Transcript Funding Mechanism

The Diabetic Retinopathy
Clinical Research Network
Treatment for Central-involved DME in
Eyes with Very Good Visual Acuity
Presenter: Carl W. Baker, MD
1
OCT CSF = 358
ETDRS VA Letter
Score = 83
(20/25)
2
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:
• Initiate intravitreal anti-VEGF promptly
• Initiate focal/grid laser promptly
o If VA worsens, begin anti-VEGF
• Observe
o If DME worsening on OCT, begin anti-VEGF or laser
o If VA worsens, begin anti-VEGF
3
What do we already know?
In Protocol I, ranibizumab + deferred or
prompt laser for CI-DME provided VA
outcomes superior to prompt focal/grid
laser alone
• 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
4
What do we already know?
 In ETDRS – 20/25 or better eyes with CI-DME that
lost 5 or more letters at 2 years
o Focal laser  27%
o Observation  40%
• OCT not available to closely follow improvement or
worsening of DME
• Clinical characteristics of the cohort may have
changed since the time of ETDRS
• Deferred Anti-VEGF as a rescue treatment not
evaluated as part of treatment approach
5
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)
6
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
24
7
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?
8
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?
9
Study Design
Randomized, multi-center clinical trial
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*
• 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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Outcome Measures
Primary Outcome
 % with VA loss of ≥ 5 letters at 2 years
Secondary Outcomes









Mean change in VA letter score
% with at least 10 and 15 letter VA gain/loss
Visual acuity area under the curve
Mean change in OCT CSF thickness
% with 1 or 2 log step gain or loss on OCT
Number of injections/lasers performed
Worsening/improvement of DR severity level
Low contrast visual acuity
Safety outcomes
11
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
12
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
13
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
14
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)
• The investigator is comfortable with the eye being
randomized to any of the three treatment groups
• Minimal history of prior DME treatment
o No more than 1 laser, 4 injections at least 12 months ago
 Non-study eye:
• Investigator must be willing to use (or switch to
using) study aflibercept on the non-study eye if
needed
15
VA and OCT Variability
 There is inherent measurement variability
 There may also be day to day actual variability,
particularly in patients with diabetes
 Two separate measurements are required to
confirm the eye truly has good vision with DME
• Randomization criteria slightly relaxed for OCT central
subfield thickness (~5% less than screening cutoff),
however investigator must still confirm DME on
clinical exam
16
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 in next 6
17
months
OCT CSF = 400
VA Letter Score = 89
ERM present
EXCLUDED
18
Baseline Testing Procedures
 Visual acuity and OCT eligibility must be
confirmed at 2 visits within 1 to 28 days
 Screening Visit
• Refraction followed by E-ETDRS visual acuity testing
using the refraction obtained in the study eye
• OCT in the study eye
o Cirrus and Spectralis only
• Ocular exam may be done to rule out exclusions;
however, data collection and official eligibility
assessment occurs at randomization
• Fundus photography may be done at screening or
randomization
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Baseline Testing Procedures
 Randomization Visit
• Refraction followed by E-ETDRS visual acuity testing
using the refraction obtained in both eyes
• Low-contrast visual acuity in the study eye (select
sites)
• OCT in the study eye
• Ocular exam in both eyes
• Fundus photographs in the study eye (if not done at
screening visit)
• Measurement of blood pressure
• HbA1c
o The same lab or DCA Vantage must be used at
baseline and follow-up
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FA Sub-study
 Certification – each investigator will indicate
whether they routinely perform FA prior to
focal/grid laser and whether they would be
willing to collect FA in this study
 Randomization Visit – For investigators who
indicate FA will be collected
• FA will be obtained on all participants at baseline
 Follow-up Visits – For investigator who indicate
FA will be collected
• FA will be obtained at following prior to repeat
focal/grid treatment for eyes randomized to laser
group
21
Randomization Form
 Before submitting, investigator MUST
• Confirm eligibility
• Confirm patient’s willingness to accept any of the
treatment assignments and to complete all
treatment/follow-up
o This is particularly important in this study since the
treatment approaches are so varied (no treatment
vs injection in the eye)
o Investigator is responsible for making sure patient
has been properly informed of potential
risks/benefits via consent process
• Be available to perform whatever the randomized
treatment is THAT DAY as applicable
22
Randomization
 Approximately 702 study eyes (one per
participant) assigned to one of the three
treatment groups
