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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
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
2
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 center-
involved 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 under investigation
Background: Laser Therapy for DME
Background: Laser Therapy for DME
Background: Anti-VEGF Therapy for DME
Background: Anti-VEGF Therapy for DME
3
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
Background: Intravitreal Triamcinolone for DME
Background: Intravitreal Triamcinolone for DME
4
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
5
Study RationaleStudy 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
6
Laser-Ranibizumab-Triamcinolone Randomized Clinical Trial for DME: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.
7
Study DesignStudy Design
Primary outcome: Change in visual acuity from baseline to 1 year (intent to treat analysis)
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
Follow-up Schedule Follow-up Schedule
8
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
Study Enrollment and CompletionStudy Enrollment and Completion
9
Ranibizumab+Prompt Laser
N = 187
Ranibizumab+Deferred Laser
N = 188
Sham+Prompt Laser
N = 293
Triamcinolone+Prompt Laser
N = 186
Eyes Randomized: N = 854 (691 Participants)
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
10
Baseline CharacteristicsBaseline CharacteristicsSham
+Prompt
Laser
Ranibizumab
+Prompt
Laser
Ranibizumab
+Deferred
Laser
Triamcinolone
+Prompt
Laser
Median age 63 62 64 62
Diabetes type
Type I 9% 6% 8% 8%
Type II 89% 92% 90% 89%
Uncertain 3% 2% 2% 3%
Median E-ETDRS©
visual acuity letter score (Snellen equivalent)
65 (20/50) 66 (20/50) 66 (20/50) 66 (20/50)
Median OCT CSF thickness (µm) 407 371 382 374
11
Injections/Sham Prior to 1 YearInjections/Sham Prior to 1 YearSham
+Prompt
Laser
N = 274
Ranibizumab
+Prompt
Laser
N = 171
Ranibizumab
+Deferred
Laser
N = 178
Triamcinolone
+Prompt
Laser
N =176
Maximal possible # of sham/injections 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%
*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
12
Laser Treatments Prior to 1 YearLaser Treatments Prior to 1 Year
Sham
+Prompt
Laser
Ranibizumab
+Prompt
Laser
Ranibizumab
+Deferred
Laser*
(permitted starting at 24-
week visit)
Triamcinolone
+Prompt
Laser
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
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).
13
Sham
+Prompt
Laser
N = 293
Ranibizumab
+Prompt
Laser
N = 187
Ranibizumab
+Deferred Laser
N = 188
Triamcinolone
+Prompt
Laser
N = 186
Eyes with alternative treatments(number of treatments)
14 (25) 1 (1) 0 1 (1)
Per protocol (failure‡ criteria met) 5 1 0 1
Deviations from protocol - clinical care
9 0 0 0
Alternative* Treatments Prior to 1 YearAlternative* Treatments Prior to 1 Year
*Alternative 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 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
14
Sham
+Prompt
Laser
N = 274
Ranibizumab
+Prompt
Laser
N = 171
Ranibizumab
+Deferred
Laser
N = 178
Triamcinolone
+Prompt
Laser
N = 176
Eyes with alternative treatments*(number of treatments)
29 (55) 1 (1) 0 3 (4)
Per protocol (failure‡ criteria met) 20 1 0 2
Deviations from protocol - clinical care
9 0 0 1
Alternative* Treatments From 1 Yearand Prior to 2 Years
Alternative* Treatments From 1 Yearand Prior to 2 Years
* 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
Visual AcuityVisual Acuity
15
Mean Change in Visual Acuity* at Follow-up Visits
Mean Change in Visual Acuity* at Follow-up Visits
16* Values that were ±30 letters were assigned a value of 30P-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.
