The Diabetic Retinopathy Clinical Research NetworkThe Diabetic Retinopathy

Clinical Research Network

Prompt PRP vs Ranibizumab+Deferred PRP for PDR Study

Jennifer K. Sun, 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, EY14229, EY018817 

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DisclosuresDisclosures

Dr. Sun has served as a consultant for Abbott Labs, EISAI, Genentech, and Novartis

She receives research support from Boston Micromachines, Genentech, and Optovue

This presentation will discuss off-label use of ranibizumab for proliferative diabetic retinopathy

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Anti-VEGF Treatment and DR Severity Anti-VEGF Treatment and DR Severity Clinical trials of anti-VEGF treatment for DME have

clearly demonstrated a beneficial effect of anti-VEGF on overall DR severity level

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DRCR.net Protocol IChange in DR severity from baseline to1-year visit*

Sham

+Prompt

Laser

Ranibizumab

+Prompt

Laser or Deferred Laser

P value for comparison with Sham

Baseline Severity: Severe NPDR or worse

N = 83 N = 121

Improved by ≥2 levels 19% 28% 0.04

Worsened by ≥2 levels 8% 1% 0.03

*Photos were missing or ungradeable for 61 eyes in the sham+prompt laser group, 72 eyes in the ranibizumab groups, and 33 eyes in the triamcinolone+prompt laser group

Protocol I: PDR-related Outcomes During 1 Year of Follow-up

Protocol I: PDR-related Outcomes During 1 Year of Follow-up

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Sham

N = 293

Ranibizumab

N = 375

Triamcinolone

N = 186

Reported vitreous hemorrhage OR received PRP

8% 3% 3%

P Value for comparison with sham -- 0.002 0.02

Cumulative Probability of Worsening of Retinopathy for Eyes with Non-PDR at Baseline

Cumulative Probability of Worsening of Retinopathy for Eyes with Non-PDR at Baseline

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1-Year 2-Years 3-Years

Cumulative Probability of Worsening of Retinopathy for Eyes with PDR at Baseline

Cumulative Probability of Worsening of Retinopathy for Eyes with PDR at Baseline

66

1-Year 2-Years 3-Years

Median (Quartile) # of InjectionsEyes with Non-PDR at BaselineMedian (Quartile) # of InjectionsEyes with Non-PDR at Baseline

77

 Ranibizumab + prompt laser

Ranibizumab + deferred laser

Traimcinolone + prompt

laserNon-Proliferative Diabetic Retinopathy at Baseline

Year 1* 8 (6, 10) 8 (6, 10) 3 (2, 3)

Year 2† 2 (0, 3) 2 (0, 5) 1 (0, 2)

Year 3§ 1 (0, 2) 1 (0, 4) 1 (0, 2)

Total§ 12 (9, 14) 10 (8, 16) 5 (3, 8)

*Only included eyes that completed 1-year visit†Only included eyes that completed 2-year visit prior to protocol change§Only included eyes that completed 3-year visit prior to protocol change

Median (Quartile) # of InjectionsEyes with PDR at Baseline

Median (Quartile) # of InjectionsEyes with PDR at Baseline

88

 Ranibizumab + prompt laser

Ranibizumab + deferred laser

Traimcinolone + prompt

laser

Proliferative Diabetic Retinopathy at Baseline

Year 1* 9 (6, 11) 10 (8, 11) 3 (2, 4)

Year 2† 1 (0, 6) 5 (1, 8) 1 (0, 2)

Year 3§ 0 (0, 2) 1 (0, 4) 0 (0, 1)

Total§ 11 (7, 19) 17 (9, 22) 5 (3, 7)

*Only included eyes that completed 1-year visit†Only included eyes that completed 2-year visit prior to protocol change§Only included eyes that completed 3-year visit prior to protocol change

3 fold higher risk in sham

group

Cumulative probabilities calculated using the Kaplan-Meier method. Progression was defined by (1) progression from NPDR (DR severity level < 60) at baseline to PDR (DR severity level 60) at a later time point, (2) need for PRP laser, (3) vitreous hemorrhage (AE or slit lamp grade 0 at baseline to > 0 at a later time point, (4) cases identified by ophthalmoscopy, (5) vitrectomy, (6) iris neovascularization AE, or (7) retinal neovascularization AE. 1 month = 30 days. AE, adverse event; PRP, panretinal photocoagulation.

RISE/RIDE: Risk of PDR Outcomes in Sham vs Ranibizumab Groups

RISE/RIDE: Risk of PDR Outcomes in Sham vs Ranibizumab Groups

Time to First Progression to PDR Outcome

Months

How Often & How Long to Continue Anti-VEGF for PDR?