 Stratified by site and fellow-eye DME treatment
• If the fellow eye is being seen more frequently than
the study eye, it may influence the number of
treatments performed in the study eye
• Rather than excluding patients that are already
receiving DME treatment in the non-study eye, this will
be used as a stratification factor during randomization
23
Follow-Up Schedule
 Total follow-up through 2 years
 Visit schedule will vary by treatment group and
disease progression
• Prompt anti-VEGF group: visits every 4 weeks through
24 weeks, then every 4 to 16 weeks depending on
whether injections are being given
• Deferred groups (observation and laser groups): visits
at 8 and 16 weeks, then every 16 weeks unless vision
and/or OCT are worsening or anti-VEGF is initiated
(visits every 4, 8 or 16 weeks depending on disease
progression and treatment)
 All participants will have visits at 1 and 2 years
24
Follow-up Testing
All Protocol Visits:
 Protocol refraction in the study eye followed by EETDRS VA testing in each eye
 OCT on the study eye (same device as at baseline)
 Ocular exam on the study eye at each visit and on the
non-study eye only if study anti-VEGF treatment has
been given
Additional Annual Visit Procedures:




Non-study eye refraction prior to visual acuity
Low-contrast visual acuity (at select sites)
Fundus photography in the study eye
HbA1c (also at 16 weeks)
• The same lab or DCA Vantage that was used at baseline
should be used
Criteria for Initiating Anti-VEGF in
Deferred Groups
 Visual acuity worsening of at least 10 letters at
one visit or 5 to 9 letters at 2 consecutive visits
• If VA loss of 5 to 9 letters, subject is seen in 4 (±2)
weeks to check for continued vision loss
• Requiring a second confirmation visit for 5 to 9 letter
loss will minimize initiation of treatment unnecessarily
due to measurement error or other variability
• Delaying treatment for 2 to 6 weeks is not likely to be
harmful to the participant
 OCT worsening alone will not warrant anti-VEGF
• However, subject will be seen more frequently to
check for vision loss and delaying treatment in this
case is not likely to be harmful to the participant
26
Retreatment Criteria Once AntiVEGF Initiated
(either at baseline or when criteria met)
 Improving on OCT or VA  Inject
• Improving = OCT CSF thickness decreased by ≥ 10%
or VA letter score improved by ≥ 5
 Worsening on OCT or VA  Inject
• Worsening = OCT CSF thickness increased by >10%
or VA letter score decreased by >5
 Stable: not improving or worsening on OCT or
VA  Inject unless stable since last 2 injections OR it is
before 24-wk visit and OCT is > machine-specific
threshold (250 µm equivalent) or VA worse than 20/20
27
Principles of DRCR.net DME
Intravitreal Anti-VEGF Treatment
 An eye will be considered a “failure” if after 24
weeks of anti-VEGF and at least 13 weeks since
“complete” laser has been given, DME is still
present on OCT and clinical exam, VA letter score
is ≥ 10 letters worse than baseline at 2
consecutive visits and there has been no
improvement from prior injections or laser
 Once “failure” is met, treatment is at
investigator discretion
Principles of DRCR.net DME
Intravitreal Anti-VEGF Treatment
If the investigator’s desired treatment
plan deviates from the retreatment
protocol, the Protocol Chair or designee
must be contacted prior to deviating
from retreatment protocol, including:
• Desire to defer an injection when injection
indicated by protocol
• Desire to inject when injection should be
deferred per protocol
Injection Preparation Reminders
 Two individuals must confirm the study eye and
drug number against the printout or website
 Mark the eye for injection
 Apply topical anesthetic
 Place the lid speculum
 Apply povidone iodine directly over and
surrounding the injection site (allowing
sufficient time for the povidone iodine to dry)
• DRCR.net injections must NOT be given without the
use of povidone iodine in any circumstance
 Pre- and post-injection topical antibiotics can be
30
applied at the discretion of the investigator
Focal/Grid Laser Treatment
Criteria after Anti-VEGF initiated
 Once anti-VEGF is initiated, laser can be
added at investigator discretion if:
• ≥24 weeks since first anti-VEGF injection
• OCT CSF is ≥machine-specific threshold or
there is edema threatening the fovea AND
• The eye has not improved on OCT or VA
compared with either of the last two
consecutive injections
 After 24 weeks, if OCT or VA are worsening
from the last two injections, laser should
be given
Focal/Grid Laser Re-Treatment
Once focal/grid laser has been initiated
(either at baseline for laser group or
when criteria are met), retreatment with
laser will be performed unless one of the
following is present:
• Laser has been given in <13 weeks
• The OCT CSF is < machine-specific
threshold (250 micron equivalent) and there
is no edema threatening the fovea
• Complete focal/grid laser has been given
• The OCT or VA has improved since last
laser
Complete the Visit Instructions
Because the eye is stable for only one visit or is worsening since the last visit, an injection of Aflibercept in the right eye must be given
at this visit.
Focal/grid photocoagulation should not be performed at this visit.
