Transcript The Diabetic Retinopathy Clinical Research Network

The Diabetic Retinopathy Clinical
Research Network
Randomized Trial Evaluating Ranibizumab
Plus Prompt or Deferred Laser or
Triamcinolone Plus Prompt Laser for
Diabetic Macular Edema
1
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
Background:
Laser Therapy for DME
 Focal/grid photocoagulation has been the
standard care for DME for the past 25 years
 In a randomized, multicenter clinical trial,
DRCR.net showed (Protocol B – IVT vs Laser):
 Focal/grid photocoagulation in eyes with centerinvolved DME produces gradual visual acuity
improvement of ≥2 lines in about 30% of eyes after 2
years, although approximately 20% of laser treated eyes
worsen by ≥2 lines
 Other treatment modalities, including anti-vascular
endothelial growth factor (VEGF) therapy and
steroids, alone or in combination with laser, are 2
under investigation
Background:
Anti-VEGF Therapy for DME
 VEGF levels are increased in the retina and
vitreous of eyes with diabetic retinopathy
 Therapy that inhibits VEGF may represent a useful
therapeutic modality which targets the underlying
pathogenesis of DME
 Prior studies, that were small with short-term
follow-up, have reported promising results
3
Background:
Intravitreal Triamcinolone for DME
 Intravitreal triamcinolone was evaluated
previously as a treatment for DME in a
randomized trial conducted by DRCR.net
(Protocol B – IVT vs Laser):
 Results suggested that triamcinolone treatment without
laser was not superior to focal/grid photocoagulation
 Results suggested that triamcinolone treatment without
laser likely was superior to no treatment
4
Study Rationale
 To determine if anti-VEGF therapy alone or in
combination with laser, or if triamcinolone in
combination with laser, might result in improved
outcomes compared with laser alone for
treatment of DME, the DRCR.net designed a
clinical trial to evaluate 3 treatment modalities
for DME in comparison with focal/ grid laser:
 Intravitreal ranibizumab+prompt (within 1 week)
focal/grid laser
 Intravitreal ranibizumab + focal/grid laser
deferred for at least 24 weeks
 Intravitreal triamcinolone+prompt (within 1
week) focal/grid laser
5
Laser-Ranibizumab-Triamcinolone
Randomized Clinical Trial for DME:
Study Objective
Evaluate efficacy and safety of 0.5-mg intravitreal
ranibizumab plus prompt (within 1 week) or deferred
laser (≥24 weeks), or 4-mg intravitreal triamcinolone
plus prompt (within 1 week) laser, in comparison
with sham plus prompt laser for treatment of
diabetic macular edema.
6
Study Design
Randomized, multi-center clinical trial
At least one eye meeting all of the following criteria:
• Electronic-ETDRS© best corrected visual acuity
letter score of 78 to 24 (~20/32 to 20/320)
• Definite retinal thickening due to diabetic macular
edema involving the center of the macula on
clinical examination
• Central subfield (Stratus OCT™) ≥250 µm
Primary outcome: Change in visual acuity from
baseline to 1 year (intent to treat analysis)
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Follow-up Schedule
Baseline to
1 Year
1 Year to
3 Years
• Every subject has a follow-up visit at 1 year
• Follow-up every 4 weeks
• All groups except ranibizumab plus deferred
laser group: Additional follow-up visit occurs 3
to 10 days after injection if focal/grid laser also is
to be given
• Every subject has a follow-up visit at 2 years
• Follow-up every 4 to 16 weeks depending on
treatment group, disease progression, and
treatment administered
• Triamcinolone plus prompt laser group only:
Additional safety visit every 4 weeks after
triamcinolone injection
8
Study Enrollment and Completion
Eyes Randomized:
N = 854 (691 Participants)
Sham
+Prompt Laser
N = 293
Ranibizumab
+Prompt Laser
N = 187
Ranibizumab
+Deferred Laser
N = 188
Triamcinolone
+Prompt Laser
N = 186
1 Year Visit Completion:
94%*
2 Year Visit Completion:
87%**
* Includes deaths
** Includes deaths and excludes pending and dropped who are not yet in window
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Baseline Characteristics
Sham
+Prompt
Laser
Ranibizumab
+Prompt
Laser
Ranibizumab
+Deferred
Laser
Triamcinolone
+Prompt
Laser
63
62
64
62
Type I
9%
6%
8%
8%
Type II
89%
92%
90%
89%
3%
2%
2%
3%
65 (20/50)
66 (20/50)
66 (20/50)
66 (20/50)
407
371
382
374
Median age
Diabetes type
Uncertain
Median E-ETDRS©
visual acuity letter
score (Snellen
equivalent)
Median OCT CSF
thickness (µm)
10
Injections/Sham Prior to 1 Year
Sham
+Prompt
Laser
N = 274
Ranibizumab
+Prompt
Laser
N = 171
Ranibizumab
+Deferred
Laser
N = 178
Triamcinolone
+Prompt
Laser
N =176
13 sham*
13 drug
13 drug
9 sham/4 drug
Median number of
sham/study drug
injections to 1 year
11*
8
9
5 sham/3 drug
AE Precluding Study
Drug Injection†
NA
2%
2%
15%
Compliance with
sham/drug injection
when required by
protocol
96%
95%
97%
97%
Masked participant
with 1 study eye
identified correct
assignment at 1 year
10%
88%
90%
44%
Maximal possible # of
sham/injections
11
*Excludes 56 eyes among 163 participants with 2 study eyes unmasked at baseline when assigned ranibizumab + deferred laser.