Change in Visual Acuity (LOCF) at 1 Year*
Change in Visual Acuity (LOCF) at 1 Year*
17
Change in Visual Acuity (letters)
Sham
+Prompt
Laser
N = 293
Ranibizumab
+Prompt
Laser
N = 187
Ranibizumab
+Deferred
Laser
N = 188
Triamcinolone
+Prompt
Laser
N = 186
Mean +3 +9 +9 +4
Difference in mean change from Sham +Prompt Laser
[P Value]**
+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
Change in Visual Acuity at 2 Years*Change in Visual Acuity at 2 Years*
18
Change in Visual Acuity (letters)
Sham
+Prompt
Laser
N = 163
Ranibizumab
+Prompt
Laser
N = 106
Ranibizumab
+Deferred
Laser
N = 112
Triamcinolone
+Prompt
Laser
N = 103
Mean +2 +7 +10 0
Difference in mean change from Sham +Prompt Laser
[P Value]**+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
≥10 Letter Improvement in Visual Acuity at Follow-up Visits
≥10 Letter Improvement in Visual Acuity at Follow-up Visits
19P 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
Visit Week
≥15 Letter Improvement in Visual Acuity at Follow-up Visits
≥15 Letter Improvement in Visual Acuity at Follow-up Visits
20
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
≥10 Letter Worsening in Visual Acuity at Follow-up Visits
≥10 Letter Worsening in Visual Acuity at Follow-up Visits
21
Visit Week
P values for the difference in proportion of 10 letter worsening 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 = 0.75
≥15 Letter Worsening in Visual Acuity at Follow-up Visits
≥15 Letter Worsening in Visual Acuity at Follow-up Visits
22
Visit Week
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
≥10 Letter Improvement or Worsening in Visual Acuity at Follow-up Visits
≥10 Letter Improvement or Worsening in Visual Acuity at Follow-up Visits
23
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
Visu
al A
cuity
>
10 L
ette
r Im
prov
emen
t
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
55%
Sham+Prompt LaserRanibizumab+Prompt LaserRanibizumab+Deferred LaserTriamcinolone+Prompt Laser
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
Visu
al A
cuity
>
10 L
ette
r W
orse
ning
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
55%
Sham+Prompt LaserRanibizumab+Prompt LaserRanibizumab+Deferred LaserTriamcinolone+Prompt Laser
N = 799 (52 weeks)N = 484(104 weeks)
> 10 Letter Improvement > 10 Letter Worsening
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 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 Improvement or Worsening In Visual Acuity at Follow-up Visits
24
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
Vis
ual A
cuity
>
15 L
ette
r Im
prov
emen
t
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
55%
Sham+Prompt LaserRanibizumab+Prompt LaserRanibizumab+Deferred LaserTriamcinolone+Prompt Laser
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
Vis
ual A
cuity
>
15 L
ette
r W
orse
ning
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
55%
Sham+Prompt LaserRanibizumab+Prompt LaserRanibizumab+Deferred LaserTriamcinolone+Prompt Laser
N = 799 (52 weeks)N = 484 (104 weeks)
≥15 Letter Improvement ≥15 Letter Worsening
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
Visual AcuitySubgroup Analyses
Visual AcuitySubgroup Analyses
25
26
Subgroup AnalysesSubgroup 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
Change in Visual Acuity at 1 Year Stratified by Baseline Visual AcuityChange in Visual Acuity at 1 Year
Stratified by Baseline Visual Acuity
27
N=146
Change in Visual Acuity at 1 Year Stratified by Baseline CSF
Change in Visual Acuity at 1 Year Stratified by Baseline CSF
28
Change in Visual Acuity at 1 Year Stratified by Prior DME TreatmentChange in Visual Acuity at 1 Year Stratified by Prior DME Treatment
29
Change in Visual Acuity at 1 Year Stratified by Number of Study EyesChange in Visual Acuity at 1 Year
Stratified by Number of Study Eyes
30
N=130
Change in Visual Acuity (LOCF) at 1 Year Stratified by Eyes with Diffuse vs. Focal Edema at Baseline as
Graded by Study Ophthalmologist
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
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*
Mean Change in Visual Acuity at Follow-up Visits among Eyes that were
Pseudophakic at Baseline*
33
Visit Week
* Values that were ±30 letters were assigned a value of 30
Retinal ThickeningRetinal Thickening
34
Mean Change in Central Subfield Thickening at Follow-up Visits
Mean Change in Central Subfield Thickening at Follow-up Visits
35
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.
Central Subfield Thickness <250 µm with at Least a 25 µm Decrease in Thickness from Baseline at
Follow-up Visits
Central Subfield Thickness <250 µm with at Least a 25 µm Decrease in Thickness from Baseline at
Follow-up Visits
36
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.
