the diabetic retinopathy clinical research network randomized clinical trial evaluating intravitreal...
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The Diabetic Retinopathy Clinical Research NetworkThe 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
1
Background Vitreous Hemorrhage and Vitrectomy
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 2
BackgroundUse of anti-VEGF for vitreous hemorrhage
BackgroundUse 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
BackgroundUse of Saline for vitreous hemorrhage
BackgroundUse 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 ObjectivesStudy 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-upStudy 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 Multicenter Double-Masked Trial
Primary Outcome: Proportion of eyes with vitrectomy by 16 weeks.
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Study EnrollmentStudy Enrollment
261 Eyes Randomized(61 Sites)
12 Week Visit Completion 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. 7
Follow-up Schedule 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
8
Follow-Up TreatmentFollow-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 VitrectomyPrior to 8 Week Study VisitGuidelines for VitrectomyPrior 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 Vitrectomy8 to 16 Weeks
Guidelines for Vitrectomy8 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 TreatmentPRP 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 SummaryRecruitment Summary
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Original goal reached
Recruitment Resumed
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100
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250
300
Original Goal Reached
RecruitmentResumed
Baseline Subject CharacteristicsBaseline Subject Characteristics
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Ranibizumab N=125
Saline N=136
Women 52% 51%
Age (yrs)(Median 25,75th percentile)
61 (50, 67) 58 (49, 64)
Race
White 54% 51%
African-American 16% 16%
Hispanic or Latino 26% 25%
Other 4% 8%
Type 1 Diabetes 17% 23%
Type 2 Diabetes 81% 73%
Uncertain 2% 4%
Baseline Subject CharacteristicsBaseline Subject Characteristics
15
Subject Characteristics Ranibizumab N=125
Saline N=136
Duration of Diabetes - yrs(Median 25th,75th percentile)
19 (12, 28) 21 (16, 27)
Hemoglobin A1c - %(Median 25th,75th percentile)
7.7 (6.7, 8.7) 8.0 (6.9, 9.3)
Pre-existing cardiovascular condition
35% 44%
Pre-existing hypertension 84% 86%
Baseline Study Eye Characteristics
Baseline Study Eye Characteristics
16
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 AcuityMedian (75th, 25th Percentile); Snellen Equivalent
34 (61, 0) 20/200
(20/63, <20/800)
28 (59, 0) 20/320
(20/63, <20/800)
OCT Signal Strength
= 0 60% 72%
> 0 40% 28%
Baseline Study Eye Characteristics
Baseline Study Eye Characteristics
Ranibizumab N=125
Saline N=136
Duration of Vitreous Hemorrhage
<1 Month 53% 55%
1-3 Months 33% 29%
4-6 Months 6% 8%
>6 Months 9% 8%
IOP - mmHg Median (25th, 75th percentile)
15 (12, 17) 14 (12,17)
17
Total Number of Intravitreal InjectionsIn Eyes without vitrectomy or “complete PRP”
prior to 8 weeks
Total Number of Intravitreal InjectionsIn Eyes without vitrectomy or “complete PRP”
prior to 8 weeks
Number of Injections Ranibizumab Injection
Saline Injection
N = 91 N = 103
0 0 0
1 3 7
2 7 14
3 81 81
4 0 1†
† One 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 indicated for the study participant.
18
Total Number of Intravitreal InjectionsIn Eyes with vitrectomy or “complete PRP”
prior to 8 weeks
Total Number of Intravitreal InjectionsIn Eyes with vitrectomy or “complete PRP”
prior to 8 weeks
Number of Injections Ranibizumab Injection
Saline Injection
N = 33 N = 33
0 0 1¥
1 19 20
2 13 9
3 1 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.
