Transcript Funding Mechanism

The Diabetic Retinopathy
Clinical Research Network
Randomized Trial Evaluating Short-Term
Effects of Intravitreal Ranibizumab or
Triamcinolone Acetonide on Diabetic
Macular Edema Following Panretinal
Photocoagulation
Joseph M. Googe, MD
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
Background
PRP in Eyes with Central DME
 Scatter or panretinal photocoagulation (PRP) is
standard treatment for PDR
 Reported side effects of PRP include:
• Worsening macular edema and loss of visual acuity
(prior to OCT)
• DRCR.net protocol F reported PRP in 1 or 4 sittings,
respectively, results in median +14 or +15 µm increase
in OCT CSF (25th, 75th percentile = +5 or +6, +20 or +34
µm) with little decreased acuity 17 weeks after initiating
PRP in eyes without central DME
2
Background
• Is change in OCT CSF and change in visual acuity
similar in eyes receiving PRP with central DME which,
around the same time, also receive focal/grid laser for
the DME?
• 3 DRCR.net protocols evaluating focal/grid laser for
DME as a monotherapy showed a median decrease in
CSF of 30 microns and a median increase in VA of 1 or
2 letters following focal/grid laser of central DME
without PRP (at 16 weeks)
3
Background
PRP in Eyes with Central DME
If some eyes with central DME receiving PRP at the
time of focal/grid laser have at least short term
substantial worsening of macular edema and visual
acuity loss, . . .
. . . then reducing the proportion of eyes with
worsening of macular edema and visual acuity loss
following PRP might improve quality of life for
individuals undergoing this therapy in the short term
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Background
Anti-VEGF and Triamcinolone for DME
 Inflammation and increased levels of vascular
endothelial growth factor (VEGF) contribute to the
development or exacerbation of DME
 DRCR.net , RESTORE, RIDE and RISE reported benefits for ≥1
year after initiating intravitreal ranibizumab for DME in the
absence of DR requiring prompt PRP (Protocol I)
 DRCR.net studies and other studies have suggested a benefit of
intravitreal corticosteroids for DME (though not superior to
ranibizumab or focal/grid laser)
 Anti-VEGF drugs or corticosteroids might have a role in
reducing PRP-induced exacerbation of macular edema
in eyes with DME and severe NPDR or PDR for which
PRP is given around the time that focal/grid is given for
6
the DME
Laser-Ranibizumab-Triamcinolone+PRP
Randomized Clinical Trial for DME
Study Objective
Evaluate short term effects of intravitreal
ranibizumab or intravitreal triamcinolone on
exacerbation of macular edema and associated
visual acuity loss in eyes requiring PRP for severe
NPDR or PDR and receiving focal/grid laser for
center-involved DME.
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Study Design
Randomized, multi-center clinical trial
At least 1 eye meeting all of the following criteria:
Severe NPDR or PDR requiring prompt PRP
Presence of central DME on clinical exam and CST
on OCT ≥250 microns
Best corrected E-ETDRS visual acuity letter score
≥24 (~20/320 or better)
Sham+
Focal/Grid/PRP
Laser
Ranibizumab+
Focal/Grid/PRP
Laser
Triamcinolone+
Focal/Grid/PRP
Laser
Primary outcome: Change in visual acuity from
baseline to 14 weeks (intent to treat analysis)
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Follow-up Schedule
Baseline to
2 Weeks
4 Weeks
•
•
•
•
1st injection at baseline
Safety visit 3-10 days
Focal/grid laser 3-10 days
Initial PRP (following focal/grid ) 3-14
days
• 2nd injection (ranibizumab for
ranibizumab group and sham for sham
and triamcinolone groups)
• Follow-up visit
14 Weeks
• Primary outcome visit
34 Weeks &
56 Weeks
• Safety follow-up visits
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Study Enrollment
Eyes Randomized:
N = 364 (333 Study Participants)
Sham+
Focal/Grid Laser
& PRP
N = 133
Ranibizumab+
Focal/Grid Laser
& PRP
N = 116
Triamcinolone+
Focal/GridLaser
& PRP
N = 115
14 Week Visit Completion* (Primary Outcome):
95%
56 Week Visit Completion*:
87%
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*Includes deaths
Baseline Characteristics (N=345)
Overall
Median age (yrs)
Women
57
39%
Race
White
61%
African-American
13%
Hispanic or Latino
23%
Asian
2%
Other
1%
Unknown/not reported
1%
Median HbA1c (%)
8.1
Diabetes type
Type I
13%
Type II
84%
Uncertain
3%
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Baseline Characteristics
Sham+
Focal/Grid &
PRP
N = 123
Ranibizumab+
Focal/Grid &
PRP
N = 113
Triamcinolone+
Focal/Grid &
PRP
N = 109
67 (20/50)
68 (20/50)
67 (20/50)
Median OCT CSF
thickness (µm)
355
352
359
No prior treatment for
DME
65%
66%
66%
Median E-ETDRS©
visual acuity letter
score (Snellen
equivalent)
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Panretinal Photocoagulation Treatment
Sham+
Focal/Grid/PRP
Laser
Ranibizumab+ Triamcinolone+
Focal/Grid/PRP Focal/Grid/PRP
Laser
Laser
Number of PRP
sittings performed*
1
40%
34%
38%
2
47%
50%
46%
12%
15%
15%
1%
2%
2%
3 or 4†
PRP not done
•Number of sittings planned prior to randomization was similar to the
number of sittings performed.