† % of visits reported; 12% of eyes in the triamcinolone group compared with 3% and 4% in the ranibizumab groups
Laser Treatments Prior to 1 Year
Sham
+Prompt
Laser
Ranibizumab
+Prompt
Laser
Ranibizumab
+Deferred
Laser*
(permitted
starting at 24week visit)
Median number of
laser treatments
including baseline
3
2
0
2
Proportion of eyes
receiving laser at
48-week visit
26%
16%
8%
21%
No, only 1, only 2
or 3 more lasers
after baseline
Triamcinolone
+Prompt
Laser
13%,
27%,
31%,
32%,
70%,
20%,
26%,
30%,
40%,
20%
27%,
11%
10%,
1%
28%,
15%
* 3 eyes deviated from the protocol and received laser prior to 24 weeks (2 were given laser at the 1
week safety visit and 1 at the 20 week visit).
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Alternative* Treatments Prior to 1 Year
Eyes with alternative
treatments
(number of treatments)
Per protocol (failure‡
criteria met)
Deviations from
protocol - clinical
care
*Alternative
Sham
+Prompt
Laser
N = 293
Ranibizumab
+Prompt
Laser
N = 187
Ranibizumab
+Deferred
Laser
N = 188
Triamcinolone
+Prompt
Laser
N = 186
14 (25)
1 (1)
0
1 (1)
5
1
0
1
9
0
0
0
treatments include: intravitreal bevacizumab, intreavitreal triamcinolone acetonide,
vitrectomy, and intravitreal bevacizumab + intravitreal triamcinolone.
‡Failure is defined as: ≥10 letter loss from baseline, OCT CSF ≥250 µm, DME present on clinical
13
exam that is cause of visual loss, “complete laser” given AND ≥13 weeks since last laser
treatment with no improvement since the last laser treatment
Alternative* Treatments From 1 Year
and Prior to 2 Years
Eyes with alternative
treatments*
(number of treatments)
Per protocol (failure‡
criteria met)
Deviations from
protocol - clinical
care
Sham
+Prompt
Laser
N = 274
Ranibizumab
+Prompt
Laser
N = 171
Ranibizumab
+Deferred
Laser
N = 178
Triamcinolone
+Prompt
Laser
N = 176
29 (55)
1 (1)
0
3 (4)
20
1
0
2
9
0
0
1
* Alternative treatments include: intravitreal bevacizumab, intravitreal ranibizumab intreavitreal triamcinolone
acetonide, vitrectomy, intravitreal bevacizumab + intravitreal ranibizumab, and intravitreal bevacizumab +
intravitreal ranibizumab + intravitreal triamcinolone.
‡ Failure is defined as: ≥10 letter loss from baseline, OCT CSF ≥250 µm, DME present on clinical exam that is
cause of visual loss, “complete laser” given AND ≥13 weeks since last laser treatment with no improvement
since the last laser treatment
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Visual Acuity
15
Mean Change in Visual Acuity* (Letter
Score) at Follow-up Visits
Mean Change in Visual Acuity from Baseline
(Letter Score)
11
10
Sham+prompt
laser
9
8
Ranibizumab+
prompt laser
7
6
Primary outcome time point
5
Ranibizumab+
deferred laser
4
Triamcinolone
+prompt laser
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
Visit Week
that were ±30 letters were assigned a value of 30
16
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.