Two or More Step Improvement in the Logarithmic Transformation of Optical Coherence Tomography*
Data from Baseline
Two or More Step Improvement in the Logarithmic Transformation of Optical Coherence Tomography*
Data from Baseline
37
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
Change in Retinal Thickening at 1 Year*Change in Retinal Thickening at 1 Year*
38
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
Difference in mean change from Sham Prompt+Laser
[P Value]**
-55[P<0.001]
-49[P<0.001]
-52[P<0.001]
Thickness <250 µm with at least a 25 µm decrease from baseline
27% 53% 42% 47%
*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 sham+prompt laser, 2 in ranibizumab+deferred laser and 2 in triamcinolone+prompt laser]
Change in Retinal Thickening at 2 Years*Change in Retinal Thickening at 2 Years*
39
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
Difference in mean change from Sham + Laser [P Value]**
-31[P = 0.01]
-36[P = 0.004]
-3[P = 0.81]
Thickness <250 µm with at least a 25 µm decrease from baseline
38% 54% 55% 44%
*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 eyesª 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 ranibizumab+prompt laser, 1 in ranibizumab+deferred laser and 2 in triamcinolone+prompt laser
Comparison of Visual Acuity and OCT Central Subfield
Thickness
Comparison of Visual Acuity and OCT Central Subfield
Thickness
40
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
Mean
Ch
an
ge i
n V
isu
al
Acu
ity
fro
m B
aseli
ne (
lett
er
sco
re)
0
1
2
3
4
5
6
7
8
9
10
11
12
Sham+Prompt LaserRanibizumab+Prompt LaserRanibizumab+Deferred LaserTriamcinolone+Prompt Laser
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
>2
Ste
p Im
pro
vem
ent
in L
og
OC
T f
rom
Bas
elin
e
0%
10%
20%
30%
40%
50%
60%
Sham+Prompt LaserRanibizumab+Prompt LaserRanibizumab+Deferred LaserTriamcinolone+Prompt Laser
Mean Change in Visual Acuity ≥2 Step Improvement in Log OCT
RetinopathyRetinopathy
41
42
Step Changes of Improvement/Worsening in Diabetic Retinopathy by Baseline Severity
Step Changes of Improvement/Worsening in Diabetic Retinopathy by Baseline Severity
Change from baseline to 1-year visit*
Sham
+Prompt
Laser
Ranibizumab
+Prompt
Laser or Deferred Laser
Triamcinolone
+Prompt
Laser
Baseline Severity: Moderately Severe NPDR or Better
N = 150 N = 182 N = 80
Improved by ≥2 levels 4% 25% 25%
Worsened by ≥2 levels 7% 3% 3%
P value for comparison with Sham
P = 0.08 P =0.17
Baseline Severity: Severe NPDR or worse
N = 83 N = 121 N = 70
Improved by ≥2 levels 19% 28% 13%
Worsened by ≥2 levels 8% 1% 3%
P value for comparison with Sham
P = 0.03 P = 0.17
*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
Retinopathy Progression During 1 Year of Follow-up
Retinopathy Progression During 1 Year of Follow-up
43
Sham
N = 293
Ranibizumab
N = 375
Triamcinolone
N = 186
Reported vitreous hemorrhage OR received PRP
8% 3% 3%
P Value for comparison with sham -- 0.002 0.02
SafetySafety
44
45
Major Ocular Adverse Events During 2-Years of Follow-up
Major Ocular Adverse Events During 2-Years of Follow-up
45
Sham
+Prompt Laser
N = 293
Ranibizumab
+Prompt Laser
N = 187
Ranibizumab
+Deferred Laser
N = 188
Triamcinolone
+Prompt Laser
N = 186
Number of injections 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%)
Retinal detachment§ 0 0 1 (1%) 0
Vitrectomy 15 (5%) 4 (2%) 7 (4%) 2 (1%)
Vitreous Hemorrhage 27 (9%) 6 (3%) 8 (4%) 7 (4%)*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. ‡ 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.