How Often & How Long to Continue Anti-VEGF for PDR?

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8 Days after Anti-VEGFBaseline 8 mo after Last Anti-VEGF

Safety of Anti-VEGF in Eyes with PDRSafety of Anti-VEGF in Eyes with PDR• Endophthalmitis

11From Goldberg RA, Am J Ophthalmol. 2012;153(2):204-208.Bhavsar AR, et al. Arch Ophthalmol. 2012 Jun;130(6):809-10.

Safety of Anti-VEGF in Eyes with PDRSafety of Anti-VEGF in Eyes with PDR• Traction detachment

In most eyes with PDR without traction threatening the macula, anti-VEGF appears safe and well-tolerated

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From Arevalo JF, et al. Br J Ophthalmol. 2008;92(2):213-6.

DRCR.net Protocol J Intravitreal SalineIntravitreal

Ranibizumab

Traction and/or Rhegmatogenous RD on Clinical Exam 6 (5%) 5 (4%)

Traction and/or Rhegmatogenous RD on Ultrasonography 0 3 (2%)

RD on Adverse Event Form 9 (7%) 7 (5%)

Traction and/or Rhegmatogenous RD on Any of the 3 Above 10 (8%) 11 (8%)

BackgroundBackground Current standard treatment for PDR is panretinal

photocoagulation (PRP)• 96% reduction in severe vision loss with timely therapy!

BUT, PRP is• Inherently destructive• Adverse effects on visual function

Would initial treatment of PDR with intravitreal anti-VEGF delay or prevent need for PRP?

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Protocol S: Study Objective and Treatment Groups

Protocol S: Study Objective and Treatment Groups

Prompt PRP

To determine if visual acuity outcomes at 2 years in eyes with PDR (with or without concurrent DME) that receive anti-VEGF therapy with deferred PRP are non-

inferior to those in eyes that receive prompt PRP.

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0.5mg ranibizumab with deferred PRP

Important Secondary Objectives(assuming visual acuity outcomes are non-inferior)Important Secondary Objectives(assuming visual acuity outcomes are non-inferior) Compare visual function outcomes (including

Humphrey visual field testing and study participant self-reports of visual function)

Determine percent of eyes not requiring PRP when intravitreal anti-VEGF is given in the absence of prompt PRP

Compare safety outcomes Perform cost effectiveness analysis

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Major Inclusion CriteriaMajor Inclusion Criteria Age ≥ 18 years

Type 1 or 2 diabetes

PDR for which PRP is planned but in the investigator’s opinion can be deferred for at least 4 weeks if an intravitreal anti-VEGF injection is given

Visual acuity (Snellen equivalent) 20/320 or better

Note: eyes with or without DME may be enrolled

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Major Exclusion CriteriaMajor Exclusion Criteria Systemic

• Significant renal disease• BP > 180/110• Cardiac event or stroke within 4 months

Study eye• Prior PRP• Tractional retinal detachment involving the macula• NV of the angle• History of intravitreal anti-VEGF within past 2 months• History of corticosteriod in the past 4 months

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Follow-up ScheduleFollow-up Schedule

Baseline to 1 Year

1 Year to 3 Years

• Both groups: Visits every 16 weeks • IVR+Deferred PRP group: Visits every 4

weeks to evaluate for ranibizumab…interval may only be extended if PRP is given

• Both groups: Visits every 16 weeks • IVR+Deferred PRP group: Visit every 4-16w

to evaluate for ranibizumab…interval is extended if injections for PDR continually deferred

• Primary outcome visit at 2 years

• Annual visits for data collection only• Treatment as part of usual care

4 to 5Years

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Treatment for DMETreatment for DME If DME present at baseline causing VA loss,

ranibizumab must be given If DME develops during follow-up, treatment is at

investigator discretion using study ranibizumab and/or focal/grid laser with Protocol I retreatment criteria as guidelines

Additional follow-up visits for DME retreatment are at the discretion of the investigator (not part of visit schedule) 19

Study TimelineStudy Timeline

2020

Dec 2013 Feb 2014 Dec 2014 Feb 2015 Dec 2017

Last 1-Year Visit

Last 1-Year Visit

Review of Primary

Outcome Data

Review of Primary

Outcome Data

Last 2-Year Visit

Last 2-Year Visit

First 2-Year (Primary

Outcome) Visit

First 2-Year (Primary

Outcome) Visit

Last 5-Year Visit

Last 5-Year Visit

Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)

Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)

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