* Values
Change in Visual Acuity (LOCF)
at 1 Year*
Change in
Visual Acuity
(letters)
Mean
Difference in
mean change from
Sham +Prompt
Laser
[P Value]**
Sham
+Prompt
Laser
N = 293
+3
Ranibizumab Ranibizumab
+Prompt
+Deferred
Laser
Laser
N = 187
N = 188
Triamcinolone
+Prompt
Laser
N = 186
+9
+9
+4
+5.8
[P<0.001]
+6.0
[P<0.001]
+1.1
[P = 0.31]
*Visits occurring between 308 and 420 days from randomization were included as 1-year visits. When more
than 1 visit occurred in this window, data from the visit closest to the 1-year target date were used. For other
eyes with out any 1-year data (19 eyes in the sham+prompt laser group, 16 eyes in the ranibizumab+prompt
laser group, 10 eyes in the ranibizumab+deferred laser group, and 10 eyes in the triamcinolone+prompt laser
group) the last observation carried forward (LOCF) method was used to impute data for the primary analysis.
**Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity
17
Change in Visual Acuity at 2 Years*
Change in Visual
Acuity (letters)
Mean
Difference in mean
change from Sham
+Prompt Laser
[P Value]**
Sham
+Prompt
Laser
N = 163
Ranibizumab
+Prompt
Laser
N = 106
Ranibizumab
+Deferred
Laser
N = 112
Triamcinolone
+Prompt
Laser
N = 103
+2
+7
+10
0
+5.0
[P = 0.01]
+7.2
[P<0.001]
-1.6
[P = 0.43]
*Visits occurring between 616 and 840 days from randomization were included as 2-year visits
**Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity
18
≥10 Letter Improvement in Visual Acuity
at Follow-up Visits
Visit Week
P values for the difference in proportion of 10 letter improvement in visual acuity from sham+prompt laser at 19
the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001;
triamcinolone+prompt laser = 0.16
≥15 Letter Improvement in Visual Acuity
at Follow-up Visits
Visit Week
P values for the difference in proportion of 15 letter improvement in visual acuity from sham+prompt laser at
the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001;
triamcinolone+prompt laser = 0.07
20
≥10 Letter Worsening in Visual Acuity at
Follow-up Visits
Visit Week
P values for the difference in proportion of 10 letter worsening in visual acuity from sham+prompt laser at the
21
52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser =0.001; triamcinolone+prompt
laser = 0.75
≥15 Letter Worsening in Visual Acuity at
Follow-up Visits
Visit Week
P values for the difference in proportion of 15 letter worsening in visual acuity from sham+prompt laser at the
22
52-week visit: ranibizumab+prompt laser = 0.009; ranibizumab+deferred laser = 0.01; triamcinolone+prompt
laser = 0.95
≥10 Letter Improvement or Worsening in
Visual Acuity at Follow-up Visits
> 10 Letter Worsening
55%
50%
50%
Visual Acuity >10 Letter Worsening
Visual Acuity >10 Letter Improvement
> 10 Letter Improvement
55%
45%
40%
35%
30%
25%
20%
15%
10%
Sham+Prompt Laser
Sham+Prompt Laser
Ranibizumab+Prompt Laser
Ranibizumab+Deferred Laser
Triamcinolone+Prompt Laser
Ranibizumab+Prompt Laser
45%
Ranibizumab+Deferred Laser
40%
Triamcinolone+Prompt Laser
35%
N = 799 (52 weeks)
N = 484(104 weeks)
30%
25%
20%
15%
10%
5%
5%
0%
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
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
Visit Week
Visit Week
P values for the difference in proportion of 10 letter improvement in visual acuity from sham+prompt laser at
the 52-week visit: : ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001;
triamcinolone+prompt laser = 0.16
P values for the difference in proportion of 10 letter worsening in visual acuity from sham+prompt laser at the
23
52-week visit: : ranibizumab+prompt laser <0.001; ranibizumab+deferred laser =0.001; triamcinolone+prompt
laser = 0.75
≥15 Letter Improvement or Worsening In
Visual Acuity at Follow-up Visits
≥15 Letter Worsening
55%
50%
50%
Sham+Prompt Laser
45%Ranibizumab+Prompt Laser
Ranibizumab+Deferred Laser
40%Triamcinolone+Prompt Laser
Visual Acuity >15 Letter Worsening
Visual Acuity >15 Letter Improvement
≥15 Letter Improvement
55%
45%
40%
35%
30%
25%
20%
15%
10%
5%
Sham+Prompt Laser
Ranibizumab+Prompt Laser
Ranibizumab+Deferred Laser
Triamcinolone+Prompt Laser
35%
30%
25%
N = 799 (52 weeks)
N = 484 (104 weeks)
20%
15%
10%
5%
0%
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
Visit Week
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
Visit Week