† Only 1 study participant had 4 PRP sittings performed
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Panretinal Photocoagulation Treatment
Sham+
Focal/Grid/PRP
Laser
N = 122
Ranibizumab+ Triamcinolone+
Focal/Grid/PRP Focal/Grid/PRP
Laser
Laser
N = 111
N = 107
PRP automated
pattern used
30%
19%
20%
Median total number
of burns
1541
1410
1430
Proportion of eyes
with PRP completed
in the protocol
window
89%
87%
81%
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Additional Treatment for DME
Sham+
Ranibizumab+
Focal/Grid/PRP Focal/Grid/PRP
Laser
Laser
N = 123
N = 113
Triamcinolone+
Focal/Grid/PRP
Laser
N = 109
Prior to 14 weeks
Eyes with additional treatments
0
0
0
71
48
45
Bevacizumab (+/- Laser)
22
17
9
Ranibizumab (+/- Laser)
1
3
3
Triamcinolone (+/- Laser)
10
12
7
Laser
31
10
21
Vitrectomy
2
1
0
Bevacizumab+Triamcinolone (+/- Laser)
2
0
2
Triamcinolone+Vitrectomy
0
1
0
28 (39)
23 (32)
17 (32)
14 weeks to 56 weeks
Eyes with additional treatments
Additional treatment*
Eyes with non-protocol antiVEGF trt (# of trts applied)
*Number of eyes, each combination of treatment only counted once
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Visual Acuity
17
Primary Outcome
Change in Visual Acuity at 14 Weeks
Change in visual
acuity (letters)
Mean
Difference in mean
change from Sham
+Focal/Grid/PRP
Laser [P Value]*
Sham+
Focal/Grid/PRP
Laser
N = 123
Ranibizumab+
Focal/Grid/PRP
Laser
N = 113
Triamcinolone+
Focal/Grid/PRP
Laser
N = 109
-4
+1
+2
+5.6
[P < 0.001]
+6.7
[P < 0.001]
*Adjusted for baseline visual acuity, number of planned PRP sittings, and
correlation between 2 study eyes.
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Mean Change in Visual Acuity* from
Baseline
Mean Change in Visual Acuity
from Baseline (letter score)
5
4
Sham+Focal/Grid/PRP Laser
Ranibizumab+Focal/Grid/PRP Laser
Triamcinolone+Focal/Grid/PRP Laser
3
2
1
0
-1
-2
-3
-4
-5
0
4
14
34
Randomized Phase
(DME treatment according to protocol)
* Values
56
Safety Phase
Safety Phase
(DME treatment at investigator discretion)
(DME treatment at investigator discretion)
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that were ±30 letters were assigned a value of 30
Change in Visual Acuity at 56 Weeks
Change in visual
acuity (letters)
Mean
Difference in mean
change from Sham
+Focal/Grid/PRP
Laser [P Value]*
Sham+
Focal/Grid/PRP
Laser
N = 111
Ranibizumab+
Focal/Grid/PRP
Laser
N = 95
Triamcinolone+
Focal/Grid/PRP
Laser
N = 93
-6
-4
-5
+1.9
[P = 0.44]
+1.2
[P = 0.63]
*Adjusted for baseline visual acuity, number of planned PRP sittings, and
correlation between 2 study eyes.
