Transcript presentation - Jaeb Center for Health Research

The Diabetic Retinopathy Clinical
Research Network
Protocol I: Clinical Applications
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
Diabetic Macular Edema Treatment
 Focal/Grid
•
~25 years following ETDRS
 Intravitreal
•
Steroids
~10 years
 Anti-VEGF
•
Photocoagulation
Agents
Late stage studies ~15 months
Mean Change in Visual Acuity*
DRCR Protocol I Overall Study: 854 eyes, 691 participants
11
Ranibizumab
+ deferred laser
10
Letter Improvement
9
Ranibizumab
+ prompt laser
8
7
P<0.001
6
Primary Outcome
Time Point (1 Year)
5
Sham
+ prompt laser
4
3
2
1
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104
Weeks
that were ±30 letters were assigned a value of 30
P-values for difference in mean change in visual acuity from sham+prompt laser at the 52-week visit:
ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; and triamcinolone+prompt laser=0.31.
3
* Values
Background

Protocol I demonstrated that
ranibizumab (with prompt or deferred
focal/grid laser) resulted in superior
visual acuity outcomes compared with
laser alone through 2 years

The treatment regimen for ranibizumab
(with prompt or deferred laser ) was very
detailed and facilitated by a real-time
web-based system
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Purpose of this Presentation
To discuss clinical applications that
might provide clinicians with:
•
a simplified approach to retreatment
•
in accord with the general opinion of
the DRCR.net investigators, and is
•
based on the Protocol I retreatment
algorithm
5
Visit/Treatment Schedule: Year 1 – the “4:2:7” Guide
‘7’ additional follow-up visits every 4 weeks;
‘4’ required
injections
‘2’ required
required injection if improvement† but not
injections if not success* since last injection; otherwise
optional
a success*
Primary Endpoint
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Sham+Prompt
Laser
Ranibizumab
+Prompt Laser
Ranibizumab
+Deferred Laser
**Triamcinolone
+Prompt Laser
 Visits were every 4 weeks regardless of whether
the eye status was successful, improved, or
failed.
*Success: Visual acuity letter score ≥84 (~20/20) or
OCT CSF <250 µm; retreatment at investigator
discretion.
† Improvement: OCT central subfield thickness
decreased by >10% or visual acuity letter score
improved by >5.
Sham+prompt laser
Ranibizumab+prompt laser
Ranibizumab+deferred laser
Triamcinolone+prompt laser
**Triamcinolone q 16 wks w/ sham q 4 wks in
between.
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Follow-up Visits at and After 52 Week Visit
if Ranibizumab Injection Given
Ranibizumab
+Deferred
or Prompt Laser
68…………104
52
56
60
64
Drug
Drug
Drug
Drug
Drug
Drug
Visit
Visit*
Visit*
Visit*
Visit*
Visit*
 Four wks after any ranibizumab injection, the study eye is evaluated for
possible additional ranibizumab injection using retreatment criteria as in year 1:
If not a success*, but improvement† since last injection, retreatment required;
otherwise, retreatment is up to investigator.
*Success: Visual acuity letter score ≥84 (~20/20) or OCT CSF <250 µm;
retreatment at investigator discretion.
† Improvement: OCT central subfield thickness decreased by >10% or visual
acuity letter score improved by >5.
7
Follow-up Visits at and After 52 Week Visit
if Ranibizumab Not Given (4 to 8 to 16 Weeks)
52
Ranibizumab
+deferred
No Drug
or
Prompt Laser
Visit
56
60
No Drug
No Drug
Visit
Visit
64
68……………….……84
No Drug
Skip Visit
Visit
No Drug
Skip 16
wks
Visit
 If a ranibizumab injection is not given at the current and previous 2
visits (e.g. week 60 above), the next follow-up visit is in 8 weeks.
 If at the next 8 week interval visit the injection is deferred again, the
next follow-up visit is in 16 weeks; visits continue every 16 weeks
unless a ranibizumab injection is given, at which point the visit
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schedule goes back to 4 week intervals.
SIMPLIFIED Retreatment and Follow-up of
Center-Involved DME with Anti-VEGF
Assessment 1 month
after initial serial
series of injection(s)
DME
Improving?
No Injection and
return in 1 month
NO
YES
Re-inject and
Return in 1 Month
YES
DME
Worsens or
Recurs?
NO
Double Follow-Up Interval
Up to 4 Months
Anti-VEGF Treatment Concepts
 For
which eyes with DME should
anti-VEGF therapy be considered?
Clinical Practice
Considerations
DRCR.net Study
Patients could be enrolled if
they had edema involving the
center of the macula defined as
central subfield thickness
≥250µm and vision impairment
defined as Snellan equivalent of
20/32 to 20/320.
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Anti-VEGF Treatment Concepts
 For
which eyes with DME should
anti-VEGF therapy be considered?
Clinical Practice
Considerations
Patients with edema
involving the center
of the macula
DRCR.net Study
Patients could be enrolled if
they had edema involving the
center of the macula defined as
central subfield thickness
≥250µm and vision impairment
defined as Snellan equivalent of
20/32 to 20/320.
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Anti-VEGF Treatment Concepts
 What
follow-up interval could be
considered after initiating therapy?
Clinical Practice
Considerations
DRCR.net Study
4 required injections at 4weekly intervals, followed by 2
injections at next 4-weekly
intervals unless edema
resolved or vision improved to
20/20 or better
† “Improvement” in the DRCR.net study was defined as “increase of at least 5 letters
(approximately 1 line) in visual acuity or at least a 10% reduction in the central
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subfield thickness on OCT since the last injection.
Anti-VEGF Treatment Concepts
 What
follow-up interval could be
considered after initiating therapy?
Clinical Practice
Considerations
DRCR.net Study