P values for the difference in proportion of 15 letter improvement in visual acuity from sham+prompt laser at
the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001;
triamcinolone+prompt laser = 0.07
P values for the difference in proportion of 15 letter worsening in visual acuity from sham+prompt laser at the
52-week visit: : ranibizumab+prompt laser = 0.009; ranibizumab+deferred laser = 0.01; triamcinolone+prompt
laser = 0.95
24
Visual Acuity
Subgroup Analyses
25
Subgroup Analyses
 No obvious clinically important difference in
results at 1-year 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
Description of edema by ophthalmologist as
predominantly focal or predominantly diffuse
 In the subset of pseudophakic eyes at baseline
(n = 273), visual acuity improvement in the
triamcinolone+prompt laser group appeared
comparable to the ranibizumab groups
26
Change in Visual Acuity at 1 Year
Stratified by Baseline Visual Acuity
N=146
27
Change in Visual Acuity at 1 Year
Stratified by Baseline CSF
28
Change in Visual Acuity at 1 Year
Stratified by Prior DME Treatment
29
Change in Visual Acuity at 1 Year
Stratified by Number of Study Eyes
N=130
30
Change in Visual Acuity (LOCF) at 1 Year Stratified
by Eyes with Diffuse vs. Focal Edema at Baseline as
Graded by Study Ophthalmologist
31
Change in Visual Acuity at 1 Year
Stratified by Pseudophakic at Baseline
32
Mean Change in Visual Acuity at Follow-up Visits
among Eyes that were
Pseudophakic at Baseline*
Visit Week
* Values that were ±30 letters were assigned a value of 30
33
Retinal Thickening
34
Mean Change in Central Subfield
Thickening at Follow-up Visits
Visit Week
P values are for the difference in mean change in OCT CSF retinal thickness from sham+prompt laser at the 52-week visit:
ranibizumab+prompt laser <0.001, ranibizumab+deferred laser <0.001, and triamcinolone+prompt laser <0.001.
35
Central Subfield Thickness <250 µm with at Least a
25 µm Decrease in Thickness from Baseline at
Follow-up Visits
Visit Week
P values for difference in proportion in OCT central subfield thickness <250 microns with at least a 25 µm decrease in
thickness from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001, ranibizumab+deferred laser =
0.001, and triamcinolone+prompt laser <0.001.
36
Two or More Step Improvement in the Logarithmic
Transformation of Optical Coherence Tomography*
Data from Baseline
Visit Week
*Logarithmic optical coherence tomography is calculated by taking the log base 10 of the ratio of the central
subfield thickness divided by 200 and rounded to the nearest hundredth
37
Change in Retinal Thickening at 1 Year*
Change in OCT
Central
Subfield
Thickeninga
Sham
+Prompt
Laser
N = 271
Ranibizumab
+Prompt
Laser
N = 171
Ranibizumab
+Deferred
Laser
N = 175
Triamcinolone
+Prompt
Laser
N = 173
Mean change from
baseline (µm)
-102
-131
-137
-127
-55
[P<0.001]
-49
[P<0.001]
-52
[P<0.001]
53%
42%
47%
Difference in mean
change from Sham
Prompt+Laser
[P Value]**
Thickness <250 µm
with at least a 25
µm decrease from
baseline
27%
*Visits occurring between 308 and 420 days from randomization were included as 1 year visits. When more than 1 visit occurred in
this window, data from the visit closest to the 1 year target date were used.
**Analysis of covariance adjusted for baseline OCT retinal thickness and visual acuity and correlation between 2 study eyes
a Missing data for 22 eyes in the sham+prompt laser group, 16 eyes in the ranibizumab+prompt laser group, 13 in the
ranibizumab+deferred Laser, and 13 eyes in the triamcinolone+prompt laser group (includes missing and ungradeable data [3 in 38
sham+prompt laser, 2 in ranibizumab+deferred laser and 2 in triamcinolone+prompt laser]
Change in Retinal Thickening at 2 Years*
Change in OCT
Central
Subfield
Thickeninga
Sham
+Prompt
Laser
N = 152
Ranibizumab
+Prompt
Laser
N = 99
Ranibizumab
+Deferred
Laser
N = 100
Triamcinolone
+Prompt
Laser
N = 93
Mean change from
baseline (µm)
-133
-144
-170
-95
-31
[P = 0.01]
-36
[P = 0.004]
-3
[P = 0.81]
54%
55%
44%
Difference in mean
change from Sham
+ Laser [P Value]**
Thickness <250 µm
with at least a 25 µm
decrease from
baseline
38%
*Visits occurring between 616 and 840 days from randomization were included as 2-year visits. When more than 1 visit occurred
in this window, data from the visit closest to the 2-year target date were used.
