The Diabetic Retinopathy Clinical Research Network

Report
The Diabetic Retinopathy Clinical
Research Network
One-Year Results from a Randomized Clinical Trial
Evaluating Intravitreal Ranibizumab or Saline for
Vitreous Hemorrhage from Proliferative Diabetic
Retinopathy
Abdhish Bhavsar, MD for the Diabetic Retinopathy Clinical Research Network
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 and
EY018817
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Financial Disclosures
 Research Grant Support: DRCR, Genentech
2
Study Objectives
 To determine if intravitreal injections of ranibizumab
decrease the proportion of eyes in which vitrectomy is
performed by 16 weeks 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 through 16 weeks, and
safety through 52 weeks, of anti-VEGF therapy as
treatment for vitreous hemorrhage due to PDR.
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Study Design, Enrollment, Follow-up
Randomized, Multi-center ,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: Treatment group comparison of the
cumulative probabilities of vitrectomy by 16 weeks of
randomization.
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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 (primary outcome) = 95% Overall*
(96% Ranibizumab Injection; 95% Saline Injection)
52 Week Visit Completion (additional safety outcomes)
(80% Ranibizumab Injection; 83% Saline Injection)
* One death occurred prior to the 12 week visit and 5 deaths were reported between 12 to 52 weeks
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of study follow-up.
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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Study 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.
 Prior to the 16 week endpoint, the decision to perform
vitrectomy was based on study guidelines.
 Further treatment following the 16 week endpoint was at
Investigator discretion.
 PRP was to be initiated as soon as possible
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Baseline Study Eye Characteristics
Ranibizumab
N = 125
Saline
N = 136
Prior PRP
50%
57%
Prior Treatment for DME
42%
42%
Prior treatment with anti-VEGF for DME
8%
13%
34 (0,61) 20/200
28 (0,59) 20/320
<1 Month
53%
55%
1-3 Months
33%
29%
4-6 Months
6%
8%
>6 Months
9%
8%
E-ETDRS Visual Acuity letter score Median (25th,
75th Percentile); Snellen Equivalent
Duration of Vitreous Hemorrhage
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Non-Protocol Study Eye
Treatment Post 16 weeks
Ranibizumab
Injection
Saline
Injection
Number of Eyes with Non-Protocol Study Eye
Treatment for DME
20
32
Intravitreal Bevacizumab (Avastin)
15
25
Intravitreal Ranibizumab (Lucentis)
0
5
Intravitreal Pegaptanib (Macugen)
2
0
Other: Unspecified Anti-VEGF
0
1
Intravitreal Kenalog Injection
0
1
Intravitreal Triamcinolone Acetonide
2
0
Intravitreal Triesence
1
0
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Vitrectomy
Primary Outcome
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Cumulative Probability of
Vitrectomy by 16 Weeks
Conclusions
Primary Outcome
 This study suggests little likelihood of a clinically
important difference between ranibizumab and saline
on the rate of vitrectomy by 16 weeks in eyes with
VH from PDR.
 As a result of having substantially overestimated the
control group rate when estimating sample size, the
study may not have been sufficiently powered to
detect a treatment group difference.
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Vitrectomy
Secondary Outcome
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Cumulative Probability of
Vitrectomy by 52 Weeks
No follow-up contact was performed between 16 to 52 weeks
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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
Cumulative Probability of “Complete” PRP
(in absence of vitrectomy) by 52 Weeks
No follow-up contact was performed between 16 to 52 weeks.
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Visual Acuity at Follow-up Visits
Secondary Outcome
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Mean Change in Visual Acuity from
Baseline Prior to 16 Weeks
Mean Change in
Letter Score
25
20
Ranibizumab
Saline
†P=0.04
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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Mean Change in Visual Acuity from
Baseline – Up to 52 weeks
Mean Change in
Letter Score
35
30
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Ranibizumab
Saline
20
15
10
5
0
Baseline
4-weeks
8-weeks
12-weeks
52-weeks
No follow-up contact was performed between 16 weeks to 52 weeks.
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Conclusions
Secondary Outcomes
 By 52 weeks, the rate of vitrectomy remained
similar between the two treatment groups with
over 1/3 of eyes in both groups undergoing
vitrectomy.
 Short term secondary outcomes including visual
acuity improvement, increased PRP completion
rates, and reduced recurrent VH rates suggest
biologic activity of ranibizumab by 16 weeks of
study follow-up.
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Conclusions
Secondary Outcomes
 The ability to perform PRP appeared slightly better
in the ranibizumab group throughout one-year of
follow-up; however the improvement in mean
visual acuity observed at 12 weeks was no longer
present at 52 weeks.
 It should be noted that treatment after the 16 week
endpoint was at the investigator’s discretion.
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Safety Outcomes
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Ocular Adverse Events of Interest
Ranibizumab
Injection
N = 125
Saline Injection
N = 136
Prior to 16 weeks¥
6%
17%
16 weeks – 52 weeks
13%
13%
Prior to 16 weeks¥
8%
8%
16 weeks – 52 weeks
7%
10%
Ocular Events
Recurrent Vitreous Hemorrhage
Traction and/or Rhegmatogenous Retinal
Detachment
¥ Treatment
comparison for recurrent vitreous hemorrhage was performed using
Fisher Exact test (P-value = 0.01)
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Conclusions
Safety Outcomes
 Intravitreal ranibizumab does not appear to
increase the risk of retinal detachment
throughout one-year of study follow-up.
 The evaluation of intravitreal saline versus
ranibizumab given at baseline, 4 and 8 weeks
after randomization in eyes with vitreous
hemorrhage, showed no difference in safety
between the two treatment groups at 52 weeks.
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Discussion
 Whether vitrectomy rates after saline or
ranibizumab are different than observation alone
cannot be determined from this study.
 Further follow-up on these two groups indicate a
relatively high incidence of vitrectomy in both
groups by one year.
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