Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred

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The Diabetic Retinopathy Clinical
Research Network
Randomized Trial Evaluating Ranibizumab
Plus Prompt or Deferred Laser or
Triamcinolone Plus Prompt Laser for
Diabetic Macular Edema
Michael Elman, 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:
Protocol B – IVT vs Laser
 Intravitreal triamcinolone was evaluated
previously as a “monotherapy” treatment for DME
in a randomized trial conducted by DRCR.net ():
 Results suggested that IVT without laser was not
superior to focal/grid photocoagulation
 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
2
Laser-Ranibizumab-Triamcinolone
Randomized Clinical Trial for DME:
Study Objective
Evaluate efficacy and safety of:
• 0.5-mg intravitreal ranibizumab plus prompt laser
(within 1 week); or
• 0.5-mg intravitreal ranibizumab plus 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.
3
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)
4
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+promt laser
Ranibizumab+deferred laser
Triamcinolone+prompt laser
5
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.
6
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
7
schedule goes back to 4 week intervals.
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 (Primary Outcome) Completion:
94%*
2 Year Visit Completion:
87%**
* Includes deaths
** Includes deaths and excludes pending and dropped who are not yet in window
8
Baseline Characteristics
Median age
Sham
+Prompt
Laser
Ranibizumab
+Prompt
Laser
Ranibizumab
+Deferred
Laser
Triamcinolone
+Prompt
Laser
63
62
64
62
9%
6%
8%
8%
89%
92%
90%
89%
3%
2%
2%
3%
65 (20/50)
66 (20/50)
66 (20/50)
66 (20/50)
407
371
382
374
Diabetes type
Type I
Type II
Uncertain
Median E-ETDRS©
visual acuity letter
score (Snellen
equivalent)
Median OCT CSF
thickness (µm)
9
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
10
*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
Additional Information On Injections/Sham to 2 Yrs
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
Median drug
injections prior to 2
years
n/a
11
Out of
26
maximum 9
13
Out of
26
maximum 3
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
11
Out ofPrior
Out of
Outto
of
Out of
Laser Treatments
1
Year
4
4
2
4
maximum
maximum
Sham
+Prompt
Laser
Ranibizumab
+Prompt
Laser
Ranibizumab
+Deferred
Laser*
(permitted
starting at 24week 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%
maximum
No, only 1, only 2
or 3 more lasers
after baseline
maximum
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).
12
Visual Acuity
13
Mean Change in Visual Acuity (Letters)*
at Follow-up Visits
11
10
Sham+prompt
laser
9
8
Ranibizumab+
prompt laser
7
Primary outcome time point
6
5
4
Ranibizumab+
deferred laser
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
that were ±30 letters were assigned a value of 30
14
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
15
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
16
≥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 17
the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001;
triamcinolone+prompt laser = 0.16
≥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
18
52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser =0.001; triamcinolone+prompt
laser = 0.75
Visual Acuity
Subgroup Analyses
19
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
20
Change in Visual Acuity at 1 Year
Stratified by Pseudophakic at Baseline
21
Retinal Thickening
22
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.
23
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 24
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
Mean change from
baseline (µm)
-133
Difference in mean
change from Sham
+ Laser [P Value]**
Thickness <250 µm
with at least a 25 µm
decrease from
baseline
Ranibizumab
+Prompt
Laser
N = 99
-144
-31
[P = 0.01]
38%
54%
Ranibizumab Triamcinolone
+Prompt
+Deferred
Laser
Laser
Both
groups
N = 100
N = 93
still have
central
-170 DME
-95
in about 45%
at 2 yr
-36
-3
[P = 0.004]
[P = 0.81]
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 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
25
ranibizumab+prompt laser, 1 in ranibizumab+deferred laser and 2 in triamcinolone+prompt laser
Retinopathy
(hidden pearl within the trial)
26
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
27
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
28
Safety
29
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.
30
‡ 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
31
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%
32
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.
33
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
34
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
So what is your Standard Care for
Center Involved DME?
36
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.
So how are you following patients and
determining when to re-treat?
37
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 place 4 mandatory injections and then
continue treatment, as needed, until stabilization
or lack of further improvement is noted.
38
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.
39
Intravitreal Triamcinolone
Summary
 Intravitreal triamcinolone combined with focal/grid laser
did not result in superior VA outcomes compared with
laser alone, despite 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, but
is associated with an increased risk of intraocular
pressure elevation.
So what will your first line management recommendation be
for pseudophakic patients?
40
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