** Analysis of covariance adjusted for baseline OCT retinal thickness and visual acuity and correlation between 2 study eyes
ª Excluding pending- Missing data for 2 eyes in the sham+prompt laser group, 2 eyes in the ranibizumab+prompt laser group, 2
in the ranibizumab +deferred laser, and 6 eyes in the triamcinolone+prompt laser group; Ungradeable data for 1 in the
39
ranibizumab+prompt laser, 1 in ranibizumab+deferred laser and 2 in triamcinolone+prompt laser
≥2 Step Improvement in Log OCT
Mean Change in Visual Acuity
>2 Step Improvement in LogOCT from Baseline
Mean Change in Visual Acuity from Baseline (letter score)
Comparison of Visual Acuity
and OCT Central Subfield
Thickness
12
11
10
9
8
7
6
5
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
Visit Week
60%
50%
40%
Sham+Prompt Laser
30%
Ranibizumab+Prompt Laser
Ranibizumab+Deferred Laser
Triamcinolone+Prompt Laser
20%
Sham+Prompt Laser
Ranibizumab+Prompt Laser
Ranibizumab+Deferred Laser
Triamcinolone+Prompt Laser
10%
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
Visit Week
40
Retinopathy
41
Step Changes of Improvement/Worsening in
Diabetic Retinopathy by Baseline Severity
Sham
+Prompt
Laser
Ranibizumab
+Prompt
Laser or
Deferred Laser
Triamcinolone
+Prompt
Laser
N = 150
N = 182
N = 80
Improved by ≥2 levels
4%
25%
25%
Worsened by ≥2 levels
7%
3%
3%
P = 0.08
P =0.17
N = 83
N = 121
N = 70
Improved by ≥2 levels
19%
28%
13%
Worsened by ≥2 levels
8%
1%
3%
P = 0.03
P = 0.17
Change from baseline to 1-year
visit*
Baseline Severity: Moderately
Severe NPDR or Better
P value for comparison with
Sham
Baseline Severity: Severe NPDR or
worse
P value for comparison with
Sham
*Photos were missing or ungradeable for 61 eyes in the sham+prompt laser group, 72 eyes in the ranibizumab
groups, and 33 eyes in the triamcinolone+prompt laser group
42
Retinopathy Progression During 1
Year of Follow-up
Reported vitreous
hemorrhage OR
received PRP
P Value for
comparison with
sham
Sham
N = 293
Ranibizumab
N = 375
Triamcinolone
N = 186
8%
3%
3%
--
0.002
0.02
43
Safety
44
Major Ocular Adverse Events
During 2-Years of Follow-up
Sham
+Prompt
Laser
N = 293
Number of injections
Ranibizumab
+Prompt
Laser
N = 187
Ranibizumab
+Deferred
Laser
N = 188
Triamcinolone
+Prompt
Laser
N = 186
1833
2140
685
Endophthalmitis*
1 (<1%)
2 (1%)
2 (1%)
0
Pseudoendophthalmitis†
1(<1%)
0
0
1 (1%)
Ocular vascular event‡
1 (<1%)
1 (1%)
1 (1%)
3 (2%)
0
0
1 (1%)
0
Vitrectomy
15 (5%)
4 (2%)
7 (4%)
2 (1%)
Vitreous Hemorrhage
27 (9%)
6 (3%)
8 (4%)
7 (4%)
Retinal detachment§
*One case unrelated to study drug injection (following cataract extraction) in the sham+prompt laser group; 1 case related to study drug injection
and 1 case unrelated to injection (following cataract surgery) in the ranibizumab+prompt laser group; 2 cases related to study drug injection in the
ranibizumab+deferred laser group. The 3 cases related to study drug injection in the ranibizumab groups are 0.08% of ranibizumab study drug
injections given.
† One case unrelated to the study drug injection (vitreous opacity with hypopyon) and one case related to study drug injection in the
triamcinolone group.
45
‡ Includes 2 central retinal vein occlusions and 4 branch retinal vein occlusions.
§Includes 1 traction retinal detachment with proliferative diabetic retinopathy and prior panretinal photocoagulation at baseline.
