Transcript The Diabetic Retinopathy Clinical Research Network

The Diabetic Retinopathy
Clinical Research Network
Randomized Clinical Trial Evaluating
Intravitreal Ranibizumab or Intravitreal Saline
for Vitreous Hemorrhage from Proliferative
Diabetic Retinopathy
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
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Background
Vitreous Hemorrhage and Vitrectomy
 In at least 5% of cases, proliferative diabetic
retinopathy (PDR) can lead to vitreous
hemorrhage even after panretinal
photocoagulation (PRP) is initiated which
• can substantially affect vision and
• may preclude performing complete PRP.
 Current treatment for non-clearing vitreous
hemorrhage is vitrectomy
• Surgical complications
• Recovery time
• Some patients may fear surgery
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Background
Use of anti-VEGF for vitreous hemorrhage
 Intravitreal anti-vascular endothelial growth factor
(anti-VEGF) is a potential alternative to vitrectomy
• VEGF is shown to be major causative factor in
PDR
• While hemorrhage absorbs, anti-VEGF drug may
cause temporary or permanent regression of
NVD/NVE, reducing the likelihood of additional
hemorrhage until PRP is applied
• Small case series suggest anti-VEGF causes
short-term clearing of vitreous hemorrhage
3
Background
Use of Saline for vitreous hemorrhage
 Unknown if effects seen with anti-VEGF are
from fluid injection alone
 Prior study found that saline injected eyes were
5 times more likely to have visual improvement
at 2 months (26% vs. 6%) and 3 times more
likely at 3 months (36% vs. 11%) compared with
eyes under observation alone
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Study Objectives
To determine if intravitreal injections of
ranibizumab decrease the proportion of eyes in
which vitrectomy is performed compared with
saline injections in eyes presenting with vitreous
hemorrhage from PDR.
• Note: This trial was not a comparison of anti-VEGF
with observation or sham injection; rather the trial was
a comparison of intravitreal anti-VEGF with intravitreal
saline injection
To assess the efficacy and safety of anti-VEGF
therapy as treatment for vitreous hemorrhage
due to PDR.
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Study Design, Enrollment, Follow-up
Randomized Multicenter Double-Masked Trial
At least one eye that met all of the following criteria:
 Vitreous hemorrhage causing vision impairment,
presumed to be from PDR, and precluding completion
of PRP
 Immediate vitrectomy is not required
 Visual acuity is light perception or better
 No prior anti-VEGF treatment for VH
Primary Outcome: Proportion of eyes with
vitrectomy by 16 weeks.
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Study Enrollment
261 Eyes Randomized
(61 Sites)
Intravitreal Injection
of 0.5 ranibizumab
N = 125
Intravitreal Injection
0.9% sodium chloride
N = 136
12 Week Visit Completion
95% Overall*
(96% Ranibizumab Injection; 95% Saline Injection)
* One death occurred prior to the 12 week visit.
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Follow-up Schedule
Phase 1
Phase 2
4 WK VISIT
8 WK VISIT
12 WK VISIT
26 WK
Phone Call
52 WK VISIT
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Follow-Up Treatment
 Follow-up injections performed at 4 and 8
weeks unless:
• Vitreous hemorrhage had cleared enough
to complete PRP or
• Vitrectomy had been performed.
 All eyes were to be treated with complete
PRP as soon as possible.
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Guidelines for Vitrectomy
Prior to 8 Week Study Visit
 Vitrectomy was not to be performed unless one
of the following was present:
• Traction retinal detachment involving or
threatening the macula
• Rhegmatogenous retinal detachment
• Angle neovascularization
• Progressive iris neovascularization
• Neovascular glaucoma or ghost cell
glaucoma resulting in increased IOP that
could not be controlled medically
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Guidelines for Vitrectomy
8 to 16 Weeks
 Vitrectomy could be performed (but was not
required) if there was failure of substantial
clearing of vitreous hemorrhage such that the
study participant’s need for vitrectomy and its
associated benefits outweighed its risks.
