the diabetic retinopathy clinical research network one-year results from a randomized clinical trial...

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 

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Financial DisclosuresFinancial Disclosures

Research Grant Support:  DRCR, Genentech

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Study ObjectivesStudy 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-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, Multi-center ,Double Masked Trial

Primary Outcome: Treatment group comparison of the cumulative probabilities of vitrectomy by 16 weeks of

randomization.4

Study EnrollmentStudy 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 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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Study TreatmentStudy 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 CharacteristicsBaseline 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 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 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 Vitrectomy Primary Outcome

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Cumulative Probability of Vitrectomy by 16 Weeks Cumulative Probability of Vitrectomy by 16 Weeks

ConclusionsPrimary Outcome

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.

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Vitrectomy Vitrectomy Secondary Outcome

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Cumulative Probability of Vitrectomy by 52 Weeks

Cumulative Probability of Vitrectomy by 52 Weeks

No follow-up contact was performed between 16 to 52 weeks

“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

Cumulative Probability of “Complete” PRP (in absence of vitrectomy) by 52 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 VisitsVisual 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 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

han

ge

in L

et-

ter

Sco

re

†P=0.04

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Mean Change in Visual Acuity from Baseline – Up to 52 weeks

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-weeks0

5

10

15

20

25

30

35RanibizumabSaline

Mea

n C

han

ge

in L

et-

ter

Sco

re

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ConclusionsSecondary Outcomes

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

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.

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Safety Outcomes Safety Outcomes

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Ocular Adverse Events of InterestOcular Adverse Events of Interest

Ocular 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

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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DiscussionDiscussion 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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