Elevated Intraocular Pressure/Glaucoma
During 2-Years of Follow-up
Sham
+Prompt
Laser
N = 293
Ranibizumab
+Prompt
Laser
N = 187
Ranibizumab
+Deferred
Laser
N = 188
Triamcinolone
+Prompt Laser
N = 186
Increase ≥10 mmHg
from baseline
8%
9%
6%
42%
IOP ≥30 mmHg
3%
2%
3%
27%
Initiation of IOPlowering meds at any
visit*
5%
5%
3%
28%
Number of eyes
meeting ≥1 of the
above
11%
11%
7%
50%
<1%
1%
0
1%
Elevated Intraocular
Pressure/Glaucoma
Glaucoma surgery**
*Excludes eyes with IOP lowering medications at baseline
**Includes 2 filter and 2 cilliary body destruction
46
Cataract Surgery During 2-Years of
Follow-up
Sham
+Prompt
Laser
Phakic at
baseline
Eyes that had
cataract surgery
Ranibizumab Ranibizumab Triamcinolone
+Prompt
+Deferred
+Prompt
Laser
Laser
Laser
N = 192
N = 131
N = 134
N = 124
12%
12%
13%
55%
47
Cumulative Probability of
Cataract Surgery Over 2-Years
Cumulative Probability of Cataract
100%
90%
Sham+Laser
Ranibizumab
Triamcinolone
80%
70%
60%
59%
50%
40%
30%
20%
14%
10%
14%
0%
0
120
4
240
8
360
12
480
16
600
20
720
24
840
Month
48
Number of Deaths
Sham Ranibizumab Triamcinolone
N = 130
N = 375
N = 186
Deaths*
7 (5%)
15 (4%)
6 (3%)
*Study participants with 2 study eyes are counted in their injection group.
49
Cardiovascular or Cerebrovascular
Events According to Antiplatelet Trialists’
Collaboration through 2-Years
Sham‡
N* = 130
Ranibizumab Triamcinolone
N* = 375
N* = 186
Non-fatal myocardial infarction
3%
1%
3%
Non-fatal cerebrovascular
accident-ischemic or
hemorrhagic (or unknown)
6%
2%
2%
Vascular death (from any
potential vascular or unknown
cause†)
5%
2%
2%
12%
5%
6%
Any APTC event
* N=Number of Study Participants. Study participants with 2 study eyes are assigned to the non-sham group.
Multiple events within a study participant are only counted once per event.
‡One participant had a non-fatal myocardial infarction and a non-fatal stroke (only counted once in the any
cardiovascular event row)
†Four of the vascular deaths in the sham group, 1 of the vascular deaths in the ranibizumab group, and 1 of the
vascular deaths in the triamcinolone group were from an unknown cause
50
Discussion
51
Intravitreal Ranibizumab
Summary
 Intravitreal ranibizumab with prompt or
deferred (≥24 weeks) focal/grid laser had
superior VA and OCT outcomes compared
with focal/grid laser treatment alone.
•
•
•
~50% of eyes had substantial improvement (≥10
letters) while ~30% gained ≥15 letters
Substantial visual acuity loss (≥10 letters) was
uncommon
Results were similar whether focal/grid laser was
given starting with the first injection or it was
deferred >24 weeks
52
Intravitreal Ranibizumab
Summary
 If ranibizumab is to be given as it was in
this study, the data indicate a need to
follow eyes continuously undergoing this
treatment
•
Additional ranibizumab and/or laser were needed in
most eyes through ≥2 years, even if ‘success’
criteria were met early in the course of treatment.
53
Intravitreal Ranibizumab
Treatment Protocol
Results are based on rigorous adherence to a
detailed retreatment protocol on a web-based realtime data entry system that provided feedback to
the treating physician regarding the treatment to
be prescribed at each follow-up visit.
The underlying rationale of the treatment algorithm
is to continue treatment, as needed, until
stabilization or lack of further improvement is
noted.
54
Intravitreal Ranibizumab
Treatment Protocol
 Once a retreatment is withheld, the algorithm is
designed to identify when there is a need to reinitiate treatment.
•
The goal was to avoid substantial vision loss while
also avoiding a regimen which requires monthly
treatments regardless of the clinical course.
 The impact of different retreatment approaches
or use of other anti-VEGF drugs (such as
bevacizumab) in clinical practice cannot be
determined from this study.
55
Intravitreal Ranibizumab
Conclusion
Ranibizumab as applied in this study,
although uncommonly associated with
endophthalmitis, should be considered
for patients with DME and
characteristics similar to those in this
clinical trial.
