The Diabetic Retinopathy Clinical Research Network
description
Transcript of The Diabetic Retinopathy Clinical Research Network
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
RetinopathyAbdhish 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
1
Financial Disclosures
Research Grant Support: DRCR, Genentech
2
Study ObjectivesTo 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. 3
Study Design, Enrollment, Follow-up
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
Randomized, Multi-center ,Double Masked Trial
Primary Outcome: Treatment group comparison of the cumulative probabilities of vitrectomy by 16 weeks of
randomization.4
Study Enrollment261 Eyes Randomized
(61 Sites)
12 Week Visit Completion (primary outcome) = 95% Overall* (96% Ranibizumab Injection; 95% Saline Injection)
Intravitreal Injection of 0.5 ranibizumab
N = 125
Intravitreal Injection 0.9% sodium chloride
N = 136
* One death occurred prior to the 12 week visit and 5 deaths were reported between 12 to 52 weeks of study follow-up. 5
52 Week Visit Completion (additional safety outcomes)(80% Ranibizumab Injection; 83% Saline Injection)
Follow-up Schedule
Phase 1 Phase 2
4 WK VISIT
16 WK Primary Outcome Time
Point
Treatment for VH at investigator discretion
26 WK Phone Call
8 WK VISIT
12 WK VISIT
52 WK VISIT
6
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
7
Baseline Study Eye Characteristics
8
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%
E-ETDRS Visual Acuity letter score Median (25th, 75th Percentile); Snellen Equivalent
34 (0,61) 20/200 28 (0,59) 20/320
Duration of Vitreous Hemorrhage<1 Month 53% 55%1-3 Months 33% 29%4-6 Months 6% 8%>6 Months 9% 8%
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 25Intravitreal Ranibizumab (Lucentis) 0 5Intravitreal Pegaptanib (Macugen) 2 0Other: Unspecified Anti-VEGF 0 1Intravitreal Kenalog Injection 0 1Intravitreal Triamcinolone Acetonide 2 0Intravitreal Triesence 1 0
9
Vitrectomy Primary Outcome
10
Cumulative Probability of Vitrectomy by 16 Weeks
ConclusionsPrimary 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.
12
Vitrectomy Secondary Outcome
13
14
Cumulative Probability of Vitrectomy by 52 Weeks
No follow-up contact was performed between 16 to 52 weeks
“Complete” Panretinal PhotocoagulationSecondary Outcome
15
Cumulative Probability of “Complete” PRP (in absence of vitrectomy) by 16 Weeks
Cumulative Probability of “Complete” PRP (in absence of vitrectomy) by 52 Weeks
17No follow-up contact was performed between 16 to 52 weeks.
Visual Acuity at Follow-up VisitsSecondary Outcome
18
Mean Change in Visual Acuity from Baseline Prior to 16 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.
Baseline 4-weeks 8-weeks 12-weeks0
5
10
15
20
25RanibizumabSaline
Mea
n C
hang
e in
Let
-te
r Sco
re
†P=0.04
19
Mean Change in Visual Acuity from Baseline – Up to 52 weeks
No follow-up contact was performed between 16 weeks to 52 weeks.
Baseline 4-weeks 8-weeks 12-weeks 52-weeks05
101520253035
RanibizumabSaline
Mea
n C
hang
e in
Let
-te
r Sco
re
20
ConclusionsSecondary 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. 21
ConclusionsSecondary 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.
22
Safety Outcomes
23
Ocular Adverse Events of InterestOcular Events
Ranibizumab InjectionN = 125
Saline InjectionN = 136
Recurrent Vitreous Hemorrhage
Prior to 16 weeks¥ 6% 17%
16 weeks – 52 weeks 13% 13%
Traction and/or Rhegmatogenous Retinal Detachment
Prior to 16 weeks¥ 8% 8%
16 weeks – 52 weeks 7% 10%
¥ Treatment comparison for recurrent vitreous hemorrhage was performed using Fisher Exact test (P-value = 0.01) 24
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.
25
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.
26