46
Elevated Intraocular Pressure/Glaucoma During 2-Years of Follow-up
Elevated Intraocular Pressure/Glaucoma During 2-Years of Follow-up
46
Elevated Intraocular Pressure/Glaucoma
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 IOP-lowering meds at any visit*
5% 5% 3% 28%
Number of eyes meeting ≥1 of the above
11% 11% 7% 50%
Glaucoma surgery** <1% 1% 0 1%
*Excludes eyes with IOP lowering medications at baseline**Includes 2 filter and 2 cilliary body destruction
47
Cataract Surgery During 2-Years of Follow-up
Cataract Surgery During 2-Years of Follow-up
47
Sham
+Prompt
Laser
Ranibizumab
+Prompt
Laser
Ranibizumab
+Deferred Laser
Triamcinolone
+Prompt Laser
Phakic at baseline
N = 192 N = 131 N = 134 N = 124
Eyes that had cataract surgery
12% 12% 13% 55%
Cumulative Probability of Cataract Surgery Over 2-Years
Cumulative Probability of Cataract Surgery Over 2-Years
48Month
0 120 240 360 480 600 720 8400%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Sham+LaserRanibizumab Triamcinolone
84 12 16 20 24
59%
14%
14%
Number of DeathsNumber of Deaths
49
Sham
N = 130
Ranibizumab
N = 375
Triamcinolone
N = 186
Deaths* 7 (5%) 15 (4%) 6 (3%)
*Study participants with 2 study eyes are counted in their injection group.
50
Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’
Collaboration through 2-Years
Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’
Collaboration through 2-Years
50
Sham‡
N* = 130
Ranibizumab
N* = 375
Triamcinolone
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%
Any APTC event 12% 5% 6%
* 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
DiscussionDiscussion
51
52
Intravitreal Ranibizumab Summary
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
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Intravitreal Ranibizumab Summary
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.
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Intravitreal Ranibizumab Treatment Protocol
Intravitreal Ranibizumab Treatment Protocol
Results are based on rigorous adherence to a detailed retreatment protocol on a web-based real-time 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.
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Intravitreal Ranibizumab Treatment Protocol
Intravitreal Ranibizumab Treatment Protocol
Once a retreatment is withheld, the algorithm is designed to identify when there is a need to re-initiate 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.
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Intravitreal Ranibizumab Conclusion
Intravitreal Ranibizumab Conclusion
Ranibizumab as applied in this study, Ranibizumab as applied in this study, although uncommonly associated with although uncommonly associated with endophthalmitis, should be considered endophthalmitis, should be considered for patients with DME and for patients with DME and characteristics similar to those in this characteristics similar to those in this clinical trial. clinical trial.
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Intravitreal Triamcinolone Summary
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 ranibizumab groups. 57
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Intravitreal Triamcinolone Conclusion
Intravitreal Triamcinolone Conclusion
In pseudophakic eyes, intravitreal intravitreal triamcinolone with prompt focal/grid laser may triamcinolone with prompt focal/grid laser may be equally effective as ranibizumab at be equally effective as ranibizumab at improving visual acuity and reducing retinal improving visual acuity and reducing retinal thickening, but is associated with an increased thickening, but is associated with an increased risk of intraocular pressure elevation.risk of intraocular pressure elevation.
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Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)
Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)
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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
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Additional SlidesAdditional Slides
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Study Enrollment and CompletionStudy 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 participants who are not yet in window)
Study Enrollment and CompletionStudy Enrollment and Completion
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Ranibizumab+Prompt Laser
N = 187
Completed=274 (94%)
Completed=171 (91%)
Completed=178 (95%)
Completed=176 (95%)
Ranibizumab+Deferred Laser
N = 188
Sham+Prompt Laser
N = 293
Triamcinolone+Prompt Laser
N = 186
Eyes Randomized: N = 854 (691 Participants)
1 Year Visit
Completed=163 Completed=106 Completed=112 Completed=103
Pending=91 Pending=56 Pending=55 Pending=63
2 Year Visit
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Protocol B: VA and OCT CSF Results at 1 and 2 Years
