Transcript Funding Mechanism

The 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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Disclosures
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
 Clinical trials of anti-VEGF treatment for DME have
clearly demonstrated a beneficial effect of anti-VEGF
on overall DR severity level
Sham
+Prompt
Laser
Ranibizumab
+Prompt
Laser or Deferred
Laser
N = 83
N = 121
Improved by ≥2 levels
19%
28%
0.04
Worsened by ≥2 levels
8%
1%
0.03
DRCR.net Protocol I
Change in DR severity from baseline to
1-year visit*
Baseline Severity: Severe NPDR or
worse
P value for
comparison with
Sham
*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
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Protocol I: PDR-related Outcomes
During 1 Year of Follow-up
Reported vitreous
hemorrhage OR received
PRP
P Value for comparison with
sham
Sham
N = 293
Ranibizumab
N = 375
Triamcinolone
N = 186
8%
3%
3%
--
0.002
0.02
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Cumulative Probability of Worsening of Retinopathy
for Eyes with Non-PDR at Baseline
1-Year
2-Years
3-Years
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Cumulative Probability of Worsening of
Retinopathy for Eyes with PDR at Baseline
1-Year
2-Years
3-Years
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Median (Quartile) # of Injections
Eyes with Non-PDR at Baseline
Ranibizumab +
prompt laser
Ranibizumab +
deferred laser
Non-Proliferative Diabetic Retinopathy at Baseline
Year 1*
8 (6, 10)
8 (6, 10)
Year 2†
2 (0, 3)
2 (0, 5)
Year 3§
Total§
Traimcinolone +
prompt
laser
3 (2, 3)
1 (0, 2)
1 (0, 2)
1 (0, 4)
1 (0, 2)
12 (9, 14)
10 (8, 16)
5 (3, 8)
*Only
included eyes that completed 1-year visit
included eyes that completed 2-year visit prior to protocol change
§Only included eyes that completed 3-year visit prior to protocol change
†Only
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Median (Quartile) # of Injections
Eyes with PDR at Baseline
Ranibizumab +
prompt laser
Ranibizumab +
deferred laser
Traimcinolone +
prompt
laser
Proliferative Diabetic Retinopathy at Baseline
Year 1*
9 (6, 11)
10 (8, 11)
Year 2†
1 (0, 6)
5 (1, 8)
Year 3§
0 (0, 2)
1 (0, 4)
Total§
11 (7, 19)
17 (9, 22)
3 (2, 4)
1 (0, 2)
0 (0, 1)
5 (3, 7)
*Only
included eyes that completed 1-year visit
included eyes that completed 2-year visit prior to protocol change
§Only included eyes that completed 3-year visit prior to protocol change
†Only
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RISE/RIDE: Risk of PDR Outcomes in
Sham vs Ranibizumab Groups
Time to First Progression to PDR Outcome
3 fold higher
risk in sham
group
Months
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.
How Often & How Long to
Continue Anti-VEGF for PDR?
Baseline
Days
after
8 8mo
after
LastAnti-VEGF
Anti-VEGF
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Safety of Anti-VEGF in Eyes with PDR
• Endophthalmitis
From
Goldberg
RA, Am J Ophthalmol. 2012;153(2):204-208.
Bhavsar AR, et al. Arch Ophthalmol.
2012
Jun;130(6):809-10.
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Safety of Anti-VEGF in Eyes with PDR
• Traction detachment
Intravitreal Saline
Intravitreal
Ranibizumab
Traction and/or Rhegmatogenous
RD on Clinical Exam
6 (5%)
5 (4%)
Traction and/or Rhegmatogenous
RD on Ultrasonography
0
3 (2%)
9 (7%)
7 (5%)
DRCR.net Protocol J
RD on Adverse Event Form
Traction and/or Rhegmatogenous
10 (8%)
RD on Any of theFrom
3 Above
Arevalo JF, et al. Br J Ophthalmol. 2008;92(2):213-6.
11 (8%)
In most eyes with PDR without traction threatening the
macula, anti-VEGF appears safe and well-tolerated
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Background
 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
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 noninferior to those in eyes that receive prompt PRP.
Prompt PRP
0.5mg ranibizumab
with deferred PRP
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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 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 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 Schedule
Baseline to
1 Year
1 Year to
3 Years
4 to 5
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
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Treatment 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)
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Study Timeline
Last 1-Year
Visit
Dec 2013
First 2-Year
(Primary
Outcome)
Visit
Feb 2014
Last 2-Year
Visit
Review of
Primary
Outcome
Data
Last 5-Year
Visit
Dec 2014
Feb 2015
Dec 2017
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Thank You on Behalf of Diabetic Retinopathy
Clinical Research Network (DRCR.net)
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