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Visual Acuity
Subgroup Analysis
21
Subgroup Analyses
 No obvious clinically important difference in
results at 14-week primary outcome visit for
any of the following subgroups:
•
•
•
•
•
•
Prior treatment for DME
Baseline visual acuity
Baseline OCT-measured central subfield thickening
Baseline level of diabetic retinopathy on photos
Baseline HbA1c level
Description of edema by ophthalmologist as
predominantly focal or predominantly diffuse
• PRP in a single sitting vs. multiple sittings
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Retinal Thickening
23
Change in Retinal Thickening at 14 Weeks*
Change in OCT
Central Subfield
Thickening*
Mean change from
baseline (µm)
Sham+
Focal/Grid/PRP
Laser
N = 115
Ranibizumab+
Focal/Grid/PRP
Laser
N = 100
Triamcinolone+
Focal/Grid/PRP
Laser
N = 103
-5
-39
-92
-35
[P = 0.007]
-100
[P < 0.001]
Difference in mean
change from Sham+
Focal/Grid/PRP Laser
[P Value] †
Thickness ≥10%
increase with at least a
25 µm increase from
baseline
38%
17%
10%
Thickness <250 µm with
at least a 25 µm
decrease from baseline
10%
17%
27%
* Missing (or ungradeable) data as follows for the sham+focal/grid/PRP laser group, ranibizumab+focal/grid/PRP laser group,
and triamcinolone+focal/grid/PRP laser groups, respectively: 3, 3, 2
† Adjusted for baseline OCT retinal thickness and visual acuity, number of planned PRP sittings, and correlation between 2
study eyes.
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Correlation between Visual Acuity and
Central Subfield Thickness at 14 Weeks
Sham+
Focal/Grid/PRP
Laser
Central subfield thickness
≥10% increase with at least
a 25 µm increase from
baseline
Above OCT CST change
AND concordant decrease
in visual acuity of ≥10
letters at 14 weeks
Ranibizumab+ Triamcinolone+
Focal/Grid/PRP Focal/Grid/PRP
Laser
Laser
N=44
N=17
N=10
15 (34%)
2 (12%)
1 (10%)
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Mean Change in OCT Central Subfield
Thickness from Baseline (microns)
Mean Change in Retinal Thickness
from Baseline
120
Sham+Focal/Grid/PRP Laser
Ranibizumab+Focal/Grid/PRP Laser
Triamcinolone+Focal/Grid/PRP Laser
100
80
60
40
20
0
-20
-40
-60
-80
-100
-120
0
4
14
Randomized Phase
(DME treatment according to protocol)
34
56
Safety Phase
(DME treatment at investigator discretion)
Safety Phase
(DME discretion)
27
Safety
29
Major Ocular Adverse Events
Prior to the 14-Week Visit
Adverse events prior to
the 14-week visit
Sham+
Focal/Grid/PR
P Laser
N = 133
Number of injections
Ranibizumab+
Focal/Grid/PRP
Laser
N = 116
Triamcinolone+
Focal/Grid/PRP
Laser
N = 115
227
115
Endophthalmitis*
0
1 (0.9%)
0
Ocular vascular event
0
0
0
Traction retinal
detachment
3 (2%)
1 (1%)
1 (1%)
Vitrectomy
1 (1%)
0
1 (1%)
16 (12%)
6 (5%)
7 (6%)
Vitreous Hemorrhage
* One case related to study drug injection in the ranibizumab+focal/grid/PRP laser group.
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Major Ocular Adverse Events
from 14 Weeks to 56 Weeks
Sham+
Focal/Grid/PRP
Laser
N = 131
Ranibizumab+
Focal/Grid/PRP
Laser
N = 111
Triamcinolone+
Focal/Grid/PRP
Laser
N = 112
Endophthalmitis
0
0
0
Ocular vascular event
0
0
0
4 (3%)
5 (5%)
1 (1%)
Vitrectomy
17 (13%)
8 (7%)
7 (6%)
Vitreous Hemorrhage
28 (21%)
25 (23%)
20 (18%)
Adverse events from 14
to 56 weeks
Traction retinal detachment
31
Elevated Intraocular Pressure/Glaucoma
Prior to the 14-Week Visit
Sham+
Focal/Grid/PRP
Laser
N = 133
Number of injections
Ranibizumab+ Triamcinolone+
Focal/Grid/PRP Focal/Grid/PRP
Laser
Laser
N = 116
N = 115
227
115
Elevated Intraocular
Pressure/Glaucoma
Increase ≥10 mmHg from
baseline
3 (2%)
0
20 (17%)
IOP ≥30 mmHg
2 (2%)
0
5 (4%)
Initiation of IOP-lowering
meds at any visit*
2 (2%)
0
2 (2%)
3 (2%)
0
20 (17%)
0
0
0
Number of eyes
meeting ≥1 of the above
Glaucoma surgery
*Excludes eyes with IOP lowering medications at baseline
32
Elevated Intraocular Pressure/Glaucoma
from 14 Weeks to 56 Weeks
Elevated Intraocular
Pressure/Glaucoma
Sham+
Focal/Grid/PRP
Laser
N = 131
Ranibizumab+ Triamcinolone+
Focal/Grid/PRP Focal/Grid/PRP
Laser
Laser
N = 111
N = 112
Increase ≥10 mmHg from
baseline
6 (5%)
6 (5%)
10 (9%)
IOP ≥30 mmHg
4 (3%)
4 (4%)
4 (4%)
Initiation of IOP-lowering
meds at any visit*
7 (5%)
5 (5%)
17 (15%)
11 (8%)
7 (6%)
20 (18%)
0
1 (1%)
1 (1%)
Number of eyes
meeting ≥1 of the above
Glaucoma surgery†
*Excludes eyes with IOP lowering medications at baseline
† Includes 2 Ahmed valve (neovascular glaucoma)
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Cataract Surgery During Follow-up
 Up to 14 weeks none of the phakic eyes in all
groups required CE
 14 to 56 weeks CE was performed in a small
percentage of patients (2 to 3 % in sham and
ranibizumab groups and 6% in the TA group).