 Primary outcome time point was at 16 weeks to
include cases where decision was made at 12
weeks to perform vitrectomy.
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PRP Treatment
 PRP was to be initiated as soon as possible
 “Complete” PRP defined as
• 500 micron size burns on the retina placed no
further than 1 to 2 burn widths apart beginning
~3000 µm from macular center and extending
to equator for 12 clock hours.
 If vitreous hemorrhage cleared and it was
determined that “complete” PRP was already
given, further treatment was not required.
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Recruitment Summary
300
250
200
Original
Original
Goal goal
reached
Reached
Recruitment
Recruitment
Resumed
Resumed
150
100
50
0
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Baseline Subject Characteristics
Women
Age (yrs)
(Median 25,75th percentile)
Race
White
African-American
Hispanic or Latino
Other
Type 1 Diabetes
Type 2 Diabetes
Uncertain
Ranibizumab
N=125
52%
Saline
N=136
51%
61 (50, 67)
58 (49, 64)
54%
16%
26%
4%
51%
16%
25%
8%
17%
81%
2%
23%
73%
4%
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Baseline Subject Characteristics
Subject Characteristics
Duration of Diabetes - yrs
Ranibizumab
N=125
Saline
N=136
19 (12, 28)
21 (16, 27)
7.7 (6.7, 8.7)
8.0 (6.9, 9.3)
35%
44%
84%
86%
(Median 25th,75th percentile)
Hemoglobin A1c - %
(Median 25th,75th percentile)
Pre-existing
cardiovascular condition
Pre-existing hypertension
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Baseline Study Eye
Characteristics
Prior PRP
Prior Treatment for DME
Prior treatment with antiVEGF for DME
E-ETDRS Visual Acuity
Median (75th, 25th Percentile);
Snellen Equivalent
OCT Signal Strength
=0
>0
Ranibizumab
N=125
50%
42%
Saline
N=136
57%
42%
8%
13%
34 (61, 0)
28 (59, 0)
20/200
20/320
(20/63, <20/800) (20/63, <20/800)
60%
40%
72%
28%
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Baseline Study Eye
Characteristics
Ranibizumab
N=125
Duration of Vitreous Hemorrhage
<1 Month
53%
1-3 Months
4-6 Months
>6 Months
IOP - mmHg
Median (25th, 75th percentile)
33%
6%
9%
15 (12, 17)
Saline
N=136
55%
29%
8%
8%
14 (12,17)
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Total Number of Intravitreal Injections
In Eyes without vitrectomy or “complete PRP”
prior to 8 weeks
Number of Injections
0
1
2
3
4
† One
Ranibizumab
Injection
N = 91
0
Saline
Injection
N = 103
0
3
7
81
7
14
81
0
1†
subject was given masked intravitreal study drug at the 12-week follow-up visit when a study
injection was not scheduled per protocol. Since an injection was not scheduled, a drug number
according to the randomized treatment was not obtained, and it is possible that the wrong
randomized treatment was performed. The investigator did believe that an injection was medically
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indicated for the study participant.
Total Number of Intravitreal Injections
In Eyes with vitrectomy or “complete PRP”
prior to 8 weeks
Number of Injections
Ranibizumab
Injection
Saline
Injection
0
N = 33
0
N = 33
1¥
1
19
20
2
3
13
1
9
3
¥ After
consenting and randomizing, 1 subject changed their mind and did
not want to receive study drug – the participant remained in the study but
was never injected.
