1. 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 

2. 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

3. 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
DRCR.net Protocol I
Change in DR severity from baseline to
1-year visit*
Sham
+Prompt
Laser
Ranibizumab
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
Change from baseline to
1-year visit*
Sham
+Prompt
Laser
Ranibizumab
Laser or Deferred Laser
P value for comparison with Sham
Baseline Severity: Moderately Severe NPDR or Better
N = 150
N = 182
Improved by ≥2 levels 4%
25%
<.001
Worsened by ≥2 levels 7% 3%
0.08 3

4. Protocol I: PDR-related Outcomes During 1 Year of Follow-up
Sham
N = 293
Ranibizumab
N = 375
Triamcinolone
N = 186
Reported vitreous hemorrhage OR received PRP 8% 3%
P Value for comparison with sham --
0.002
0.02
Eyes assigned to the ranibizumab groups or the triamcinolone+prompt laser groups, respectively, appeared less likely to have a vitreous hemorrhage or receive panretinal photocoagulation than the sham+prompt laser group (3% [P=0.002] and 3% , [P=0.02] respectively vs. 8%) during the first year of follow up.

5. Cumulative Probability of Worsening of Retinopathy for Eyes with Non-PDR at Baseline
1-Year
2-Years
3-Years
NMB: Edited title

6. Cumulative Probability of Worsening of Retinopathy for Eyes with PDR at Baseline
1-Year
2-Years
3-Years
NMB: Edited title

7. Median (Quartile) # of Injections Eyes with Non-PDR at Baseline
Ranibizumab + prompt laser
Ranibizumab + deferred laser
Traimcinolone +
prompt
laser
Non-Proliferative Diabetic Retinopathy at Baseline
Year 1*
8 (6, 10)
3 (2, 3)
Year 2†
2 (0, 3)
2 (0, 5)
1 (0, 2)
Year 3§
1 (0, 4)
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
NMB: Edited title; made font larger

8. 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)
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
NMB: Edited and increased font

9. 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.

10. How Often & How Long to Continue Anti-VEGF for PDR?
Baseline
8 mo after Last Anti-VEGF
8 Days after Anti-VEGF

11. Safety of Anti-VEGF in Eyes with PDR
Endophthalmitis
Arevalo JF, Maia M, Flynn HW Jr, Saravia M, Avery RL, Wu L, Eid Farah M, Pieramici DJ, Berrocal MH, Sanchez JG. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol Feb;92(2):213-6.
Goldberg RA, Flynn HW Jr, Isom RF, Miller D, Gonzalez S. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol Feb;153(2): 11
Bhavsar AR, et al. Arch Ophthalmol Jun;130(6):
From Goldberg RA, Am J Ophthalmol. 2012;153(2):

12. Safety 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
DRCR.net Protocol J
Intravitreal Saline
Intravitreal Ranibizumab
Traction and/or Rhegmatogenous RD on Clinical Exam
6 (5%)
5 (4%)
Traction and/or Rhegmatogenous RD on Ultrasonography
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%)
From Arevalo JF, et al. Br J Ophthalmol. 2008;92(2):213-6.
Arevalo JF, Maia M, Flynn HW Jr, Saravia M, Avery RL, Wu L, Eid Farah M, Pieramici DJ, Berrocal MH, Sanchez JG. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol Feb;92(2):213-6.
Goldberg RA, Flynn HW Jr, Isom RF, Miller D, Gonzalez S. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol Feb;153(2): 12

13. 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? 13

14. 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 non-inferior to those in eyes that receive prompt PRP.
Prompt PRP
0.5mg ranibizumab with deferred PRP
1414

15. 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 15

16. 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 16

17. 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

18. Follow-up Schedule 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
Baseline to
1 Year
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
1 Year to
3 Years
4 to 5
Years
Annual visits for data collection only
Treatment as part of usual care

19. 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) 19

20. First 2-Year (Primary Outcome) Visit Review of Primary Outcome Data
Study Timeline
First 2-Year (Primary Outcome) Visit
Review of Primary Outcome Data
Last 1-Year Visit
Last 2-Year Visit
Last 5-Year Visit
Dec Feb Dec Feb Dec 2017

21. Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)21