19
Non-Protocol Study Eye Treatment for DME Prior to 16 weeks
Non-Protocol Study Eye Treatment for DME Prior to 16 weeks
Ranibizumab Injection
N = 4
Saline Injectio
nN = 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 Vitrectomy
Primary Outcome
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Cumulative Probability of Vitrectomy by 16 Weeks Cumulative Probability of Vitrectomy by 16 Weeks
0 4 8 12 16-10%
0%
10%
20%
30%
40%
50%
60%
17%
13%
RanibizumabSaline
Cu
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lati
ve
Pro
ba
bil
ity
P = 0.38
Vitrectomy Status Over TimeVitrectomy Status Over Time
Ranibizumab InjectionN = 125
Saline InjectionN = 136
Vitrectomy performed up to 8 weeks 2% 2%
Vitrectomy performed between 8 weeks and 16 weeks 10% 14%
Vitrectomy performed by 16 weeks 12% 16%
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Cumulative Probability of Vitrectomy by 20 Weeks Cumulative Probability of Vitrectomy by 20 Weeks
0 4 8 12 16 20-10%
0%
10%
20%
30%
40%
50%
60%
28%
23%
RanibizumabSaline
Cu
mu
lati
ve
Pro
ba
bil
ity
P = 0.35
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“Complete” Panretinal Photocoagulation
“Complete” Panretinal PhotocoagulationSecondary 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
16 Weeks
0 4 8 12 160%
10%
20%
30%
40%
50%
60%
31%
44%
RanibizumabSaline
Cu
mu
lati
ve P
rob
abil
ity
P = 0.07
Visual Acuity at Follow-up VisitsVisual Acuity at Follow-up Visits
Secondary Outcome
27
Mean Change in Visual Acuity from Baseline
Mean Change in Visual Acuity from Baseline
† 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
25
Ranibizumab
Saline
Mea
n C
han
ge
in L
ette
r S
core †P = 0.04
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Visual Acuity Binary Outcomes at12 Week Visit
Visual Acuity Binary Outcomes at12 Week Visit
12 Week Visit
Ranibizumab InjectionN = 119
Saline InjectionN = 129
P value*
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. 29
OCT Signal Strength OCT Signal Strength
Exploratory Outcome
30
OCT Signal Strength at Follow UpOCT Signal Strength at Follow Up
Ranibizumab Injection
Saline Injection Pvalue
Baseline N =124 N = 134-
= 0 60% 72%
Among Participants with Baseline OCT = 0
4 Week Visit N =70 N =890.50
> 0* 36% 30%
8 Week Visit N = 69 N = 870.33
> 0* 46% 38%
12 Week Visit N = 66 N = 880.87
> 0* 52% 50%
* Defined as a composite outcome of OCT >0 and no vitrectomy prior to the study visit. 31
Safety Outcomes Safety Outcomes
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Ocular Adverse Events of InterestPrior to 16 weeks
Ocular Adverse Events of InterestPrior to 16 weeks
Ocular EventsRanibizumab
InjectionN = 125
Saline InjectionN = 136
Endophthalmitis 0 1 (< 1%)
Angle or iris neovascularization
1 ( 1%) 4 (3%)
Neovascular glaucoma 1 (1%) 1 (<1%)
Cataract Surgery 0 2 (2%)
Recurrent vitreous hemorrhage¥
8 (6%) 23 (17%)
¥ Treatment comparison for recurrent vitreous hemorrhage was performed using Fisher Exact test (P-value = 0.01)
33
Retinal Detachments Prior to 16 weeks
Retinal Detachments Prior to 16 weeks
Ranibizumab InjectionN = 125
Saline InjectionN = 136
Traction retinal detachment only
8 (6%) 9 (7%)
Rhegmatogenous retinal detachment only
1(<1%) 2(2%)
Combined retinal detachment
1(<1%) 0
Any Retinal Detachment 10 (8%) 11(8%)
34
Elevated Intraocular Pressure Prior to 16 weeks
Elevated Intraocular Pressure Prior to 16 weeks
Ranibizumab InjectionN = 125
Saline InjectionN = 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%
Glaucoma surgery at anytime
0 0
Elevated IOP/Glaucoma 13% 14%
Percentages represent the number of eyes with at least 1 occurrence.
Systemic Adverse EventsSystemic Adverse Events
Cardiovascular Events
Ranibizumab InjectionN = 125
SalineInjectionN = 136
Non-fatal myocardial infarction 0 4
Non-fatal stroke –ischemic or hemorrhagic
1 2
Vascular death 2 1
Any APTC Event¥ 2 6
¥ According to Antiplatelet Trialists’ Collaboration 36
Systemic Adverse Events of InterestSystemic Adverse Events of Interest
Ranibizumab InjectionN = 125
Saline InjectionN = 136
Kidney-related events 7 9
Hypertension-related event
4 9
Cardiovascular-related event
12 14
Summary of Causes of Deaths
Age Treatment Group Cause of Death Days in Study
53 Ranibizumab Unknown 7
Cell counts are the number of participants with at least one of the given event during the study
DiscussionDiscussion
38
DiscussionRationale for Saline Injections
DiscussionRationale 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
39
Rates of VitrectomyRates of Vitrectomy
40
Trials OutcomeAnti-VEGF Injection
Saline Injection
ObservationGroup
DRCR- Protocol N
Vitrectomy by 16 weeks
N = 12513%
N = 13617% -
Vitrase Study
Persistence of VH by 12 weeks -
N = 19368% -
Bevacizumab† Vitrectomy by 12-14 weeks
N = 4010% -
N = 4045%
Pegaptanib¥ Vitrectomy by 16 weeks
N = 1540% - -
† 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).
DiscussionRates of Vitrectomy
DiscussionRates of Vitrectomy
Rate of vitrectomy following intravitreal ranibizumab or saline in DRCR.net trial appears lower than expected with observation
41
ConclusionsPrimary Outcome
ConclusionsPrimary 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
ConclusionsSecondary Outcomes
ConclusionsSecondary 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 ConsiderationsOther Considerations
Outcomes of intravitreal ranibizumab or saline compared with observation or sham treatment cannot be determined from this study
44
AcknowledgementsAcknowledgementsTop 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)
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 staff46