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Non-Protocol Study Eye Treatment
for DME Prior to 16 weeks
Ranibizumab
Saline
Injection
Injection
N=4
N=4
Number of Eyes with Non-Protocol
Study Eye Treatment for DME
3
4
Intravitreal Bevacizumab (Avastin)
1*
1**
Intravitreal Triamcinolone Acetonide
1*
0
Focal/Grid Laser Photocoagulation
2
3
Note: only focal/grid laser was permitted per protocol prior to 16 weeks
*Same eye received bevacizumab and triamcinolone for DME after vitreous
hemorrhage cleared and PRP was considered “complete”
**DME treatment performed 1 week post-vitrectomy
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Vitrectomy
Primary Outcome
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Cumulative Probability of
Vitrectomy by 16 Weeks
60%
Ranibizumab
Saline
Cumulative Probability
50%
P = 0.38
40%
30%
17%
20%
10%
13%
0%
-10%
0
4
8
12
16
Vitrectomy Status Over Time
Vitrectomy performed up
to 8 weeks
Vitrectomy performed
between 8 weeks and 16
weeks
Vitrectomy performed by
16 weeks
Ranibizumab
Injection
N = 125
Saline
Injection
N = 136
2%
2%
10%
14%
12%
16%
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Cumulative Probability of
Vitrectomy by 20 Weeks
60%
Ranibizumab
Saline
Cumulative Probability
50%
P = 0.35
40%
28%
30%
20%
23%
10%
0%
-10%
0
4
8
12
16
20
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“Complete” Panretinal
Photocoagulation
Secondary Outcome
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Cumulative Probability of “Complete”
PRP (in absence of vitrectomy) by
16 Weeks
60%
Ranibizumab
Saline
Cumulative Probability
50%
P = 0.07
44%
40%
31%
30%
20%
10%
0%
0
4
8
12
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Visual Acuity at Follow-up Visits
Secondary Outcome
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Mean Change in Visual Acuity from
Mean Change in Letter Score
Baseline
25
Ranibizumab
20
†P
= 0.04
Saline
15
10
5
0
Baseline
4-weeks
8-weeks
12-weeks
† Treatment comparison for the mean change in visual acuity at the 12 week visit was performed
using a longitudinal mixed model adjusting for baseline visual acuity.
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Visual Acuity Binary Outcomes at
12 Week Visit
12 Week Visit
Ranibizumab Saline
P
Injection
Injection
value*
N = 119
N = 129
VA better than 69 letter
score (>20/50) and no
vitrectomy
45%
33%
0.10
Severe VA deficiency
≤38 letter score
(<20/200)
20%
27%
0.30
Very severe VA
deficiency ≤4 letter
score (<20/800)
11%
16%
0.25
*P-values were obtained using a logistic regression model adjusted by baseline
visual acuity.
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OCT Signal Strength
Exploratory Outcome
30
OCT Signal Strength at Follow Up
Ranibizumab
Injection
Saline Injection
N =124
N = 134
Baseline
60%
72%
=0
Among Participants with Baseline OCT = 0
4 Week Visit
> 0*
8 Week Visit
> 0*
12 Week Visit
> 0*
N =70
N =89
36%
30%
N = 69
N = 87
46%
38%
N = 66
N = 88
52%
50%
* Defined as a composite outcome of OCT >0 and no vitrectomy prior to the study visit.
P
value
-
0.50
0.33
0.87
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Safety Outcomes
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Ocular Adverse Events of Interest
Prior to 16 weeks
Ocular Events
Endophthalmitis
Angle or iris
neovascularization
Neovascular glaucoma
Cataract Surgery
Recurrent vitreous
hemorrhage¥
Ranibizumab
Injection
N = 125
0
1 ( 1%)
Saline
Injection
N = 136
1 (< 1%)
4 (3%)
1 (1%)
0
1 (<1%)
2 (2%)
8 (6%)
23 (17%)
¥ Treatment
comparison for recurrent vitreous hemorrhage was performed using
Fisher Exact test (P-value = 0.01)
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Retinal Detachments
Prior to 16 weeks
Ranibizumab
Injection
N = 125
Traction retinal detachment
8 (6%)
only
Rhegmatogenous retinal
1(<1%)
detachment only
Combined retinal
1(<1%)
detachment
Any Retinal Detachment
10 (8%)
Saline
Injection
N = 136
9 (7%)
2(2%)
0
11(8%)
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Elevated Intraocular Pressure
Prior to 16 weeks
Ranibizumab
Injection
N = 125
Saline
Injection
N = 136
Increase of IOP ≥10 mm
Hg from baseline
6%
8%
IOP ≥30 mmHg
3%
3%
Currently on IOP-lowering
medication, but not at
baseline
10%
10%
0
0
13%
14%
Glaucoma surgery at
anytime
Elevated IOP/Glaucoma
Percentages represent the number of eyes with at least 1 occurrence.