56
Intravitreal Triamcinolone
Summary
 Intravitreal triamcinolone combined with focal/grid
laser did not result in superior VA outcomes
compared with laser alone.
 Intravitreal triamcinolone did result in a greater
reduction in retinal thickening at 1 year but not 2
years compared with laser alone.
 In an analysis limited to pseudophakic eyes, the
triamcinolone group’s outcome for VA appeared
to be of similar magnitude to that of the 2
57
ranibizumab groups.
Intravitreal Triamcinolone
Conclusion
 In pseudophakic eyes, intravitreal
triamcinolone with prompt focal/grid laser may
be equally effective as ranibizumab at
improving visual acuity and reducing retinal
thickening, but is associated with an increased
risk of intraocular pressure elevation.
58
Thank You on Behalf of Diabetic Retinopathy
Clinical Research Network (DRCR.net)
 52 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 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
59
Additional Slides
60
Study Enrollment and Completion
 854 study eyes (691 study participants) from 52
clinical sites
 Treatment Groups
•Sham+prompt laser: N= 293
•Ranibizumab+prompt laser group: N= 187
•Ranibizumab+deferred laser: N= 188
•Triamcinolone+prompt laser: N= 186
 1 year visit completion rate* = 95%
• Including deaths = 94%
 2 year visit completion rate† = 91%
• Including deaths = 87%
*1-year analysis window +/- 8 weeks; N=799 completed of 841 (Excludes deaths)
† 2-year analysis window +/- 16 weeks; N=484 completed of 534 (Excludes deaths, pending, and dropped 61
participants who are not yet in window)
Study Enrollment and Completion
Eyes Randomized: N = 854
(691 Participants)
Sham
+Prompt Laser
N = 293
Completed=274
(94%)
Pending=91
Completed=163
Ranibizumab
+Prompt Laser
N = 187
Completed=171
(91%)
Pending=56
Completed=106
Ranibizumab
+Deferred Laser
N = 188
Completed=178
(95%)
Pending=55
Completed=112
Triamcinolone
+Prompt Laser
N = 186
Completed=176
(95%)
1 Year
Visit
Pending=63
Completed=103
2 Year
Visit
62
Protocol B: VA and OCT CSF Results at
1 and 2 Years
Change in VA at 1 Year
Mean change from
baseline (letters)
Change in VA at 2 Years
(primary outcome)
Mean change from
baseline (letters)
Change in OCT CSF at 1
Year
Mean change from
baseline (microns)
Change in OCT CSF at 2
Years
Mean change from
baseline (microns)
Laser
1 mg
4 mg
N = 286
N = 230
N = 221
+1
0
0
N = 272
N = 220
N = 204
+2
-2
-4
N = 278
N = 225
N = 213
-98
-55
-93
N = 220
N = 178
N = 162
-139
-86
-77
63
Protocol I: VA and OCT CSF Results at 1 and
2 Years
Change in VA at 1 Year
(LOCF)
Mean change from
baseline (letters)
Change in VA at 2 Years
Mean change from
baseline (letters)
Change in OCT CSF at
1 Year
Mean change from
baseline (microns)
Change in OCT CSF at
2 Years
Mean change from
baseline (microns)
Sham
+Prompt
Laser
Ranibizumab
+Prompt
Laser
Ranibizumab
+Deferred
Laser
Triamcinolone
+Prompt
Laser
N = 293
N = 187
N = 188
N = 186
+3
+9
+9
+4
N = 163
N = 106
N = 112
N = 103
+2
+7
+10
0
N = 271
N = 171
N = 175
N = 173
-102
-131
-137
-127
N = 152
N = 99
N = 100
N = 93
-133
-144
-170
-95
64
Additional Information on Injections/Sham Prior to 1 Year
Sham
+Prompt
Laser
N = 274
Ranibizumab Ranibizumab Triamcinolone
+Prompt
+Deferred
+Prompt
Laser
Laser
Laser
N = 171
N = 178
N = 176
Success criteria* at
16-week study visit
and no injection
31 (11%)
47 (25%)
41 (22%)
38 (20%)
No more injections
through 1 year of 16week successes*†
13 (42%)
17 (36%)
15 (37%)
10 (27%)
% of eyes meeting
success criteria* at
1-year study visit
32%
64%
52%
56%
% of eyes with letter
score >84 (~>20/20)
at 1-year study visit
8%
13%
13%
11%
65
*VA letter score ≥84 (~20/20 or better) or OCT CSF <250 microns
†Excludes 56 eyes among 163 participants with two study eyes unmasked at baseline when assigned ranibizumab+deferred laser
Additional Information On Injections/Sham to 2 Years
Sham
+Prompt
Laser
N = 274
Ranibizumab Ranibizumab Triamcinolone
+Prompt
+Deferred