34
Cardiovascular Events According to Antiplatelet
Trialists’ Collaboration* through 56 Weeks
Non-fatal myocardial infarction
Non-fatal cerebrovascular accident
Vascular or
or unknown
unknown death
death
Vascular
Sham
Ranibizumab
Triamcinolone
4
14
Randomized Phase
(DME treatment according to protocol)
34
56
Safety Phase
(DME treatment at investigator discretion)
*Antiplatelet Trialists’ Collaboration. BMJ. 1994 Jan 8;308(6921):81-106.
Non-fatal cerebrovascular accidents include ischemic, hemorrhagic or unknown. Vascular death includes any potential vascular or
unknown cause.
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Summary
Randomized Phase
 14 week primary outcome visit:
• Both ranibizumab and triamcinolone significantly
improved visual acuity (+5.6 and +6.7 letters) and
retinal thickness (-35 and -100 microns) compared to
sham injection in eyes with central DME receiving
focal/grid laser and requiring prompt PRP
Safety Phase
 14 week to 56 week visits:
• Differences in visual acuity and retinal thickness
outcomes seen at 14 weeks not sustained
40
Summary
Safety
 Ranibizumab:
• Endophthalmitis: one eye receiving ranibizumab
• Long term safety of ranibizumab injections remains
largely unknown
 Triamcinolone:
• Increased risk of elevated IOP between 14 and 56
weeks; even with only one treatment at baseline
• Not associated with higher incidence of cataract
surgery (unlike prior studies)
o Why? Only 1 injection? Younger cohort? Lower enthusiasm to
operate on cataracts in this advance DR cohort? Other factors?
44
Summary
Safety
 This study did not identify an increased risk of
traction retinal detachments beyond that which
could be attributed to chance alone in these
eyes which were receiving PRP for PDR or
severe NPDR.
 Cerebrovascular or cardiovascular events did
not occur with a difference in frequency among
the 3 groups that could not be attributed to
chance alone.
45
Conclusions
 The risk of short-term exacerbation of macular
edema and associated visual acuity loss
following prompt PRP in eyes also receiving
focal/grid laser for DME can be reduced by
intravitreal triamcinolone or ranibizumab.
• Benefits were not maintained at 1 year, but
study injections were discontinued after 1
(triamcinolone) or 2 (ranibizumab) injections
47
Conclusions – Other Considerations
 Single study injection of intravitreal
triamcinolone appears associated with
increased risk of elevated IOP, even between 14
and 56 weeks
 Further study seems necessary to assess longterm risks and benefits of intravitreal injections
of ranibizumab or corticosteroids in persons
with central DME also receiving prompt PRP
50
Thank You on Behalf of Diabetic Retinopathy
Clinical Research Network (DRCR.net)




48 clinical study sites
Study participants who volunteered to participate in this trial
DRCR.net Data and Safety Monitoring Committee
Genentech (provided the ranibizumab) and Allergan, Inc.
(provided the triamcinolone) for the study and collaborated in a
manner consistent with the Network’s DRCR.net Industry
Collaboration Guidelines, the DRCR.net had complete control
over the design of the protocol, ownership of the data, and all
editorial content of presentations and publications related to the
protocol.
 DRCR.net investigators and staff
51