minimal** prior treatment for DME
Prompt
anti-VEGF
Prompt laser +
deferred anti-VEGF
Observation +
deferred anti-VEGF
Primary outcome: Proportion of eyes that have lost
≥5 letters of VA at 2 years
*Confirmed at 2 visits (screening and randomization 1-28 days apart)
**No more than 1 laser and/or 4 injections, at least 12 months ago
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Treatment Groups:
Prompt Anti-VEGF
Treatment Group Description:
• Intravitreal anti-VEGF (2.0 mg aflibercept) at
randomization
• DRCR.net retreatment criteria during follow-up
Rationale:
• Protocol I and other studies have demonstrated
that anti-VEGF is well-tolerated and more effective
than laser alone in increasing vision gain and
decreasing vision loss in patients with CI DME,
but this benefit has not been established in eyes
that have good vision despite the presence of CI
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DME
Treatment Groups:
Prompt Laser + Deferred Anti-VEGF
 Treatment Group Description:
• Focal/grid laser at randomization
• Anti-VEGF only initiated if protocol criteria met
 Rationale:
• The initial use of focal/grid laser could offer
advantages over starting treatment with anti-VEGF in
terms of reducing adverse events associated with
intravitreal injections as well as fewer treatments
given over time with potentially less frequent followup
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Treatment Groups:
Observation + Deferred Anti-VEGF
 Treatment Group Description:
• Observation
• Anti-VEGF only initiated if protocol criteria met (to be
discussed)
 Rationale:
• Deferral of immediate treatment might result in
decreased inconvenience, adverse events and costs
associated with anti-VEGF treatments that are
performed as often as once a month while potentially
preserving vision in eyes with CI DME with good
vision
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Major Eligibility Criteria
 Type 1 or 2 diabetes
 Study Eye:
• Central-involved DME on clinical exam, confirmed
on OCT at two consecutive visits (1-28 days apart)
• VA letter score >79 (~20/25 or better) at two
consecutive visits (1-28 days apart)
• No or minimal history of prior DME treatment
o No more than 1 laser, 4 injections at least 12
months ago
 Non-study eye:
• Patient must be willing to use (or switch to using)
study aflibercept on the non-study eye if needed
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Major Exclusion Criteria
 Systemic
• History of chronic renal failure requiring dialysis or kidney
transplant
• Initiation of intensive insulin treatment (a pump or multiple
daily injections) within 4 months prior to randomization or
plans to do so in the next 4 months
• BP > 180/110
 Study eye
• Macular edema not due to DME (eyes with thickening due
to ERM, prior cataract surgery or other non-DME reason
should not be enrolled)
• PRP in last 4 months or anticipated in next 6 months
• History of intravitreal anti-VEGF for an ocular condition
other than DME in last 6 months or anticipated need in next
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6 months
Study Follow-Up
Treatment
Visit Schedule
• Prompt anti-VEGF Group: visits
every 4 weeks during the first 24
weeks, every 4-16 weeks thereafter
•Deferred anti-VEGF groups (focal and
observation)*: visits at 8 and 16 weeks,
followed by every 16-week visits
thereafter
Outcome
Visit Schedule
All participants will
have visits at 1 and
2 years for outcome
assessment
*For the deferred groups, if vision and/or OCT are worsening or
anti-VEGF is initiated, visits will be every 4, 8 or 16 weeks
depending on disease progression and treatment
Study Treatment
Prompt
Anti-VEGF
• Injection at baseline
• Evaluation at each visit for re-injection
based on protocol criteria
Laser
+
Deferred
Anti-VEGF
• Focal/grid laser at baseline
• Evaluation at each visit for initiating antiVEGF based on visual acuity loss
• Retreatment with laser if protocol criteria
are met
Observe
+
Deferred
Anti-VEGF
• No treatment at baseline
• Evaluation at each visit for initiating antiVEGF based on visual acuity loss
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Referrals
We Need Your Help!
 Please consider any eyes with DME involving the
center of the macula and vision ~20/32 or better
on clinic charts
 Study participants must be willing to be
randomized to laser, injections, or observation
to start and continue follow-up for 2 years
 Consenting/Screening/Randomization will be
split into several visits
 An optional “Observational Phase” is also
available for patients not ready for randomized
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treatment
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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