+Prompt
Laser
Laser
Laser
N = 171
N = 178
N = 176
% of eyes meeting
failure criteria* at 1year study visit
4%
2%
1%
2%
Maximal # of drug
injections prior to 2
years
n/a
25
25
8
Median drug
injections prior to 1
year
n/a
8
9
3
Median drug
injections prior to 2
years
n/a
11
13
4
* Failure is defined as: VA 10 or more worse than baseline, OCT CSF ≥250 microns, DME present on
clinical exam that is the cause of the visual loss, complete laser given AND ≥13w since last laser
treatment with no improvement since the last laser treatment
66
Treatment
Injection Protocol up to 48-Week Visit
 All subjects are given an injection/sham* on the day of
randomization
 Every group receives an injection/sham* at each 4-week
interval visit through the 12-week visit
 At 16 and 20-week visits, injection/sham* is at
investigator discretion if visual acuity ≥84 or OCT CSF
<250
 Between 24 and 48 weeks, the study eye is evaluated
using retreatment criteria† at each 4-week interval visit
for injection/sham*
*Both ranibizumab groups receive true injection. Sham group receives sham injection. Triamcinolone
group receives: true injection if one has not been given in the prior 15 weeks, sham otherwise.
†The retreatment criteria for evaluation: 1) reinjection with randomized treatment at investigator
discretion if VA>84 or OCT CSF <250; 2) injection if VA<84 and evidence of improvement (OCT CSF
thickness decreased by 10% or more OR VA improved 5 or more letters); 3) treated at investigator
67if
discretion if failure criteria‡ met; 4) reinjection with randomized treatment at investigator discretion
failure criteria not met but no evidence of improvement.
Treatment
Injection Protocol at and After 1-Year Visit
Sham injections are discontinued for
Groups A and D
For Groups B and C, the study eye is
evaluated for ranibizumab injection using
retreatment criteria at each 4-week interval
visit
For Group D, the study eye is evaluated for
triamcinolone injection using retreatment
criteria at each 16-week interval visit
68
Treatment
Laser Protocol
 The 3 non-deferral groups (ranibizumab,
triamcinolone, and sham) receive initial laser 3-10
days after the baseline injection
 Retreatment is given 3 to 10 days after each injection (or
at the time of visit if an injection is not given) unless
laser already given within 13 wks, maximum laser
already given, or CSF <250
 The ranibizumab + deferred laser group does not
receive laser prior to 24 weeks
 At 24-week or later visits, laser is given if CSF decreased
<10% (or increased) and VA improved <5 (or worsened)
from the last 2 consecutive injections and between the
last 2 consecutive injections and macular edema
69
needing laser still present
DRCR.net Retreatment
Algorithm Flowcharts
70
Intravitreal Injection Treatment at 16 to 48 Weeks
(Following 4 Intravitreal or Sham Injections Every 4 Weeks
Through Week 12)
71
Treatment at and after the 52-Week Follow-Up Visit
SHAM+PROMPT LASER GROUP (A)
72
Treatment at and after the 52-Week Follow-Up Visit
RANIBIZUMAB+PROMPT LASER GROUP (B)
73
Treatment at and after 52 Week Follow-Up Visit
RANIBIZUMAB+DEFERRED LASER GROUP (C)
74
Treatment at and after the 52-Week Follow-Up Visit
TRIAMCINOLONE+PROMPT LASER GROUP (D)
75
Laser Treatment at and after the 16-Week Follow-Up Visit
(Following Focal/Grid Laser Treatment at 1 Week in Groups A,
B, and D)
76
Visual Acuity Change at 1 Year
N=293
N=187
N=188
N=186
77
Visual Acuity ≥10 or ≥15 Letter
Improvement or Worsening at 1 Year
78
Visual Acuity Improvement at 1 Year
N = 293
N = 187
N = 188
N = 186
79
Visual Acuity Loss at 1 Year
N = 293
N = 187
N = 188
N = 186
80
Visual Acuity Improvement at 2 Years
N = 163
N = 106
N = 112
N = 103
81
Visual Acuity Loss at 2 Years
N = 163
N = 106
N = 112
N = 103
82
≥10 Letter Visual Acuity Improvement/Worsening
among Eyes Not Pseudophakic and Eyes that were
Pseudophakic at Baseline
Eyes not Pseudophakic at Baseline
Eyes Pseudophakic at Baseline
83