33
Intravitreal Anti-VEGF Treatment
in the Non-study Eye
 If the non-study eye is treated for any condition
which requires treatment with an anti-VEGF agent,
study aflibercept must be used
 The DRCR.net CC will provide drug for the nonstudy eye
 If non-study eye and study eye will be injected on
the same day, the study eye must be injected first
Use of Intravitreal Anti-VEGF in
the Study Eye for Non-DME Tx
 Use of study aflibercept for an FDA approved
indication other than DME is at investigator
discretion
 Any off-label use of anti-VEGF for an ocular
condition other than DME (e.g. PDR, vitreous
hemorrhage) will require discussion with and
approval by the protocol chair or designee
 Study aflibercept must be used for any antiVEGF treatment in the study eye
35
Case Example: Prompt Anti-VEGF Group
Week
0
4
8
12
16
20
24
28
32
36
40
44
OCT
300
245
249
242
245
249
275
245
245
247
249
249 245
VA
48
20/25 20/20 20/20 20/20 20/20 20/20 20/32 20/20 20/20 20/20 20/20 20/20 20/20
Category --
I
Su
Su
Su
Su
W
I
Su
Su
Su
Su
Su
A-VEGF
Laser
Required due
to
improvement
Deferred while
Success
Required 1st
time
success
Required
due to
worsening
Required 1st
time success
Deferred while
Success
Required due
to
improvement
I = improved: OCT CSF decreased by >10% or VA LS improved by >5
W= worsened: OCT CSF increased by >10% or VA LS worsened by >5
St = stable: did not improve or worsen (according to above definitions)
Su = success: stable (according to above definition) AND visual acuity
letter score >84 (~20/20) and OCT CSF <250µ or SD equivalent
Case Example: Laser+Def Anti-VEGF
Week
0
8
16
32
36
40
OCT
300
275
275
325
325
260
20/25
20/25
20/25
--
--
VA
Category --
44
48
255
255
20/32 20/32 20/20 20/20
--
--
I
20/20
St
St
A-VEGF
Laser
Return in 4
weeks to recheck VA
VA still
decreased;
initiate antiVEGF
Required
1st time
stable
I = improved: OCT CSF decreased by >10% or VA LS improved by >5
W= worsened: OCT CSF increased by >10% or VA LS worsened by >5
St = stable: did not improve or worsen (according to above definitions)
Su = success: stable (according to above definition) AND visual acuity
letter score >84 (~20/20) and OCT CSF <250µ or SD equivalent
2nd time
stable
but <24w
Case Example: Observe+Def Anti-VEGF
Week
0
8
16
24
28
32
36
40
OCT
300
325
400
400
325
300
260
260
20/25
20/25
20/25
--
--
VA
Category --
44
48
255
250
20/40 20/32 20/25 20/25 20/20 20/20
--
I
I
I
I
St
20/20
St
A-VEGF
Laser
> 10%
worsening on
OCT; return in
8 weeks
VA
decreased
10 letters;
initiate antiVEGF
Inject due to
improvement
Required
1st time
Defer 2nd
stable
time
stable
≥24w
I = improved: OCT CSF decreased by >10% or VA LS improved by >5
W= worsened: OCT CSF increased by >10% or VA LS worsened by >5
St = stable: did not improve or worsen (according to above definitions)
Su = success: stable (according to above definition) AND visual acuity
letter score >84 (~20/20) and OCT CSF <250µ or SD equivalent
Observational Phase
 Objective
• To collect additional data on the natural history of
eyes with good VA and DME (when the RCT is
declined)
 Summary
• Potential participants who are not ready/willing to be
randomized but meet certain criteria can enroll
• Collect data every 4 months while the eye is being
observed
• Follow-up will continue until…
o The eye is randomized
o Treatment is given outside of the study OR
o The patient reaches 2 years from enrollment
39
Enter RCT or Observational Phase?
Screening
Visit (OCT/VA)
Eligible
Observational
Phase
No
Yes
Ready/ Eligible
to Randomize?
Observational
Phase Follow-up
Yes
Randomize
Receive DME Trt
No
Yes
Ready/Eligible
to Randomize?
Completed
40
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)
 DME treatment and visit schedule
are determined for you!
 Contact CC prior to any deviations
from protocol treatment
***CRITICAL***
Investigator AND Coordinator Role
Enrolling the Correct Participants
Educate patient with a thorough ICF process
so that they understand:
• Time commitment
• Treatment requirements
Assess likelihood that patient will adhere to
protocol
Listen to the coordinator
Verify patient has reliable means of
transportation to study site
Consider travel distance and patient’s other
health conditions
42
Certification Requirements
 Site Specific
• IRB approval of protocol and ICF
• Contract addendum
 Investigator
• Completed 1572
•
•
•
•
•
Protocol Q+A (80% correct or higher)
Protocol acceptance form
Protocol review teleconference w/in 2 months
Investigator brochure acknowledgment (PI only)
Competing studies form
 Coordinator Requirements
• Completed mock informed consent with
investigator