Protocol B: VA and OCT CSF Results at 1 and 2 Years
Laser 1 mg 4 mg
Change in VA at 1 Year N = 286 N = 230 N = 221
Mean change from baseline (letters)
+1 0 0
Change in VA at 2 Years (primary outcome)
N = 272 N = 220 N = 204
Mean change from baseline (letters)
+2 -2 -4
Change in OCT CSF at 1 Year
N = 278 N = 225 N = 213
Mean change from baseline (microns)
-98 -55 -93
Change in OCT CSF at 2 Years
N = 220 N = 178 N = 162
Mean change from baseline (microns)
-139 -86 -77 63
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Protocol I: VA and OCT CSF Results at 1 and 2 Years
Protocol I: VA and OCT CSF Results at 1 and 2 Years
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Sham
+Prompt
Laser
Ranibizumab
+Prompt
Laser
Ranibizumab
+Deferred
Laser
Triamcinolone
+Prompt
Laser
Change in VA at 1 Year (LOCF)
N = 293 N = 187 N = 188 N = 186
Mean change from baseline (letters) +3 +9 +9 +4
Change in VA at 2 Years N = 163 N = 106 N = 112 N = 103
Mean change from baseline (letters) +2 +7 +10 0
Change in OCT CSF at 1 Year N = 271 N = 171 N = 175 N = 173
Mean change from baseline (microns) -102 -131 -137 -127
Change in OCT CSF at 2 Years N = 152 N = 99 N = 100 N = 93
Mean change from baseline (microns) -133 -144 -170 -95
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Additional Information on Injections/Sham Prior to 1 YearAdditional Information on Injections/Sham Prior to 1 YearSham
+Prompt
Laser
N = 274
Ranibizumab
+Prompt
Laser
N = 171
Ranibizumab
+Deferred
Laser
N = 178
Triamcinolone
+Prompt
Laser
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 16-week 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%
*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
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Additional Information On Injections/Sham to 2 YearsAdditional Information On Injections/Sham to 2 YearsSham
+Prompt
Laser
N = 274
Ranibizumab
+Prompt
Laser
N = 171
Ranibizumab
+Deferred
Laser
N = 178
Triamcinolone
+Prompt
Laser
N = 176
% of eyes meeting failure criteria* at 1-year 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
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TreatmentInjection Protocol up to 48-Week Visit
TreatmentInjection 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 discretion if failure criteria‡ met; 4) reinjection with randomized treatment at investigator discretion if failure criteria not met but no evidence of improvement.
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TreatmentInjection Protocol at and After 1-Year Visit
TreatmentInjection Protocol at and After 1-Year Visit
Sham injections are discontinued for
Groups A and DFor 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
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TreatmentLaser ProtocolTreatment
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 needing laser still present
DRCR.net Retreatment Algorithm FlowchartsDRCR.net Retreatment Algorithm Flowcharts
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Intravitreal Injection Treatment at 16 to 48 Weeks (Following 4 Intravitreal or Sham Injections Every 4 Weeks
Through Week 12)
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Treatment at and after the 52-Week Follow-Up VisitSHAM+PROMPT LASER GROUP (A)
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Treatment at and after the 52-Week Follow-Up VisitRANIBIZUMAB+PROMPT LASER GROUP (B)
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Treatment at and after 52 Week Follow-Up VisitRANIBIZUMAB+DEFERRED LASER GROUP (C)
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Treatment at and after the 52-Week Follow-Up VisitTRIAMCINOLONE+PROMPT LASER GROUP (D)
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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)
Visual Acuity Change at 1 YearVisual Acuity Change at 1 Year
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N=293 N=187 N=188 N=186
Visual Acuity ≥10 or ≥15 Letter Improvement or Worsening at 1 Year
Visual Acuity ≥10 or ≥15 Letter Improvement or Worsening at 1 Year
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Visual Acuity Improvement at 1 YearVisual Acuity Improvement at 1 Year
79N = 293 N = 187 N = 188 N = 186
Visual Acuity Loss at 1 YearVisual Acuity Loss at 1 Year
80N = 293 N = 187 N = 188 N = 186
Visual Acuity Improvement at 2 YearsVisual Acuity Improvement at 2 Years
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N = 163 N = 106 N = 112 N = 103
Visual Acuity Loss at 2 YearsVisual Acuity Loss at 2 Years
82N = 163 N = 106 N = 112 N = 103
≥10 Letter Visual Acuity Improvement/Worsening among Eyes Not Pseudophakic and Eyes that were
Pseudophakic at Baseline
≥10 Letter Visual Acuity Improvement/Worsening among Eyes Not Pseudophakic and Eyes that were
Pseudophakic at Baseline
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Eyes not Pseudophakic at Baseline Eyes Pseudophakic at Baseline