1. The Diabetic Retinopathy Clinical Research Network
Intravitreous Anti-VEGF Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk
Summary Slides
[Protocol version 1.0] 1

2. DRCR.net Overview Objective:
Collaborative network to facilitate multicenter clinical research of diabetic retinopathy, DME and associated conditions
Funding:
National Eye Institute (NEI) and The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-sponsored cooperative agreement initiated September 2002.
Current award

3. DRCR.net Status (as of 1/6/14)
Active
Total
Sites
(Community & Academic Centers)
119
179
Community Sites
80 (67%)
120 (67%)
Investigators
363
786
Other Personnel
979
2746
States 37 41

4. Prevention Study Background
Eyes with severe non-proliferative diabetic retinopathy (NPDR) are at high risk for DR worsening and subsequent VA loss
According to the Early Treatment Diabetic Retinopathy Study (ETDRS), of eyes with severe NPDR and no DME at baseline:
52% develop proliferative diabetic retinopathy (PDR) over 1 year
60% develop PDR with high-risk characteristics over next 5 years 4

5. Risk for Developing PDR in the ETDRS
Event
Rate
Severe NPDR
80%
Moderately severe
60%
Moderate NPDR
40%
Mild NPDR
20% 0% 1 2 3 4 5
Years

6. Background
Although some eyes may benefit from early PRP, there is currently no clear treatment mandate for severe NPDR
Deferred Scatter
Risk of Severe Visual Loss or Vx
Type 2
Early Scatter
10%
Type 1 5%
Type 2
P=0.43
P=0.0001 0% 1 2 3 4 5
Years
P (Interaction) =
Ferris F. Early photocoagulation in patients with either type I or type II diabetes. Trans Am Ophthalmol Soc. 1996;94:

7. More Recent Data: DRCR.net Trial Laser Groups (with DME at baseline)

8. DRCR.net Protocol I: Comparison to Anti-VEGF Treated Eyes

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. Proportion of Patients Requiring PRP Proportion of patients
From Baseline to Week 100
VIVID
VISTA
Proportion of patients
133
136
135
154
155
152
PRP: Panretinal Photocoagulation
IAI: Intravitreal Aflibercept Injection 10

11. DME Development
Eyes with severe NPDR and no center-involved (CI) DME at baseline are also at risk for developing DME requiring anti-VEGF treatment
15% in ETDRS developed CI-DME on photos by 2 years
DRCR.net Protocol R included eyes with non-CI DME and any level of retinopathy and 14% developed CI-DME on OCT or required treatment by 1 year

12. Primary (Short-term) Objective
To determine safety and efficacy of
prompt anti-VEGF versus observation in eyes presenting with severe NPDR and no CI-DME for prevention of vision threatening outcomes
Observation (sham injections)
Intravitreous anti-VEGF
Primary outcome: Proportion of eyes that develop PDR/PDR-related outcomes or center-involved DME causing visual acuity loss at 2 years
1212

13. Long-term Objectives
If there is a clinically important difference identified among the treatment groups for the primary outcome at 2 years, the study will also evaluate whether increased chance of prevention of PDR/DME with anti-VEGF at 2 years results in long-term beneficial visual outcomes at 4 years.

14. Summary of Rationale
The application of anti-VEGF therapy earlier in the course of disease could help to reduce future potential treatment burden in patients, at the same time resulting in similar or better long-term visual acuity outcomes.
If this study demonstrates that anti-VEGF treatment is effective and safe in the setting of severe NPDR, a new strategy to prevent vision-threatening complications will be available for patients.

15. Follow-Up and Treatment Overview
Total duration: 4 years
Visits at 1, 2, and 4 months; every 4 months thereafter
Injections (intravitreous or sham) required at each of the above visits through 2 years and subsequently based on DR severity level
If PDR or DME develop, visits may be more frequent for standardized treatment with intravitreous anti-VEGF

16. Major Inclusion/Exclusion Criteria in Study Eye
Severe NPDR (ETDRS level 53) according to investigator
4-2-1 rule
Severe hemorrhages in at least 4 quadrants, or
Definite venous beading in at least 2 quadrants, or
Moderate IRMA in at least 1 quadrant
Vision 20/25 or better
No center-involved DME on OCT
No history of DME/DR treatment in prior 12 months and <4 prior injections at any time
No prior PRP 16

17. Referrals We Need Your Help!
Please consider any (relatively) treatment naïve eyes with non-proliferative diabetic retinopathy and vision ~20/32 or better on clinic charts
Study participants must be willing to be randomized to sham or aflibercept injections and continue follow-up for 4 years
Consenting/Screening/Randomization will be split into several visits (Reading Center confirmation of DR severity level will be required)

18. Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)
Dedicated to multicenter clinical research of diabetic retinopathy, macular edema and associated disorders. 18