Systemic Adverse Events
Cardiovascular Events
Non-fatal myocardial infarction
Non-fatal stroke –ischemic or
hemorrhagic
Vascular death
Any APTC Event¥
¥ According
Ranibizumab
Injection
N = 125
0
1
Saline
Injection
N = 136
4
2
2
2
1
6
to Antiplatelet Trialists’ Collaboration
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Systemic Adverse Events of Interest
Kidney-related events
Hypertension-related
event
Cardiovascular-related
event
Ranibizumab
Injection
N = 125
7
4
Saline
Injection
N = 136
9
9
12
14
Cell counts are the number of participants with at least one of the given event
during the study
Summary of Causes of Deaths
Age
Treatment Group
Cause of Death
Days in Study
53
Ranibizumab
Unknown
7
Discussion
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Discussion
Rationale for Saline Injections
 Controls for potential effects of drug vehicle and
any physical fluid dynamic effect of an intravitreal
injection on VH
 Prior study found that saline injected eyes had
higher rate of visual acuity improvement than
eyes under observation alone
 Allowed complete masking of all study staff,
which was essential given the subjective primary
outcome measure, i.e., undergoing vitrectomy
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Rates of Vitrectomy
Trials
Outcome
DRCRProtocol N
Vitrectomy by
16 weeks
Vitrase Study
Persistence of
VH by 12 weeks
Bevacizumab†
Pegaptanib¥
Anti-VEGF
Saline Observation
Injection Injection
Group
N = 125
13%
N = 136
17%
-
-
N = 193
68%
-
Vitrectomy by
12-14 weeks
N = 40
10%
-
N = 40
45%
Vitrectomy by
16 weeks
N = 15
40%
-
-
† Intravitreal
bevacizumab and Panretinal Photocoagulation for PDR
associated with vitreous hemorrhage, Huang (2009)
¥ Use of pegaptanib for recurrent and non-clearing vitreous hemorrhage in
proliferative diabetic retinopathy, Hornan (2010).
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Discussion
Rates of Vitrectomy
 Rate of vitrectomy following intravitreal
ranibizumab or saline in DRCR.net trial
appears lower than expected with observation
41
Conclusions
Primary Outcome
 Rate of vitrectomy by 16 weeks was not
reduced by intravitreal ranibizumab
compared with intravitreal saline in eyes with
vitreous hemorrhage due to PDR.
42
Conclusions
Secondary Outcomes
 Secondary outcomes such as short-term
change in visual acuity, completion of PRP,
and frequency of recurrent vitreous
hemorrhage suggest faster hemorrhage
clearing with intravitreal ranibizumab.
 Intravitreal ranibizumab does not appear to
increase the risk of retinal detachment
43
Other Considerations
 Outcomes of intravitreal ranibizumab or
saline compared with observation or sham
treatment cannot be determined from this
study
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Acknowledgements
Top 10 Site Enrollers
•
•
•
•
•
•
•
•
•
•
Site 46; Maturi
Site 100; Friedman
Site 127; Gonzalez
Site 19; Kim
Site 39; Sharuk
Site 152; Marcus
Site 212; Jamal
Site 14; Bhavsar
Site 111; Elman
Site 207; Stoltz
Top 10 enrollers
with 100% visit
completion.
(4, 8, and 12 week visits)
•
•
•
•
Dr. Friedman
Dr. Elman
Dr. Marcus
Dr. Bhavsar
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Thank You on Behalf of Diabetic Retinopathy
Clinical Research Network (DRCR.net)
 61 clinical study sites
 Study participants who volunteered to participate in
this trial
 DRCR.net Data and Safety Monitoring Committee
 Genentech provided clinical site funding and the
ranibizumab 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
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