the diabetic retinopathy clinical research network randomized clinical trial evaluating intravitreal...

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

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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

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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

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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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200

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

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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


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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%



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)

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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.

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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.

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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

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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

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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

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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



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

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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


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)

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Retinal Detachments Prior to 16 weeks

Retinal Detachments Prior to 16 weeks



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%)

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Elevated Intraocular Pressure Prior to 16 weeks

Elevated Intraocular Pressure Prior to 16 weeks



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


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



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

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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

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Rates of VitrectomyRates of Vitrectomy

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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

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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.

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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

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Other ConsiderationsOther Considerations

Outcomes of intravitreal ranibizumab or saline compared with observation or sham treatment cannot be determined from this study

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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

the diabetic retinopathy clinical research network randomized clinical trial evaluating intravitreal...

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