Several serial monthly injections until vision and edema
are no longer improving† or
can no longer improve
4 required injections at 4weekly intervals, followed by 2
injections at next 4-weekly
intervals unless edema
resolved or vision improved to
20/20 or better
(e.g. vision 20/20 or better, or edema resolved)
† “Improvement” in the DRCR.net study was defined as “increase of at least 5 letters
(approximately 1 line) in visual acuity or at least a 10% reduction in the central
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subfield thickness on OCT since the last injection.
Anti-VEGF Treatment Concepts
 What
treatment is employed when
the DME no longer is improving?
Clinical Practice
Considerations
DRCR.net Study
If no improvement from
prior injection, decision to
re-inject was at investigator discretion. Injections
were recommended if there
still was edema to treat.
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Anti-VEGF Treatment Concepts
 What
treatment is employed when
the DME no longer is improving?
Clinical Practice
Considerations
DRCR.net Study
Focal/grid laser can be
added if it not previously
used and injections would
continue. Injections may be
withheld, but resumed if the
edema worsens.
If no improvement from
prior injection, decision to
re-inject was at investigator discretion. Injections
were recommended if there
still was edema to treat.
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Anti-VEGF Treatment Concepts
 When
should treatment be resumed
after it has not been given?
Clinical Practice
Considerations
DRCR.net Study
Re-injection was at the
investigator’s discretion if
edema recurred or worsened,
but was recommended if
there was edema to treat;
follow-up then returned to 4week intervals once
injections resumed
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Anti-VEGF Treatment Concepts
 When
should treatment be resumed
after it has not been given?
Clinical Practice
Considerations
DRCR.net Study
Re-injection was at the
Injections may be reinvestigator’s discretion if
sumed if edema recurs edema recurred or worsened,
or worsens; follow-up but was recommended if
there was edema to treat;
then returns to
monthly intervals until follow-up then returned to 4week intervals once
injection is not given
injections resumed
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Anti-VEGF Treatment Concepts
 What
follow-up is employed when
the DME does not recur or worsen
after an injection is not given?
Clinical Practice
Considerations
DRCR.net Study
Starting with the second year of
treatment, if an injection was
withheld at 3 consecutive 4weekly visits, follow-up interval
was extended to 8 weeks, and
then again to 16 weeks if
treatment still not warranted
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Anti-VEGF Treatment Concepts
 What
follow-up is employed when
the DME does not recur or worsen
after an injection is not given?
Clinical Practice
Considerations
DRCR.net Study
If injection was not
given and edema
does not recur,
follow-up may be
doubled (up to 4
months or longer).
Starting with the second year of
treatment, if an injection was
withheld at 3 consecutive 4weekly visits, follow-up interval
was extended to 8 weeks, and
then again to 16 weeks if
treatment still not warranted
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Anti-VEGF Treatment Concepts
 When
should focal/grid laser
treatment be added?
Clinical Practice
Considerations
DRCR.net Study
Randomized treatment groups
included either prompt (within 310 days) or deferred (at least 24
weeks) focal/grid laser. If
deferred, laser only could be
added if edema was still present
after 24 weeks and there was no
improvement from two prior
consecutive injections
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Anti-VEGF Treatment Concepts
 When
should focal/grid laser
treatment be added?
Clinical Practice
Considerations
DRCR.net Study
Randomized treatment groups
Focal/grid laser may
included either prompt (within 3be given initially or
10 days) or deferred (at least 24
deferred. If deferred, weeks) focal/grid laser. If
laser may be added
deferred, laser only could be
at any time if edema added if edema was still present
is no longer improv- after 24 weeks and there was no
ing after an injection. improvement from two prior
consecutive injections
21
Anti-VEGF Treatment Concepts

When should focal/grid laser be repeated
after initiation?
Clinical Practice
Considerations
DRCR.net Study
Once initiated, focal/grid
was re-applied if 1) edema
was present, 2) eye did not
have “complete” laser, and
3) it had been at least 13
weeks since last laser
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Anti-VEGF Treatment Concepts

When should focal/grid laser be repeated
after initiation?
Clinical Practice
Considerations
Focal/grid laser generally
should be repeated at any
time that edema persists
or is not improving while
giving anti-VEGF therapy
(as long as it is believed that
additional laser may be of
benefit)
DRCR.net Study
Once initiated, focal/grid
was re-applied if 1) edema
was present, 2) eye did not
have “complete” laser, and
3) it had been at least 13
weeks since last laser
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Summary

Given that duplication of the treatment approach
used within the DRCR.net trial with its elaborate
infrastructure may not be practical in all clinical
settings

This presentation provides guidelines based on
DRCR.net investigators’ opinion for a simplified
retreatment approach when using intravitreal
ranibizumab to treat center-involved DME with
vision impairment

However, it is unknown whether these or other
modifications to the DRCR.net protocol would
result in better, same or worse outcomes
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